Ovarian Endometrioid Carcinoma and Clear Cell Carcinoma: A 21-year Retrospective Study

Ovarian Endometrioid Carcinoma and Clear Cell Carcinoma: A 21-year Retrospective Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Ovarian Endometrioid Carcinoma and Clear Cell Carcinoma: A 21-year Retrospective Study Ling Zhou, Liqing Yao, Lin Dai, Honglan Zhu, Xue Ye, Shang Wang, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-115365/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract Objective This study aimed to identify the clinical characteristics of Chinese patients with ovarian endometrioid carcinoma (EC) and clear cell carcinoma (CCC) and to assess the impact of concurrent endometriosis on this group. Methods The present study reviewed the medical records of patients who received initial treatment and a postoperative pathological diagnosis of EC or CCC at our center in China between 1998 and 2018. Results Of 211 patients, 73 had pure EC, and 91 had pure CCC, and the remaining 47 had mixed cancer. The proportion of EC and CCC remained stable over past 21 years. The proportion of EC declined with aging and the age of EC onset to incline to the young. And the age of CCC onset had two peaks, namely, 36 and 77 years. After review by the pathologist, the number of endometriosis cases found in the pathological section of the analysis increased to 114, accounting for 54% of patients. As the stage progressed, the appearance of endometriosis became increasingly scarce in pathological sections(p=0.001). Compared with CCC, EC had a higher frequency of concurrent endometrial cancer (independent endometrial lesions) and estrogen and progesterone receptor expression(p=0.000). And more patients were in premenopausal state in EC group(p=0.040). In the pure group, multivariate analysis showed that correlation existed between relevance to endometriosis and worse outcomes(p=0.041). In patients with mixed cancer, mixed endometrioid histology was associated with better survival than other subtypes, even with stage III or poorly differentiated tumors(p=0.001). Conclusions CCC and EC which are common in ovarian cancer patients who have associated with endometriosis have distinct clinicopathological characteristics. Attention should be paid to ovarian cancer patients with a history of endometriosis and those with concurrent endometriosis in pathological sections. Sexual & Reproductive Medicine Cancer Biology Ovarian Endometrioid Carcinoma Ovarian Clear Cell Carcinoma Endometriosis Prognosis Figures Figure 1 Figure 1 Figure 2 Figure 2 Figure 3 Figure 3 Figure 4 Figure 4 Figure 5 Figure 5 Figure 6 Figure 6 1 Introduction Ovarian cancer is the second most common gynecologic malignancy, with over 90% of cancers arising from epithelial cells(Carmen, Birrer, & Schorge, 2012 ; K?Bel et al., 2010). The most common histology of epithelial ovarian carcinoma (EOC) is papillary serous carcinoma, accounting for 70% of all EOCs in North America, followed by the endometrioid and clear cell histological types, which account for 20–25% and 5–10% of EOCs, respectively, of EOCs(K?Bel et al., 2010; Kennedy, Biscotti, Hart, & Webster, 1989 ; Mizuno, Kikkawa, Shibata, Kajiyama, & Nomura, 2010 ; Nishida, Watanabe, Sato, & Ichikawa, 2000 ). Endometriosis is a benign gynecologic disease that is characterized by endometrial glands and stroma occurring outside the uterus. Endometriosis is a risk factor for epithelial ovarian cancer(Vercellini, Viganò, Somigliana, & Fedele, 2014 ; Viganò, Somigliana, Parazzini, & Vercellini, 2007 ), and the overall rate of malignant transformation in endometriosis has been estimated to be 0.3–0.8%, with a relative risk ranging from 1.3 to 1.9(Somigliana et al., 2006 ). The relationship between endometriosis and ovarian cancer has been classified as either a transition from endometriotic lesions to invasive ovarian carcinoma or the coexistence of ovarian cancer with endometriosis without a transition(Modesitt, Tortolero-Luna, Robinson, Gershenson, & Wolf, 2002 ; Ness, 2003 ). Sampson defined endometriosis-associated ovarian cancer (EAOC) as endometriosis that was found in the surgical specimen but not in direct continuity with the tumor(Oral et al., 2003 ; Sampson & John, 1925 ; Yoshikawa, Jimbo, Okada, Matsumoto, & Taketani, 2000 ). It is also well known that tumors associated with endometriosis are confined to specific subcategories of disease, namely, endometrioid carcinoma (EC) and clear cell carcinoma (CCC) (Kobayashi, Sumimoto, Kitanaka, Yamada, & Terao, 2008 ; Ness et al.). The prognosis of early ovarian CCC is good, but late-stage CCC is known to be less sensitive to platinum-based front-line chemotherapy and to be associated with a worse prognosis than serous adenocarcinoma or endometrioid adenocarcinoma during the same period (Bamias et al., 2010 ; Itamochi et al., 2002 ; Sugiyama et al., 2000 ; Winter et al., 2007 ). It is generally believed that the prognosis of ovarian EC is good, but there are still some patients with a poor prognosis (drug resistance, recurrence or even death), which has also been reported in the literature(Soovares, Pasanen, Bützow, & Lassus, 2017 ). There are still many unresolved problems with CCC and EC as tumors closely related to endometriosis. To obtain further insight into these endometriosis-related cancers, we reviewed and analyzed the clinical data of patients with CCC and EC in a single center over the past 20 years. We aimed to summarize the clinical experience and provide guidance for clinical work. 2 Materials And Methods Patients and clinical information With ethical approval (No. 2020PHB212-01) given for ovarian cancer specimen collection with annotated clinical information, all patients with primary EOC who were treated at Peking University People’s Hospital from 1998 to 2018 were reviewed. Individual informed patient consent was not sought, as these data were routinely obtained and used as part of these patients’ clinical care. The women were followed until December 2019 or until they died of ovarian cancer or other conditions, whichever happened first. Data from electronic medical records were retrospectively reviewed. Two pathologists reviewed the pathology details to determine whether there was concurrent endometriosis. We screened patients according to the established criteria (see the detailed process in Fig. 1 ), and patients with complete clinical data and follow-up information were included. The pathological staging was checked, and patient was restaged based on the International Federation of Obstetrics and Gynecology (FIGO) staging standard (according to the 2014 FIGO staging standard to restage ovarian cancer and according to the 2009 FIGO staging standard to restage concurrent endometrial cancer). The following information was collected: age at diagnosis, histology, history of past illnesses (hypertension/diabetes/endometriosis/breast cancer/immune system disease), FIGO stage, fertility history, first symptoms, blood cancer antigen-125 (CA-125) level (before and after surgery), tumor size and side, surgical procedure, tumor grade, surgical debulking status, endometrial pathology (concurrent endometrial lesions), chemotherapy regimen, objective response to chemotherapy, progression-free survival and overall survival. Criteria for defining factors Endometrial lesions included endometrial cancer and endometrial dysplasia. If there was endometrial cancer by uterine pathology, the Scully criteria were used to distinguish between dual primary and metastatic disease (the full description of the criteria is provided in Supplementary Table)(Williams, Bandera, Demissie, & Rodríguez-Rodríguez, 2009 ). Endometriosis-related patients were defined as patients showing endometriosis by pathology or having a history of endometriosis. Progression-free survival (PFS) was defined as the time interval from the date of primary surgery to the date of disease progression and/or recurrence. Overall survival (OS) was defined in months as the date of the primary surgery to the date of death or censoring at the date of last contact. To define residual disease status after primary debulking surgery, the largest diameter of residual disease was measured and categorized as follows: no residual disease (R0), 0.1–1 cm residual disease (R1), and > 1 cm residual disease. Statistical analysis Summary statistics were used to describe the data. Medians (ranges) or means (standard deviations) were used for continuous variables. After a normal distribution was confirmed with the Shapiro-Wilks test, the Mann-Whitney U test was used to compare median values, and Student's t-test was used to compare mean values. Categorical variables are presented as frequencies (percentages). Fisher's exact test or the χ2 test were used to analyze the distributions of characteristics according to their associations with endometriosis. Survival curve analyses were performed with the Kaplan-Meier method, and comparisons were performed using the log-rank test. A Cox proportional hazards model was used to perform univariate and multivariate analyses to evaluate the prognostic significance of the association with endometriosis and other clinicopathological features. Multivariate p-values were used to present the significance of each feature. To quantify the correlation between survival time and each independent feature, a 95% confidence interval (CI) was used. All p-values were 2-sided, and p-values less than 0.05 were considered statistically significant. The Joinpoint Regression Program 4.6.0.0 provided by the National Cancer Institute was used to determine potential changes in the temporal trends in the incidence rate. The trends in the histological subtypes of ovarian cancer were examined for every calendar year or every patient age. Linear segmented regression analysis was utilized for the model. Statistical analyses were performed using SPSS 26.0 (IBM), GraphPad Prism 8.0 and R 3.0.6 (R Foundation, Vienna, Austria; http://www.R-project.org ). 3 Results Patient demographics From 1998 to 2018, there were 1324 patients with ovarian cancer who were admitted to Peking University People’s Hospital. According to the exclusion criteria, 211 patients who were diagnosed as having clear cell or endometrioid histology were investigated (the patient selection schema is shown in Fig. 1 ). Of 211 patients, 73 had pure EC, and 91 had pure CCC. There were 47 cases of mixed cancers of other histological types, such as the serous and mucinous types. Among pure EC patients, the most common histological subtype was serous (669/938, 71.3%), followed by clear cell (104/938, 11.1%), endometrioid (89/938, 9.5%), and mucinous (76/938, 8.1%). Figure 2 show the time-specific trends and age-specific trends for each histological type. From 1998 to 2018, the proportions of ovarian cancer subtypes remained stable (Fig. 2 A). Overall, the proportion of serous ovarian cancer gradually increased with increasing age while the proportion of EC declined with aging (Fig. 2 B). The age of onset of CCC had two peaks, namely, 36 years and 77 years (Fig. 2 B). One can interpret the data as indicating that serous ovarian cancer patients were getting older, while patients with endometrioid ovarian cancer were getting younger over time (Fig. 2 C-D). Among women aged < 50 years in the cohort, the incidence rate of EC increased between 1998 and 2018 (rising by nearly 1.02% per year; Fig. 2 C). The incidence rates of the three cancer types decreased between 1998 and 2018 (clear cell, declined by 4.28% per year; serous, declined by 3.08% per year; mucinous, declined by 7.32% per year. Figure 2 C). For people ≥ 50 years old, the frequency of serous cancer increased slightly in 1998 and 2018, while that of the other three types showed a downward trend (serous, rising by nearly 1.14% per year; clear cell, declining by 0.86% per year; endometrioid, declining by 8.01% per year; mucinous, declined by 11.28% per year. Figure 2 D). Total clinical and morphological features The detailed data are presented in Tables 1 – 2 . The mean age at diagnosis of the entire population was 51.9 ± 10.9 years (range, 24–79 years), and 47.9% (101/211) of the women were postmenopausal. Table 1 Total clinical characteristics Clinicopathological Factor Number EC 73(34.6%) CCC 91(43.1%) Mix 47(22.3%) Mixed with EC 31(14.7%) Mixed with CCC 13(6.2%) Both 3(1.4%) EMs in Pathological Section 114(54.0%) Past History of EMs 16 (7.6%) Endometrial cancer 26(12.3%) Concurrent with pure EC 23(10.9%) Concurrent with pure CCC 1(0.47) Parity > 1 170 (80.6%) 0 41(19.4%) Past History of Hypertension 46(21.8%) Past History of Diabetes 18(8.5%) Overweight(BMI > 24) 89(42.4%) Dysmenorrhea 49(23.2%) Post-menopause 101(47.9%) Breast cancer 8(3.8%) Immune System Disease 7(3.3%) Initial Signs༏Symptoms Abdominal Pain 42(19.9%) Abdominal Distension 40(19.0%) Abdominal Mass 17(8.1%) Asymptomatic 68(32.2%) Vaginal Bleeding 15(7.1%) Painful Menstruation 2(0.92%) Others* 27(12.8%) *Others symptoms contain weariness ,emaciation,lower extremity edema, abnormal vaginal discharge༌irregular menstruation and change of menstrual volume. Table 2 Total characteristics of therapy and prognosis Clinicopathological Factor Number Operation 211(100%) Complete Surgical Staging 114 (54.0%) Maximal Resection 97(46.0%) Residual Disease R0 142(67.3%) R1( 2 cm 8(3.79%) Second Operation 11(5.25%) Abdominal Dropsy 0 78(37.0%) 500 ml 34(16.1%) Uncertain 18(8.5%) Lymph Nodes Excision(LMN) 188(89.1%) No 23(10.9%) Pelvic Region Only 4(1.9%) Pelvic & Abdominal region 186(88.2%) Surgery to Conserve Fertility 8(3.8%) Chemotherapy Regimens 177(83.9%) Platinum-based chemotherapy(PBC) 174(82.3%) Platinum-free chemotherapy 3(1.4%) TC 150(71.1%) Others 27(13.0%) FIGO stage I 114(54.0%) II 39(18.5%) III 54(25.6%) IV 4(1.9%) Chemotherapy Treatment Course =3 163(77.3%) Death 29(13.7%) Relapse 48(22.7%) The common symptoms at initial presentation were sequentially palpable mass, abdominal pain, incidental finding, abdominal distension and irregular vaginal bleeding. A normal preoperative serum CA-125 value was observed in 27.5% (58/211) of patients. The distribution of FIGO stage was as follows: Stage I, 54% (114/211); Stage II, 18.5% (39/211); Stage III, 25.6% (54/211); and Stage IV, 1.9% (4/211). There were 16 patients with a previous history of endometriosis. In the initial records, endometriosis was found by pathology in 41 patients. After review by the pathologist, the number of endometriosis cases found in the pathological section of the analysis increased to 114, accounting for 54% of patients. From the early stage to the late stage, the frequency of endometriosis by pathology gradually decreased (via the linear association method, p = 0.001). In this series, 114 (54.0%) patients received comprehensive staging surgery, and 97 (46.0%) patients received cytoreductive surgery. A total of 142 (67.3%) patients had no residual lesions, and 13 (6.2%) patients had residual lesions less than 1 cm in size. In total, 177 (83.9%) patients received chemotherapy, among which 174 (82.3%) received PBC. Pure clear cell and endometrioid carcinoma The present study found that the age at diagnosis was 50.0 ± 11.7 (range 24 to 79) years in the EC group and 52.6 ± 9.5 years (range 32 to 77) in the CCC group (see details in Table 3 ). Compared with CCC, EC has a higher frequency of concurrent endometrial cancer and a higher frequency of independent ovarian and endometrial lesions (including endometrial cancer and precancerous lesions, p = 0.000). According to the standard of Scully et al., patients with synchronous primary cancer of the endometrium and ovary accounted for 20.5% (15/73) of the EC group, while they accounted for only 1.1% of the CCC group (p = 0.000). The proportion of premenopausal women was higher in the EC group (p = 0.040). EC were predominantly positive for estrogen receptor (ER) and progesterone receptor (PR), but CCC exhibited lower ER and PR expression (p = 0.000) (Table 4 ). Table 3 Mean age of each group Group Age at diagnose(range) All Patients 51.8 ± 10.9(24–79) Pure Cancer 51.4 ± 10.6(24–79) EC 50.0 ± 11.7(24–79) CCC 52.6 ± 9.5(32–77) Mixed Cancer 53.4 ± 12.0(28–75) CCC, clear cell carcinoma; EC, endometrioid carcinoma. Table 4 The results of immunohistogical staining of ER and PR of pure cancer Number ER 62 EC 51(51/62, 82.3%) CCC 11(11/62, 17.7%) PR 55 EC 49(49/55, 89.1%) CCC 6(6/55, 10.9%) ER, Estrogen receptor; PR, Progesterone receptor; CCC, clear cell carcinoma; EC, endometrioid carcinoma. During the follow-up period, 17 patients (10.4%) died, and 28 patients (17.1%) experienced relapses. The 5-year OS and PFS rates of CCC patients were 88.0% and 89.9%, respectively. The 5-year OS and PFS rates of EC patients were 92.1% and 78.4%, respectively. The difference in prognosis between EC and CCC was not significant (p = 0.333. Figure 3 A-B). Survival analysis of 164 pure EOC patients with EC or CCC was performed by univariate analysis using the Kaplan-Meier method. The results showed that the factors that influenced the prognosis of pure EOC patients with EC or CCC included FIGO stage, lymphadenectomy, residual lesions, parity history, association with endometriosis and CA-125 level before and after surgery (p < 0.05). Survival analysis revealed significant differences in PFS and OS between patients whose disease was related to endometriosis compared to those whose disease was unrelated to endometriosis. The Kaplan-Meier curve for PFS showed a survival advantage for patients whose disease was unrelated to endometriosis (p = 0.01; Fig. 3 .F). The results for OS indicated that patients whose disease was unrelated to endometriosis had better survival outcomes than patients whose disease was related to endometriosis (p = 0.0057; Fig. 3 .E). Rambau P et al.(Peter et al., 2017 )reported that the expression of ER and PR was significantly associated with longer ovarian cancer-specific survival, but no association was found in this study. In the multivariate analysis of clinicopathologic variables among the entire cohort of patients, disease related to endometriosis remained a significant prognostic factor for PFS (p = 0.001; Table 5 ). FIGO stage, which was previously shown to be a prognostic factor in EOC, remained a significant prognostic factor for PFS and OS in this study cohort (Fig. 3 .C-D). Additionally, the postoperative CA-125 level was significant in the multivariate analysis for PFS. Both the univariate and multivariate analyses showed that in advanced ovarian cancer (stage II-IV), residual lesions are an independent prognostic factor (Fig. 5 ; Table 5 ). Table 5 Multivariate Cox proportional hazards analysis for PFS and OS used to adjust risk associated prognostic clinical features Pure group (n = 164) PFS OS HR (95%CI) p-value HR (95%CI) p-value Parity 0.906(0.508–1.615) 0.738 / / CA-125(before) 1.000(0.999-1.000) 0.595 1.646(0.403–6.725) 0.487 CA-125(after) 1.002(1.000-1.005) 0.044 / / FIGO 1.722(0.990–2.994) 0.054 3.981(1.821–8.706) 0.001 EM-related 4.014(1.056–15.262) 0.041 0.925(0.272–3.146) 0.047 Residual disease 0.915(0.475–1.766) 0.792 1.389(0.823–2.346) 0.219 Lymph Nodes excision 0.325(0.078–1.346) 0.325 0.925(0.272–3.146) 0.900 Mixed group (n = 47) PFS OS HR (95%CI) p-value HR (95%CI) p-value CA-125(before) 1.000(0.999–1.001) 0.835 1.000(1.000-1.001) 0.185 CA-125(after) 1.003(0.998–1.008) 0.235 / / FIGO 1.934(0.211–17.700) 0.023 1.880(0.699–5.059) 0.211 EM-related / / / / Residual disease 1.490(0.544–4.087) 0.544 1.030(0.508–2.086) 0.935 Mixed with EC 0.070(0.014–0.347) 0.001 0.425(0.107–1.684) 0.223 Appendix excision 4.460(0.350-56.794) 0.249 0.228(0.041–1.258) 0.090 Lymph Nodes excision 1.934(0.211–17.700) 0.559 1.030(0.508–2.086) 0.935 2–4 stage of patients with pure cancer PFS HR (95%CI) p-value FIGO 2.918(1.022–8.326) 0.045 R0 0.287(0.110–0.749) 0.011 CA, cancer antigen; CA-125(before):CA-125 level before surgery; CI, confidence interval; FIGO, International Federation of Gynecology and Obstetrics; HR, hazard ratio; OS, overall survival; PFS, progression-free survival. R0, Achieving optimal cytoreduction and/or removal of all macroscopic disease. Mixed carcinoma There were 47 cases of mixed cancers of other histological types, including 31 cases of cancers mixed with ECs, 13 cases of cancers mixed with CCCs, and three cases of cancers mixed with ECs and CCCs (see details in Tables 1 – 2 ). The mucinous type always appeared with the endometrioid histological type rather than with CCC (p = 0.000). During the follow-up period, 12 patients (42.6%) died, and 20 patients (25.5%) experienced relapses. The 5-year OS and PFS rates of mixed carcinoma were 77.9% and 57.4%, respectively. The difference in prognosis between mixed carcinoma and pure carcinoma was significant (p < 0.05, Fig. 6 ). The results for OS and PFS indicated that patients with pure cancer had significantly better survival outcomes (Fig. 6 ). Univariate and multivariate analyses showed that FIGO stage and cancer mixed with endometrioid histology had a statistically significant impact on the prognosis of patients with mixed cancer (Fig. 4 ; Table 5 ). Mixed endometrioid histology was associated with better survival than serous adenocarcinoma of the ovary, even with stage III or poorly differentiated tumors (p = 0.000). 4 Discussion Ovarian clear cell Carcinoma and endometrioid carcinoma This study systematically described CCC and EC data from a single center in China obtained from 1998 to 2018. The distribution and age structure of the four major histological subtypes of pure ovarian cancer in China are more similar to those of the United States than to those of Japan, another Asian country(Machida H 2019 ). There was a tendency to young people for patients with EC in age. It might be because continuous development of human society, people's bearing attitudes are constantly changing, and urbanization has transformed people's ideas on family planning. Women have fewer pregnancy and childbirths, and there are more alternative contraceptive methods, such as the use of short-acting combined contraceptives. To further determine the distribution and specific trends of ovarian cancer patients in China, multicenter, large-sample research is needed in the future. Survival analysis showed that FIGO stage is an important prognostic factor in pure cancer or mixed cancer. The residual lesion size, which is generally considered to be an independent prognostic factor, is still important in advanced pure ovarian cancer (stage II-IV). The pure cancer group had a better overall prognosis than the mixed group, and among mixed cancers, EC was always associated with a better prognosis. In another single-center study, Dawn J. Story et al. found that despite their similar response rates to platinum-based chemotherapy (PBC), endometrioid ovarian cancer has a better survival outcome than ovarian serous adenocarcinoma(Storey et al., 2008 ). Two histologic types, CCC and EC, are common histological types of ovarian cancer in patients who have associated endometriosis. However, both tumor types have distinct clinicopathological characteristics and molecular phenotypes. The high incidence of combined endometrial disease in the EC group distinguishes EC from CCC. Studies have shown that EC subtypes have a much higher chance of concurrent endometrial cancer than other histological subtypes of epithelial ovarian cancer in the same period(Williams et al., 2009 ). Our data also indicated that 12.3% (9/73) of patients with EC had coexisting endometrial atypical hyperplasia and that 20.5% (15/73) of patients with EC had synchronous endometrial cancer, which should be seriously taken into account, particularly for patients with the desire to undergo fertility-sparing surgery. A comprehensive evaluation of the endometrium might be necessary. In terms of morphological characteristics, ECs show broad morphological similarities to their endometrial counterparts. Overall, the most common molecular alterations in EC include mutations in CTNNB1 (31–53.3%), PIK3CA (15–40%), ARID1A (30%), and PPP2R1A (7–16.6%) (Bennett, Pesci, Morales-Oyarvide, Silva, & Oliva, 2018 ; Gras et al., 2015 ; Hoang, Mcconechy, Köbel, Anglesio, & Lee, 2015 ; Huang et al., 2015 ; Jones S, 2010 ; Mcconechy et al., 2014 ; Steed et al., 2016 ). Largely, these events are similar to those that have been reported for the more common endometrial EC. Similar to their endometrial counterparts, EC seems to be classifiable into molecular subgroups that correlate with survival(Parra-Herran et al., 2017 ). Add all of these together and it is not hard to see that EC is closer to endometrial cancer in all aspects. Recent studies based on targeting and exon sequencing have confirmed that there is a clonal correlation between ovarian and endometrial primary cancers. The two are not absolutely unrelated; it may be the spread from one site to another. The author believes that EC of the ovary may be an ovarian implant of indolent endometrial carcinoma and puts forward the following hypotheses: 1) The metastasis may be caused by retrograde progression of the diseased endometrium through the fallopian tube rather than blood or lymph node metastasis; 2) There is the possibility of "pseudometastasis", namely, cells detach from the primary lesion without undergoing apoptosis, spread through open spaces, and only recolonize the unique microenvironment without the ability to extensively metastasize(Anglesio et al.; Schultheis et al., 2016 ). It seems that EC is another form of endometrial cancer that grows in the ovaries. Therefore, when studying the pathogenesis of EC and CCC, there are two possibilities to consider as the determining factor—bad endometriosis or a bad endometrium. Perhaps treatment of EC that is analogous to endometrial cancer will become a new breakthrough. EC is predominantly positive for ER, but CCC exhibits lower ER expression. YASUHITO TANASE et al.(Yasuhito et al., 2012 ) proposed a model postulating that additional events, particularly deletion of ER expression, are required for CCC lesion progression. CCC pathogenesis may be a model to study the progression from estrogen-dependent to estrogen-independent disease, allowing the design of new strategies targeting the hormone response, thereby modifying disease outcome. Therefore, loss of estrogen function may be a turning point in CCC development. There are still many problems with CCC and EC in current clinical practice, but the treatment options available are likely similar to serous histological subtypes. The 2016 National Comprehensive Cancer Network (NCCN) guidelines listed hormone therapy as a postoperative adjuvant treatment option for low-grade EC. This shows that the application of treatments that target ER and PR in the treatment of EC and CCC is gradually being valued. However, further research is needed to prove the role of ER and PR in the development of endometriosis-related ovarian cancer. Recently, sophisticated proteomic tracing studies have suggested that ovarian endometrioid adenocarcinomas arise from secretory cells of endometriosis or the endometrium, while ovarian clear cell adenocarcinomas arise from ciliated cells. Importantly, it is hypothesized that the unique cellular environment dictates the development of ciliated or secretory cells, which then gain mutations to become malignant("Clear cell and endometrioid carcinomas: are their differences attributable to distinct cells of origin?," 2017). Indeed, it is worth exploring the following: Why are there two different types from the same origin (if both CCC and EC originate from endometriosis)? The relationship between endometriosis and CCC/EC After review by the pathologist, the number of endometriosis cases found in the pathological section rose from 19.4–54.0% of total cases (from 41 to 114 patients). This suggests that the proportion of EC and CCC coexisting with endometriosis was previously underestimated. The reasons for the differences before and after the pathological review may be as follows: 1) tumor cells are so aggressive that they invade and destroy most or all endometriotic tissues; 2) because pathology reports are used for the diagnosis of malignant tumors, the reporter focuses on malignant tumors rather than endometriosis; and 3) we focus more on the tumor site when taking pathological sections. In clinical work, it is very difficult to obtain specimens of endometriosis, tumor tissues and transitional tissues all at once. In this study, as the stage progressed, the appearance of endometriosis became increasingly scarce in pathological sections (p = 0.001). The probability of endometriosis coexisting in early disease is higher, which is consistent with the conclusion drawn by Kim HS et al.(Kim, Kim, Chung, & Song, 2014 ). In patients with advanced cancer, the low frequency of endometriosis might be because the endometriotic tissue was "burned out", that is, completely transformed into cancer tissue. It is also possible that malignant tumor cells proliferated rapidly and invaded endometriotic tissues and other benign tissues. Thus, the absence of endometriosis in the pathological sections of EC and CCC does not mean that it does not exist in the specimen. It may be that the pathologist did not report the endometriosis (it was not taken seriously) or that endometriosis was “hidden” under the tumor tissue. Several studies have reported that endometriosis has no effect on the prognosis of EAOC (Ju, Kang, & Kim, 2019 ; Sun et al., 2018 ), and we did find that there was no association between the presence of endometriosis and the prognosis of ovarian CCC or EC (p = 0.091 > 0.05). Considering that the absence of endometriosis does not mean that it never existed, we consider a history of endometriosis and cooccurrence of endometriosis as a whole to be a clinical pathological factor. As a result, we found that patients with endometriosis had worse outcomes. This may be explained by the abnormal immune regulation system and aberrant pelvic microenvironment in patients with endometriosis(Júlia, Sahar, & Giudice, 2019 ). As a benign disease behaving like a malignant tumor, endometriosis can invade tissues and spread elsewhere. With abnormal secretion of immune regulatory factors and abnormal activation of the complement system(Júlia et al., 2019 ), immune escape occurs and creates a favorable environment for recurrence. This is a reminder that a history of endometriosis in ovarian cancer patients should be taken seriously and that long-term management and close follow-up are necessary. To our knowledge, this is the largest retrospectively collected pure and mixed ovarian clear cell and EC set in China. We have discussed the relationship between endometriosis and EC or CCC, aiming to provide some guidance for clinical work. Attention should be paid to ovarian cancer patients with a history of endometriosis and those with concurrent endometriosis in pathological sections. This study also has some limitations. Multicenter, large-sample prospective clinical research is necessary in the future. Declarations Ethics approval and consent to participate The study was conducted in accordance with the principles of the Declaration of Helsinki and was approved by the Institute Research Medical Ethics Committee of Peking University People’s Hospital (No. 2020PHB212-01). Informed written consents were obtained from all patients prior to their enrollment in this study. Consent for publication Not applicable. Acknowledgements We thank the members of the Department of pathology, Peking University People’s Hospital for their help with the pathological reviews in this study. Authors’ contributions Ling Zhou - undertook collection, analysis and interpretation of the data and wrote the manuscript drafts. Liqing Yao- undertook collection, helped designing the indicators and programs. Lin Dai- be of assistance to many aspects of pathology. Xue Ye, Shang Wang, Ruiqiong Ma and Hongyan Chen - data collection. Huiping Liu-data collection and data analysis. Honglan Zhu- contributed to data analysis and interpretation, and critically revised the manuscript. Xiaohong Chang - responsible for the conception, design and performing of the whole study. Declaration of competing interests The authors declare no conflict of interest. Funding This work was financially supported by the National Natural Science Foundation of China (No.81971360; No.81671431) and the Beijing Municipal Natural Science Foundation (No.7182173). Availability of data and materials The dataset supporting the conclusions of this article is included within the article and its additional files. References Anglesio MS, Kan WY, Madlen M, Horlings HM, Ali B, Janine S,.. . Karnezis AN. Synchronous Endometrial and Ovarian Carcinomas: Evidence of Clonality. J Natl Cancer Inst (6), djv428. Bamias A, Psaltopoulou T, Sotiropoulou M, Haidopoulos D, Lianos E, Bournakis E,.. . Dimopoulos MA. 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The effect of concurrent endometriosis on the prognosis of women with ovarian clear cell or endometrioid carcinoma. International Journal of Gynecology Obstetrics. 2019;146(2):177–83. Júlia VJ, Sahar H, Giudice LC. (2019). The endometrial immune environment of women with endometriosis. Human Reproduction Update (5), 5. K.Bel M, Kalloger SE, Huntsman DG, Santos JL, Swenerton KD, Seidman JD, Gilks CB. Differences in tumor type in low-stage versus high-stage ovarian carcinomas. Int J Gynecol Pathol. 2010;29(3):203–11. Kennedy AW, Biscotti CV, Hart WR, Webster KD. Ovarian clear cell adenocarcinoma. Gynecol Oncol. 1989;32(3):342–9. Kim HS, Kim TH, Chung HH, Song YS. Risk and prognosis of ovarian cancer in women with endometriosis: a meta-analysis. Br J Cancer. 2014;110(7):1878–90. Kobayashi H, Sumimoto K, Kitanaka T, Yamada Y, Terao T. Ovarian endometrioma–risks factors of ovarian cancer development. Eur J Obstet Gynecol Reprod Biol. 2008;138(2):187–93. Machida H, Yamagami MK W (2019). Trends and characteristics of epithelial ovarian cancer in Japan between 2002 and 2015: A JSGO-JSOG joint study. Gynecologic Oncology . Mcconechy MK, Ding J, Senz J, Yang W, Melnyk N, Tone AA,.. . Shah SP. Ovarian and endometrial endometrioid carcinomas have distinct CTNNB1 and PTEN mutation profiles. Mod Pathol. 2014;27(1):128–34. Mizuno M, Kikkawa F, Shibata K, Kajiyama H, Nomura S. Long-term follow-up and prognostic factor analysis in clear cell adenocarcinoma of the ovary. J Surg Oncol. 2010;94(2):138–43. Modesitt SC, Tortolero-Luna G, Robinson JB, Gershenson DM, Wolf JK. (2002). Ovarian and extraovarian endometriosis-associated cancer. Obstetrics & Gynecology . Ness RB. Endometriosis and ovarian cancer: thoughts on shared pathophysiology. American Journal of Obstetrics Gynecology. 2003;189(1):280–94. Ness RB, Cramer DW, Goodman MT, Krûger KS, Kathy M, Jul MB,.. . Wu AH, Infertility. Fertility Drugs, and Ovarian Cancer: A Pooled Analysis of Case-Control Studies. 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Sampson, John A. ENDOMETRIAL CARCINOMA OF THE OVARY, ARISING IN ENDOMETRIAL TISSUE IN THAT ORGAN. American Journal of Obstetrics Gynecology. 1925;9(1):111–4. Schultheis AM, Ng CKY, De FMR, Salvatore P, Macedo GS, Sonia G,.. . Agnes V. (2016). Massively Parallel Sequencing-Based Clonality Analysis of Synchronous Endometrioid Endometrial and Ovarian Carcinomas. Journal of the National Cancer Institute (6), djv427. Somigliana E, Vigano" P, Parazzini F, Stoppelli S, Giambattista E, Vercellini P. Association between endometriosis and cancer: a comprehensive review and a critical analysis of clinical and epidemiological evidence. Gynecol Oncol. 2006;101(2):331–41. Soovares P, Pasanen A, Bützow R, Lassus H. (2017). L1CAM expression associates with poor outcome in endometrioid, but not in clear cell ovarian carcinoma. Gynecologic Oncology , S0090825817309393. Steed H, Duggan, Maire A, Warfa E. (2016). Significant frequency of MSH2/MSH6 abnormality in ovarian endometrioid carcinoma supports histotype-specific Lynch syndrome screening in ovarian carcinomas. Histopathology Official Journal of the British Division of the International Academy of Pathology . Storey DJ, Rush R, Stewart M, Rye T, Al-Nafussi A, Williams AR,.. . Gabra H. Endometrioid epithelial ovarian cancer : 20 years of prospectively collected data from a single center. Cancer. 2008;112(10):2211–20. Sugiyama T, Kamura T, Kigawa J, Terakawa N, Kikuchi Y, Kita T,.. . Taguchi K. Clinical characteristics of clear cell carcinoma of the ovary : a distinct histologic type with poor prognosis and resistance to platinum-based chemotherapy. Cancer. 2000;88(11):2584–9. Sun PE, Tae-Joong K, Hun CC, Byoung-Gie K, Duk-Soo B, Jeong-Won L. Clinical outcomes of patients with clear cell and endometrioid ovarian cancer arising from endometriosis. Journal of Gynecologic Oncology. 2018;29(2):e18-. Vercellini P, Viganò P, Somigliana E, Fedele L. Endometriosis: pathogenesis and treatment. Nature Reviews Endocrinology. 2014;10(5):261–75. Viganò P, Somigliana E, Parazzini F, Vercellini P. Bias versus causality: interpreting recent evidence of association between endometriosis and ovarian cancer. Fertility Sterility. 2007;88(3):588–93. Williams MG, Bandera EV, Demissie K, Rodríguez-Rodríguez L. Synchronous primary ovarian and endometrial cancers: a population-based assessment of survival. Obstetrics Gynecology. 2009;113(4):783–9. Winter WE, Maxwell GL, Tian C, Carlson JW, Ozols RF, Rose PG,.. . Mcguire WP. Prognostic factors for stage III epithelial ovarian cancer: a Gynecologic Oncology Group Study. Journal of Clinical Oncology Official Journal of the American Society of Clinical Oncology. 2007;25(24):3621–7. Yasuhito T, Yoshihiko Y, Hiroshi S, Hirotaka K, Akira O, Yoriko Y,.. . Toshiyuki S. Modulation of estrogenic action in clear cell carcinoma of the ovary (Review). Experimental Therapeutic Medicine. 2012;3(1):18–24. Yoshikawa H, Jimbo H, Okada S, Matsumoto K, Taketani Y. Prevalence of Endometriosis in Ovarian Cancer. Gynecol Obstet Invest. 2000;50(Suppl. 1):11–7. Suppl 1 ). Supplementary Files SupplementTable.docx SupplementTable.docx Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Minor revision 18 Feb, 2021 Review # 1 received at journal 21 Dec, 2020 Reviewer # 2 agreed at journal 09 Dec, 2020 Reviewer # 1 agreed at journal 08 Dec, 2020 Reviewers invited by journal 26 Nov, 2020 First submitted to journal 23 Nov, 2020 Editor assigned by journal 23 Nov, 2020 Submission checks completed at journal 23 Nov, 2020 Editor invited by journal 23 Nov, 2020 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-115365","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research","associatedPublications":[],"authors":[{"id":5291469,"identity":"0f0c8449-8b68-49cc-a376-c86c87bfb601","order_by":0,"name":"Ling Zhou","email":"","orcid":"","institution":"Peking University Second School of Clinical Medicine: Peking University People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Ling","middleName":"","lastName":"Zhou","suffix":""},{"id":5291470,"identity":"449f59e4-373b-48f6-9b59-b232149910e3","order_by":1,"name":"Liqing Yao","email":"","orcid":"","institution":"Fuding Hospital of Fujian 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1","display":"","copyAsset":false,"role":"figure","size":126978,"visible":true,"origin":"","legend":"Flowchart of included patients.\nCCC, clear cell carcinoma; EC, endometrioid carcinoma; EOC, epithelial ovarian cancer\n\n","description":"","filename":"Onlinefigure1.Png","url":"https://assets-eu.researchsquare.com/files/rs-115365/v1/5c235b79ca4a121004e94db0.Png"},{"id":3929302,"identity":"051c105f-f5ec-437d-8cd3-d3b3a790df4d","added_by":"auto","created_at":"2020-12-01 18:31:42","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":106487,"visible":true,"origin":"","legend":"Time and temporal trend of ovarian cancer histology with age. Lines are estimated values for modeling, and points represent actual data. (A)The annual percentage of each histological subtype among the four major primary epithelial ovarian cancers is shown. (B-D) At diagnosis, the four histological subtypes of epithelial ovarian cancer were stratified by age. (C) \u003c50 years old; (D)≥50 years old.","description":"","filename":"Onlinefigure2.Png","url":"https://assets-eu.researchsquare.com/files/rs-115365/v1/d196ab76c535964a35acba3b.Png"},{"id":3929293,"identity":"33805459-06a9-475a-9bd8-f19b5b609562","added_by":"auto","created_at":"2020-12-01 18:31:12","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":106487,"visible":true,"origin":"","legend":"Time and temporal trend of ovarian cancer histology with age. Lines are estimated values for modeling, and points represent actual data. (A)The annual percentage of each histological subtype among the four major primary epithelial ovarian cancers is shown. (B-D) At diagnosis, the four histological subtypes of epithelial ovarian cancer were stratified by age. (C) \u003c50 years old; (D)≥50 years old.","description":"","filename":"Onlinefigure2.Png","url":"https://assets-eu.researchsquare.com/files/rs-115365/v1/fcf121ee5f8c30183dca25e4.Png"},{"id":3929303,"identity":"5fc34b62-1772-40ba-a9cd-52f0092908a2","added_by":"auto","created_at":"2020-12-01 18:31:42","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":83139,"visible":true,"origin":"","legend":"Kaplan-Meier curve for OS and PFS in patients with pure cancer. No statistically significant difference in EC and CCC group (A and B). Kaplan-Meier survival curves showing the effects of FIGO stage (C and D) and relevance to EM (E and F). PFS, progression-free survival PFS, progression-free survival; OS, overall survival. CCC, clear cell carcinoma; EC, endometrioid carcinoma; EM, endometriosis.\n\n","description":"","filename":"Onlinefig3.Png","url":"https://assets-eu.researchsquare.com/files/rs-115365/v1/d30eec864350f86b27517ded.Png"},{"id":3929294,"identity":"f4b671a7-8197-47fd-a262-6d02e0086713","added_by":"auto","created_at":"2020-12-01 18:31:12","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":83139,"visible":true,"origin":"","legend":"Kaplan-Meier curve for OS and PFS in patients with pure cancer. No statistically significant difference in EC and CCC group (A and B). Kaplan-Meier survival curves showing the effects of FIGO stage (C and D) and relevance to EM (E and F). PFS, progression-free survival PFS, progression-free survival; OS, overall survival. CCC, clear cell carcinoma; EC, endometrioid carcinoma; EM, endometriosis.\n\n","description":"","filename":"Onlinefig3.Png","url":"https://assets-eu.researchsquare.com/files/rs-115365/v1/36a7c237911b88909401fe6d.Png"},{"id":3929304,"identity":"4a2be9d3-2d8c-40e2-aba0-aff0ef547c5a","added_by":"auto","created_at":"2020-12-01 18:31:42","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":71275,"visible":true,"origin":"","legend":"A comparison of PFS and OS in mixed cancer patients with different variables. Kaplan-Meier survival curves showing the effects of FIGO stage (C and D) and mixed EC (A and B). PFS, progression-free survival; OS, overall survival. CCC, clear cell carcinoma; EC, endometrioid carcinoma.","description":"","filename":"Onlinefig4.Png","url":"https://assets-eu.researchsquare.com/files/rs-115365/v1/0ec58c2ca30b9ddaa126e4c4.Png"},{"id":3929295,"identity":"da562866-2259-45c6-926a-253ceaad5a89","added_by":"auto","created_at":"2020-12-01 18:31:13","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":71275,"visible":true,"origin":"","legend":"A comparison of PFS and OS in mixed cancer patients with different variables. Kaplan-Meier survival curves showing the effects of FIGO stage (C and D) and mixed EC (A and B). PFS, progression-free survival; OS, overall survival. CCC, clear cell carcinoma; EC, endometrioid carcinoma.","description":"","filename":"Onlinefig4.Png","url":"https://assets-eu.researchsquare.com/files/rs-115365/v1/8ea05fd2bd1900f6ad0ccc66.Png"},{"id":3929305,"identity":"dac3da21-a08f-4c0d-9f8c-e4c062836e72","added_by":"auto","created_at":"2020-12-01 18:31:43","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":63085,"visible":true,"origin":"","legend":"Kaplan-Meier curve for (A) PFS and (B) OS in stage II-IV patients with pure cancer. PFS, progression-free survival; OS, overall survival. R0, no residual disease.","description":"","filename":"Onlinefig5.Png","url":"https://assets-eu.researchsquare.com/files/rs-115365/v1/b21acfc3e6d8d28960e05638.Png"},{"id":3929296,"identity":"5273d16e-ee8d-43ab-9a38-75286bda25d0","added_by":"auto","created_at":"2020-12-01 18:31:13","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":63085,"visible":true,"origin":"","legend":"Kaplan-Meier curve for (A) PFS and (B) OS in stage II-IV patients with pure cancer. PFS, progression-free survival; OS, overall survival. R0, no residual disease.","description":"","filename":"Onlinefig5.Png","url":"https://assets-eu.researchsquare.com/files/rs-115365/v1/ed3d29b54a394bceef970359.Png"},{"id":3929306,"identity":"ed071e36-a621-4e8a-bce1-454a3c7a57f4","added_by":"auto","created_at":"2020-12-01 18:31:43","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":59782,"visible":true,"origin":"","legend":"Kaplan-Meier curve for (A) OS and (B) PFS in all patients. PFS, progression-free survival; OS, overall survival. ","description":"","filename":"Onlinefig6.Png","url":"https://assets-eu.researchsquare.com/files/rs-115365/v1/20f48d4c7d69294e654ae3fa.Png"},{"id":3929297,"identity":"3ea17263-4258-4cf1-acdc-e13055ece0ae","added_by":"auto","created_at":"2020-12-01 18:31:13","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":59782,"visible":true,"origin":"","legend":"Kaplan-Meier curve for (A) OS and (B) PFS in all patients. PFS, progression-free survival; OS, overall survival. ","description":"","filename":"Onlinefig6.Png","url":"https://assets-eu.researchsquare.com/files/rs-115365/v1/1fd08e3602af77e893ac568f.Png"},{"id":13621423,"identity":"38c5aea1-9d11-41f9-9c6a-74370e4e5ae7","added_by":"auto","created_at":"2021-09-17 07:10:35","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2443221,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-115365/v1/e7b6994f-f79a-4e56-8c98-a07edf92726f.pdf"},{"id":3929300,"identity":"aff59c55-73a9-4d2c-9ff9-c15dbfcaeac3","added_by":"auto","created_at":"2020-12-01 18:31:42","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":13352,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementTable.docx","url":"https://assets-eu.researchsquare.com/files/rs-115365/v1/9f6bdb37d89019f7bcc0520a.docx"},{"id":3929291,"identity":"5e37f015-91a4-49a5-8381-9e63fec407ef","added_by":"auto","created_at":"2020-12-01 18:31:12","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":13352,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementTable.docx","url":"https://assets-eu.researchsquare.com/files/rs-115365/v1/6edba559fd4565b453decba2.docx"}],"financialInterests":"","formattedTitle":"Ovarian Endometrioid Carcinoma and Clear Cell Carcinoma: A 21-year Retrospective Study","fulltext":[{"header":"1 Introduction","content":" \u003cp\u003eOvarian cancer is the second most common gynecologic malignancy, with over 90% of cancers arising from epithelial cells(Carmen, Birrer, \u0026amp; Schorge, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2012\u003c/span\u003e; K?Bel et al., 2010). The most common histology of epithelial ovarian carcinoma (EOC) is papillary serous carcinoma, accounting for 70% of all EOCs in North America, followed by the endometrioid and clear cell histological types, which account for 20\u0026ndash;25% and 5\u0026ndash;10% of EOCs, respectively, of EOCs(K?Bel et al., 2010; Kennedy, Biscotti, Hart, \u0026amp; Webster, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e1989\u003c/span\u003e; Mizuno, Kikkawa, Shibata, Kajiyama, \u0026amp; Nomura, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e2010\u003c/span\u003e; Nishida, Watanabe, Sato, \u0026amp; Ichikawa, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e2000\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eEndometriosis is a benign gynecologic disease that is characterized by endometrial glands and stroma occurring outside the uterus. Endometriosis is a risk factor for epithelial ovarian cancer(Vercellini, Vigan\u0026ograve;, Somigliana, \u0026amp; Fedele, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e2014\u003c/span\u003e; Vigan\u0026ograve;, Somigliana, Parazzini, \u0026amp; Vercellini, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e2007\u003c/span\u003e), and the overall rate of malignant transformation in endometriosis has been estimated to be 0.3\u0026ndash;0.8%, with a relative risk ranging from 1.3 to 1.9(Somigliana et al., \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e2006\u003c/span\u003e). The relationship between endometriosis and ovarian cancer has been classified as either a transition from endometriotic lesions to invasive ovarian carcinoma or the coexistence of ovarian cancer with endometriosis without a transition(Modesitt, Tortolero-Luna, Robinson, Gershenson, \u0026amp; Wolf, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e2002\u003c/span\u003e; Ness, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e2003\u003c/span\u003e). Sampson defined endometriosis-associated ovarian cancer (EAOC) as endometriosis that was found in the surgical specimen but not in direct continuity with the tumor(Oral et al., \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e2003\u003c/span\u003e; Sampson \u0026amp; John, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e1925\u003c/span\u003e; Yoshikawa, Jimbo, Okada, Matsumoto, \u0026amp; Taketani, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e2000\u003c/span\u003e). It is also well known that tumors associated with endometriosis are confined to specific subcategories of disease, namely, endometrioid carcinoma (EC) and clear cell carcinoma (CCC) (Kobayashi, Sumimoto, Kitanaka, Yamada, \u0026amp; Terao, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e2008\u003c/span\u003e; Ness et al.).\u003c/p\u003e \u003cp\u003eThe prognosis of early ovarian CCC is good, but late-stage CCC is known to be less sensitive to platinum-based front-line chemotherapy and to be associated with a worse prognosis than serous adenocarcinoma or endometrioid adenocarcinoma during the same period (Bamias et al., \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2010\u003c/span\u003e; Itamochi et al., \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2002\u003c/span\u003e; Sugiyama et al., \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e2000\u003c/span\u003e; Winter et al., \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e2007\u003c/span\u003e). It is generally believed that the prognosis of ovarian EC is good, but there are still some patients with a poor prognosis (drug resistance, recurrence or even death), which has also been reported in the literature(Soovares, Pasanen, B\u0026uuml;tzow, \u0026amp; Lassus, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e2017\u003c/span\u003e). There are still many unresolved problems with CCC and EC as tumors closely related to endometriosis. To obtain further insight into these endometriosis-related cancers, we reviewed and analyzed the clinical data of patients with CCC and EC in a single center over the past 20\u0026nbsp;years. We aimed to summarize the clinical experience and provide guidance for clinical work.\u003c/p\u003e "},{"header":"2 Materials And Methods","content":"\u003ch2\u003ePatients and clinical information\u003c/h2\u003e\n\u003cp\u003eWith ethical approval (No. 2020PHB212-01) given for ovarian cancer specimen collection with annotated clinical information, all patients with primary EOC who were treated at Peking University People\u0026rsquo;s Hospital from 1998 to 2018 were reviewed. Individual informed patient consent was not sought, as these data were routinely obtained and used as part of these patients\u0026rsquo; clinical care. The women were followed until December 2019 or until they died of ovarian cancer or other conditions, whichever happened first.\u003c/p\u003e\n\u003cp\u003eData from electronic medical records were retrospectively reviewed. Two pathologists reviewed the pathology details to determine whether there was concurrent endometriosis. We screened patients according to the established criteria (see the detailed process in Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e), and patients with complete clinical data and follow-up information were included. The pathological staging was checked, and patient was restaged based on the International Federation of Obstetrics and Gynecology (FIGO) staging standard (according to the 2014 FIGO staging standard to restage ovarian cancer and according to the 2009 FIGO staging standard to restage concurrent endometrial cancer).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe following information was collected: age at diagnosis, histology, history of past illnesses (hypertension/diabetes/endometriosis/breast cancer/immune system disease), FIGO stage, fertility history, first symptoms, blood cancer antigen-125 (CA-125) level (before and after surgery), tumor size and side, surgical procedure, tumor grade, surgical debulking status, endometrial pathology (concurrent endometrial lesions), chemotherapy regimen, objective response to chemotherapy, progression-free survival and overall survival.\u003c/p\u003e\n\u003ch2\u003eCriteria for defining factors\u003c/h2\u003e\n\u003cp\u003eEndometrial lesions included endometrial cancer and endometrial dysplasia. If there was endometrial cancer by uterine pathology, the Scully criteria were used to distinguish between dual primary and metastatic disease (the full description of the criteria is provided in Supplementary Table)(Williams, Bandera, Demissie, \u0026amp; Rodr\u0026iacute;guez-Rodr\u0026iacute;guez, \u003cspan class=\"CitationRef\"\u003e2009\u003c/span\u003e). Endometriosis-related patients were defined as patients showing endometriosis by pathology or having a history of endometriosis. Progression-free survival (PFS) was defined as the time interval from the date of primary surgery to the date of disease progression and/or recurrence. Overall survival (OS) was defined in months as the date of the primary surgery to the date of death or censoring at the date of last contact. To define residual disease status after primary debulking surgery, the largest diameter of residual disease was measured and categorized as follows: no residual disease (R0), 0.1\u0026ndash;1\u0026nbsp;cm residual disease (R1), and \u0026gt;\u0026thinsp;1\u0026nbsp;cm residual disease.\u003c/p\u003e\n\u003ch2\u003eStatistical analysis\u003c/h2\u003e\n\u003cp\u003eSummary statistics were used to describe the data. Medians (ranges) or means (standard deviations) were used for continuous variables. After a normal distribution was confirmed with the Shapiro-Wilks test, the Mann-Whitney U test was used to compare median values, and Student's t-test was used to compare mean values. Categorical variables are presented as frequencies (percentages). Fisher's exact test or the \u0026chi;2 test were used to analyze the distributions of characteristics according to their associations with endometriosis. Survival curve analyses were performed with the Kaplan-Meier method, and comparisons were performed using the log-rank test. A Cox proportional hazards model was used to perform univariate and multivariate analyses to evaluate the prognostic significance of the association with endometriosis and other clinicopathological features. Multivariate p-values were used to present the significance of each feature. To quantify the correlation between survival time and each independent feature, a 95% confidence interval (CI) was used. All p-values were 2-sided, and p-values less than 0.05 were considered statistically significant.\u003c/p\u003e\n\u003cp\u003eThe Joinpoint Regression Program 4.6.0.0 provided by the National Cancer Institute was used to determine potential changes in the temporal trends in the incidence rate. The trends in the histological subtypes of ovarian cancer were examined for every calendar year or every patient age. Linear segmented regression analysis was utilized for the model. Statistical analyses were performed using SPSS 26.0 (IBM), GraphPad Prism 8.0 and R 3.0.6 (R Foundation, Vienna, Austria; \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.R-project.org\u003c/span\u003e\u003c/span\u003e).\u003c/p\u003e"},{"header":"3 Results","content":"\u003ch2\u003ePatient demographics\u003c/h2\u003e\n\u003cp\u003eFrom 1998 to 2018, there were 1324 patients with ovarian cancer who were admitted to Peking University People\u0026rsquo;s Hospital. According to the exclusion criteria, 211 patients who were diagnosed as having clear cell or endometrioid histology were investigated (the patient selection schema is shown in Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). Of 211 patients, 73 had pure EC, and 91 had pure CCC. There were 47 cases of mixed cancers of other histological types, such as the serous and mucinous types.\u003c/p\u003e\n\u003cp\u003eAmong pure EC patients, the most common histological subtype was serous (669/938, 71.3%), followed by clear cell (104/938, 11.1%), endometrioid (89/938, 9.5%), and mucinous (76/938, 8.1%). Figure\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e show the time-specific trends and age-specific trends for each histological type. From 1998 to 2018, the proportions of ovarian cancer subtypes remained stable (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eA). Overall, the proportion of serous ovarian cancer gradually increased with increasing age while the proportion of EC declined with aging (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eB). The age of onset of CCC had two peaks, namely, 36\u0026nbsp;years and 77\u0026nbsp;years (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eB).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOne can interpret the data as indicating that serous ovarian cancer patients were getting older, while patients with endometrioid ovarian cancer were getting younger over time (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eC-D). Among women aged\u0026thinsp;\u0026lt;\u0026thinsp;50\u0026nbsp;years in the cohort, the incidence rate of EC increased between 1998 and 2018 (rising by nearly 1.02% per year; Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eC). The incidence rates of the three cancer types decreased between 1998 and 2018 (clear cell, declined by 4.28% per year; serous, declined by 3.08% per year; mucinous, declined by 7.32% per year. Figure\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eC). For people\u0026thinsp;\u0026ge;\u0026thinsp;50\u0026nbsp;years old, the frequency of serous cancer increased slightly in 1998 and 2018, while that of the other three types showed a downward trend (serous, rising by nearly 1.14% per year; clear cell, declining by 0.86% per year; endometrioid, declining by 8.01% per year; mucinous, declined by 11.28% per year. Figure\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eD).\u003c/p\u003e\n\u003ch2\u003eTotal clinical and morphological features\u003c/h2\u003e\n\u003cp\u003eThe detailed data are presented in Tables\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e. The mean age at diagnosis of the entire population was 51.9\u0026thinsp;\u0026plusmn;\u0026thinsp;10.9\u0026nbsp;years (range, 24\u0026ndash;79\u0026nbsp;years), and 47.9% (101/211) of the women were postmenopausal.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eTotal clinical characteristics\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eClinicopathological Factor\u003c/strong\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eNumber\u003c/strong\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eEC\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e73(34.6%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCCC\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e91(43.1%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMix\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e47(22.3%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMixed with EC\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e31(14.7%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMixed with CCC\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e13(6.2%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBoth\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e3(1.4%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eEMs in Pathological Section\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e114(54.0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePast History of EMs\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e16 (7.6%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eEndometrial cancer\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e26(12.3%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eConcurrent with pure EC\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e23(10.9%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eConcurrent with pure CCC\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1(0.47)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eParity\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026gt;\u0026thinsp;1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e170 (80.6%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e41(19.4%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePast History of Hypertension\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e46(21.8%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePast History of Diabetes\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e18(8.5%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOverweight(BMI\u0026thinsp;\u0026gt;\u0026thinsp;24)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e89(42.4%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDysmenorrhea\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e49(23.2%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePost-menopause\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e101(47.9%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBreast cancer\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e8(3.8%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eImmune System Disease\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e7(3.3%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eInitial Signs༏Symptoms\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAbdominal Pain\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e42(19.9%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAbdominal Distension\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e40(19.0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAbdominal Mass\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e17(8.1%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAsymptomatic\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e68(32.2%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eVaginal Bleeding\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e15(7.1%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePainful Menstruation\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e2(0.92%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOthers*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e27(12.8%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"3\"\u003e\n\u003cp\u003e*Others symptoms contain weariness ,emaciation,lower extremity edema, abnormal vaginal discharge༌irregular menstruation and change of menstrual volume.\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab2\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eTotal characteristics of therapy and prognosis\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eClinicopathological Factor\u003c/strong\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eNumber\u003c/strong\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOperation\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e211(100%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eComplete Surgical Staging\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e114 (54.0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMaximal Resection\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e97(46.0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eResidual Disease\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eR0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e142(67.3%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eR1(\u0026lt;1cm)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e13(6.2%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1-2cm\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7(3.32%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026gt;\u0026thinsp;2\u0026nbsp;cm\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8(3.79%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSecond Operation\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11(5.25%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAbdominal Dropsy\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e78(37.0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;500\u0026nbsp;ml\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e81(38.4%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026gt;\u0026thinsp;500\u0026nbsp;ml\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e34(16.1%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUncertain\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e18(8.5%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLymph Nodes Excision(LMN)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e188(89.1%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNo\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e23(10.9%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePelvic Region Only\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4(1.9%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePelvic \u0026amp; Abdominal region\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e186(88.2%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSurgery to Conserve Fertility\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8(3.8%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eChemotherapy Regimens\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e177(83.9%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePlatinum-based chemotherapy(PBC)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e174(82.3%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePlatinum-free chemotherapy\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3(1.4%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eTC\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e150(71.1%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOthers\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e27(13.0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFIGO stage\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eI\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e114(54.0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eII\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e39(18.5%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIII\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e54(25.6%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIV\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4(1.9%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eChemotherapy Treatment Course\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e13(6.1%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026gt;=3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e163(77.3%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDeath\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e29(13.7%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRelapse\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e48(22.7%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eThe common symptoms at initial presentation were sequentially palpable mass, abdominal pain, incidental finding, abdominal distension and irregular vaginal bleeding. A normal preoperative serum CA-125 value was observed in 27.5% (58/211) of patients. The distribution of FIGO stage was as follows: Stage I, 54% (114/211); Stage II, 18.5% (39/211); Stage III, 25.6% (54/211); and Stage IV, 1.9% (4/211). There were 16 patients with a previous history of endometriosis. In the initial records, endometriosis was found by pathology in 41 patients. After review by the pathologist, the number of endometriosis cases found in the pathological section of the analysis increased to 114, accounting for 54% of patients. From the early stage to the late stage, the frequency of endometriosis by pathology gradually decreased (via the linear association method, p\u0026thinsp;=\u0026thinsp;0.001).\u003c/p\u003e\n\u003cp\u003eIn this series, 114 (54.0%) patients received comprehensive staging surgery, and 97 (46.0%) patients received cytoreductive surgery. A total of 142 (67.3%) patients had no residual lesions, and 13 (6.2%) patients had residual lesions less than 1\u0026nbsp;cm in size. In total, 177 (83.9%) patients received chemotherapy, among which 174 (82.3%) received PBC.\u003c/p\u003e\n\u003ch2\u003ePure clear cell and endometrioid carcinoma\u003c/h2\u003e\n\u003cp\u003eThe present study found that the age at diagnosis was 50.0\u0026thinsp;\u0026plusmn;\u0026thinsp;11.7 (range 24 to 79) years in the EC group and 52.6\u0026thinsp;\u0026plusmn;\u0026thinsp;9.5\u0026nbsp;years (range 32 to 77) in the CCC group (see details in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). Compared with CCC, EC has a higher frequency of concurrent endometrial cancer and a higher frequency of independent ovarian and endometrial lesions (including endometrial cancer and precancerous lesions, p\u0026thinsp;=\u0026thinsp;0.000). According to the standard of Scully et al., patients with synchronous primary cancer of the endometrium and ovary accounted for 20.5% (15/73) of the EC group, while they accounted for only 1.1% of the CCC group (p\u0026thinsp;=\u0026thinsp;0.000). The proportion of premenopausal women was higher in the EC group (p\u0026thinsp;=\u0026thinsp;0.040). EC were predominantly positive for estrogen receptor (ER) and progesterone receptor (PR), but CCC exhibited lower ER and PR expression (p\u0026thinsp;=\u0026thinsp;0.000) (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab3\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eMean age of each group\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eGroup\u003c/strong\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eAge at diagnose(range)\u003c/strong\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAll Patients\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e51.8\u0026thinsp;\u0026plusmn;\u0026thinsp;10.9(24\u0026ndash;79)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePure Cancer\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e51.4\u0026thinsp;\u0026plusmn;\u0026thinsp;10.6(24\u0026ndash;79)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eEC\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e50.0\u0026thinsp;\u0026plusmn;\u0026thinsp;11.7(24\u0026ndash;79)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCCC\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e52.6\u0026thinsp;\u0026plusmn;\u0026thinsp;9.5(32\u0026ndash;77)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMixed Cancer\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e53.4\u0026thinsp;\u0026plusmn;\u0026thinsp;12.0(28\u0026ndash;75)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"3\"\u003e\n\u003cp\u003eCCC, clear cell carcinoma; EC, endometrioid carcinoma.\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab4\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eThe results of immunohistogical staining of ER and PR of pure cancer\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/th\u003e\n\u003cth align=\"left\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eNumber\u003c/strong\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eER\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e62\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eEC\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e51(51/62, 82.3%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCCC\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11(11/62, 17.7%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePR\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e55\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eEC\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e49(49/55, 89.1%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCCC\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6(6/55, 10.9%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"3\"\u003e\n\u003cp\u003eER, Estrogen receptor; PR, Progesterone receptor; CCC, clear cell carcinoma; EC, endometrioid carcinoma.\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eDuring the follow-up period, 17 patients (10.4%) died, and 28 patients (17.1%) experienced relapses. The 5-year OS and PFS rates of CCC patients were 88.0% and 89.9%, respectively. The 5-year OS and PFS rates of EC patients were 92.1% and 78.4%, respectively. The difference in prognosis between EC and CCC was not significant (p\u0026thinsp;=\u0026thinsp;0.333. Figure\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eA-B).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSurvival analysis of 164 pure EOC patients with EC or CCC was performed by univariate analysis using the Kaplan-Meier method. The results showed that the factors that influenced the prognosis of pure EOC patients with EC or CCC included FIGO stage, lymphadenectomy, residual lesions, parity history, association with endometriosis and CA-125 level before and after surgery (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Survival analysis revealed significant differences in PFS and OS between patients whose disease was related to endometriosis compared to those whose disease was unrelated to endometriosis. The Kaplan-Meier curve for PFS showed a survival advantage for patients whose disease was unrelated to endometriosis (p\u0026thinsp;=\u0026thinsp;0.01; Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e.F). The results for OS indicated that patients whose disease was unrelated to endometriosis had better survival outcomes than patients whose disease was related to endometriosis (p\u0026thinsp;=\u0026thinsp;0.0057; Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e.E). Rambau P et al.(Peter et al., \u003cspan class=\"CitationRef\"\u003e2017\u003c/span\u003e)reported that the expression of ER and PR was significantly associated with longer ovarian cancer-specific survival, but no association was found in this study.\u003c/p\u003e\n\u003cp\u003eIn the multivariate analysis of clinicopathologic variables among the entire cohort of patients, disease related to endometriosis remained a significant prognostic factor for PFS (p\u0026thinsp;=\u0026thinsp;0.001; Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e). FIGO stage, which was previously shown to be a prognostic factor in EOC, remained a significant prognostic factor for PFS and OS in this study cohort (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e.C-D). Additionally, the postoperative CA-125 level was significant in the multivariate analysis for PFS. Both the univariate and multivariate analyses showed that in advanced ovarian cancer (stage II-IV), residual lesions are an independent prognostic factor (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e; Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab5\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eMultivariate Cox proportional hazards analysis for PFS and OS used to adjust risk associated prognostic clinical features\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003ePure group (n\u0026thinsp;=\u0026thinsp;164)\u003c/strong\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003cth colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003ePFS\u003c/strong\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003cth colspan=\"3\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eOS\u003c/strong\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHR (95%CI)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ep-value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eHR (95%CI)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ep-value\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eParity\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.906(0.508\u0026ndash;1.615)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.738\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e/\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e/\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCA-125(before)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.000(0.999-1.000)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.595\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e1.646(0.403\u0026ndash;6.725)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.487\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCA-125(after)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.002(1.000-1.005)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.044\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e/\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e/\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFIGO\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.722(0.990\u0026ndash;2.994)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.054\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e3.981(1.821\u0026ndash;8.706)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eEM-related\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.014(1.056\u0026ndash;15.262)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.041\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e0.925(0.272\u0026ndash;3.146)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.047\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eResidual disease\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.915(0.475\u0026ndash;1.766)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.792\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e1.389(0.823\u0026ndash;2.346)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.219\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLymph Nodes excision\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.325(0.078\u0026ndash;1.346)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.325\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e0.925(0.272\u0026ndash;3.146)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.900\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMixed group (n\u0026thinsp;=\u0026thinsp;47)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003ePFS\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eOS\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHR (95%CI)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ep-value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eHR (95%CI)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ep-value\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCA-125(before)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.000(0.999\u0026ndash;1.001)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.835\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e1.000(1.000-1.001)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.185\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCA-125(after)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.003(0.998\u0026ndash;1.008)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.235\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e/\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e/\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFIGO\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.934(0.211\u0026ndash;17.700)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.023\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e1.880(0.699\u0026ndash;5.059)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.211\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eEM-related\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e/\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e/\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e/\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e/\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eResidual disease\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.490(0.544\u0026ndash;4.087)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.544\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e1.030(0.508\u0026ndash;2.086)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.935\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMixed with EC\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.070(0.014\u0026ndash;0.347)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e0.425(0.107\u0026ndash;1.684)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.223\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAppendix excision\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.460(0.350-56.794)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.249\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e0.228(0.041\u0026ndash;1.258)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.090\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLymph Nodes excision\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.934(0.211\u0026ndash;17.700)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.559\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e1.030(0.508\u0026ndash;2.086)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.935\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e2\u0026ndash;4 stage of patients with pure cancer\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"4\" align=\"left\"\u003e\n\u003cp\u003ePFS\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eHR (95%CI)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003ep-value\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eFIGO\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e2.918(1.022\u0026ndash;8.326)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e0.045\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eR0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e0.287(0.110\u0026ndash;0.749)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e0.011\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"6\"\u003e\n\u003cp\u003eCA, cancer antigen; CA-125(before):CA-125 level before surgery; CI, confidence interval; FIGO, International Federation of Gynecology and Obstetrics; HR, hazard ratio; OS, overall survival; PFS, progression-free survival. R0, Achieving optimal cytoreduction and/or removal of all macroscopic disease.\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eMixed carcinoma\u003c/h2\u003e\n\u003cp\u003eThere were 47 cases of mixed cancers of other histological types, including 31 cases of cancers mixed with ECs, 13 cases of cancers mixed with CCCs, and three cases of cancers mixed with ECs and CCCs (see details in Tables\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). The mucinous type always appeared with the endometrioid histological type rather than with CCC (p\u0026thinsp;=\u0026thinsp;0.000).\u003c/p\u003e\n\u003cp\u003eDuring the follow-up period, 12 patients (42.6%) died, and 20 patients (25.5%) experienced relapses. The 5-year OS and PFS rates of mixed carcinoma were 77.9% and 57.4%, respectively. The difference in prognosis between mixed carcinoma and pure carcinoma was significant (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05, Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e6\u003c/span\u003e). The results for OS and PFS indicated that patients with pure cancer had significantly better survival outcomes (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e6\u003c/span\u003e). Univariate and multivariate analyses showed that FIGO stage and cancer mixed with endometrioid histology had a statistically significant impact on the prognosis of patients with mixed cancer (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e; Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e). Mixed endometrioid histology was associated with better survival than serous adenocarcinoma of the ovary, even with stage III or poorly differentiated tumors (p\u0026thinsp;=\u0026thinsp;0.000).\u0026nbsp;\u003c/p\u003e"},{"header":"4 Discussion","content":"\u003ch2\u003eOvarian clear cell Carcinoma and endometrioid carcinoma\u003c/h2\u003e\n\u003cp\u003eThis study systematically described CCC and EC data from a single center in China obtained from 1998 to 2018. The distribution and age structure of the four major histological subtypes of pure ovarian cancer in China are more similar to those of the United States than to those of Japan, another Asian country(Machida H \u003cspan class=\"CitationRef\"\u003e2019\u003c/span\u003e). There was a tendency to young people for patients with EC in age. It might be because continuous development of human society, people's bearing attitudes are constantly changing, and urbanization has transformed people's ideas on family planning. Women have fewer pregnancy and childbirths, and there are more alternative contraceptive methods, such as the use of short-acting combined contraceptives. To further determine the distribution and specific trends of ovarian cancer patients in China, multicenter, large-sample research is needed in the future.\u003c/p\u003e\n\u003cp\u003eSurvival analysis showed that FIGO stage is an important prognostic factor in pure cancer or mixed cancer. The residual lesion size, which is generally considered to be an independent prognostic factor, is still important in advanced pure ovarian cancer (stage II-IV). The pure cancer group had a better overall prognosis than the mixed group, and among mixed cancers, EC was always associated with a better prognosis. In another single-center study, Dawn J. Story et al. found that despite their similar response rates to platinum-based chemotherapy (PBC), endometrioid ovarian cancer has a better survival outcome than ovarian serous adenocarcinoma(Storey et al., \u003cspan class=\"CitationRef\"\u003e2008\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eTwo histologic types, CCC and EC, are common histological types of ovarian cancer in patients who have associated endometriosis. However, both tumor types have distinct clinicopathological characteristics and molecular phenotypes. The high incidence of combined endometrial disease in the EC group distinguishes EC from CCC. Studies have shown that EC subtypes have a much higher chance of concurrent endometrial cancer than other histological subtypes of epithelial ovarian cancer in the same period(Williams et al., \u003cspan class=\"CitationRef\"\u003e2009\u003c/span\u003e). Our data also indicated that 12.3% (9/73) of patients with EC had coexisting endometrial atypical hyperplasia and that 20.5% (15/73) of patients with EC had synchronous endometrial cancer, which should be seriously taken into account, particularly for patients with the desire to undergo fertility-sparing surgery. A comprehensive evaluation of the endometrium might be necessary.\u003c/p\u003e\n\u003cp\u003eIn terms of morphological characteristics, ECs show broad morphological similarities to their endometrial counterparts. Overall, the most common molecular alterations in EC include mutations in CTNNB1 (31\u0026ndash;53.3%), PIK3CA (15\u0026ndash;40%), ARID1A (30%), and PPP2R1A (7\u0026ndash;16.6%) (Bennett, Pesci, Morales-Oyarvide, Silva, \u0026amp; Oliva, \u003cspan class=\"CitationRef\"\u003e2018\u003c/span\u003e; Gras et al., \u003cspan class=\"CitationRef\"\u003e2015\u003c/span\u003e; Hoang, Mcconechy, K\u0026ouml;bel, Anglesio, \u0026amp; Lee, \u003cspan class=\"CitationRef\"\u003e2015\u003c/span\u003e; Huang et al., \u003cspan class=\"CitationRef\"\u003e2015\u003c/span\u003e; Jones S, \u003cspan class=\"CitationRef\"\u003e2010\u003c/span\u003e; Mcconechy et al., \u003cspan class=\"CitationRef\"\u003e2014\u003c/span\u003e; Steed et al., \u003cspan class=\"CitationRef\"\u003e2016\u003c/span\u003e). Largely, these events are similar to those that have been reported for the more common endometrial EC. Similar to their endometrial counterparts, EC seems to be classifiable into molecular subgroups that correlate with survival(Parra-Herran et al., \u003cspan class=\"CitationRef\"\u003e2017\u003c/span\u003e). Add all of these together and it is not hard to see that EC is closer to endometrial cancer in all aspects. Recent studies based on targeting and exon sequencing have confirmed that there is a clonal correlation between ovarian and endometrial primary cancers. The two are not absolutely unrelated; it may be the spread from one site to another. The author believes that EC of the ovary may be an ovarian implant of indolent endometrial carcinoma and puts forward the following hypotheses: 1) The metastasis may be caused by retrograde progression of the diseased endometrium through the fallopian tube rather than blood or lymph node metastasis; 2) There is the possibility of \"pseudometastasis\", namely, cells detach from the primary lesion without undergoing apoptosis, spread through open spaces, and only recolonize the unique microenvironment without the ability to extensively metastasize(Anglesio et al.; Schultheis et al., \u003cspan class=\"CitationRef\"\u003e2016\u003c/span\u003e). It seems that EC is another form of endometrial cancer that grows in the ovaries. Therefore, when studying the pathogenesis of EC and CCC, there are two possibilities to consider as the determining factor\u0026mdash;bad endometriosis or a bad endometrium. Perhaps treatment of EC that is analogous to endometrial cancer will become a new breakthrough.\u003c/p\u003e\n\u003cp\u003eEC is predominantly positive for ER, but CCC exhibits lower ER expression. YASUHITO TANASE et al.(Yasuhito et al., \u003cspan class=\"CitationRef\"\u003e2012\u003c/span\u003e) proposed a model postulating that additional events, particularly deletion of ER expression, are required for CCC lesion progression. CCC pathogenesis may be a model to study the progression from estrogen-dependent to estrogen-independent disease, allowing the design of new strategies targeting the hormone response, thereby modifying disease outcome. Therefore, loss of estrogen function may be a turning point in CCC development. There are still many problems with CCC and EC in current clinical practice, but the treatment options available are likely similar to serous histological subtypes. The 2016 National Comprehensive Cancer Network (NCCN) guidelines listed hormone therapy as a postoperative adjuvant treatment option for low-grade EC. This shows that the application of treatments that target ER and PR in the treatment of EC and CCC is gradually being valued. However, further research is needed to prove the role of ER and PR in the development of endometriosis-related ovarian cancer.\u003c/p\u003e\n\u003cp\u003eRecently, sophisticated proteomic tracing studies have suggested that ovarian endometrioid adenocarcinomas arise from secretory cells of endometriosis or the endometrium, while ovarian clear cell adenocarcinomas arise from ciliated cells. Importantly, it is hypothesized that the unique cellular environment dictates the development of ciliated or secretory cells, which then gain mutations to become malignant(\"Clear cell and endometrioid carcinomas: are their differences attributable to distinct cells of origin?,\" 2017). Indeed, it is worth exploring the following: Why are there two different types from the same origin (if both CCC and EC originate from endometriosis)?\u003c/p\u003e\n\u003ch2\u003eThe relationship between endometriosis and CCC/EC\u003c/h2\u003e\n\u003cp\u003eAfter review by the pathologist, the number of endometriosis cases found in the pathological section rose from 19.4\u0026ndash;54.0% of total cases (from 41 to 114 patients). This suggests that the proportion of EC and CCC coexisting with endometriosis was previously underestimated. The reasons for the differences before and after the pathological review may be as follows: 1) tumor cells are so aggressive that they invade and destroy most or all endometriotic tissues; 2) because pathology reports are used for the diagnosis of malignant tumors, the reporter focuses on malignant tumors rather than endometriosis; and 3) we focus more on the tumor site when taking pathological sections. In clinical work, it is very difficult to obtain specimens of endometriosis, tumor tissues and transitional tissues all at once.\u003c/p\u003e\n\u003cp\u003eIn this study, as the stage progressed, the appearance of endometriosis became increasingly scarce in pathological sections (p\u0026thinsp;=\u0026thinsp;0.001). The probability of endometriosis coexisting in early disease is higher, which is consistent with the conclusion drawn by Kim HS et al.(Kim, Kim, Chung, \u0026amp; Song, \u003cspan class=\"CitationRef\"\u003e2014\u003c/span\u003e). In patients with advanced cancer, the low frequency of endometriosis might be because the endometriotic tissue was \"burned out\", that is, completely transformed into cancer tissue. It is also possible that malignant tumor cells proliferated rapidly and invaded endometriotic tissues and other benign tissues. Thus, the absence of endometriosis in the pathological sections of EC and CCC does not mean that it does not exist in the specimen. It may be that the pathologist did not report the endometriosis (it was not taken seriously) or that endometriosis was \u0026ldquo;hidden\u0026rdquo; under the tumor tissue.\u003c/p\u003e\n\u003cp\u003eSeveral studies have reported that endometriosis has no effect on the prognosis of EAOC (Ju, Kang, \u0026amp; Kim, \u003cspan class=\"CitationRef\"\u003e2019\u003c/span\u003e; Sun et al., \u003cspan class=\"CitationRef\"\u003e2018\u003c/span\u003e), and we did find that there was no association between the presence of endometriosis and the prognosis of ovarian CCC or EC (p\u0026thinsp;=\u0026thinsp;0.091\u0026thinsp;\u0026gt;\u0026thinsp;0.05). Considering that the absence of endometriosis does not mean that it never existed, we consider a history of endometriosis and cooccurrence of endometriosis as a whole to be a clinical pathological factor. As a result, we found that patients with endometriosis had worse outcomes. This may be explained by the abnormal immune regulation system and aberrant pelvic microenvironment in patients with endometriosis(J\u0026uacute;lia, Sahar, \u0026amp; Giudice, \u003cspan class=\"CitationRef\"\u003e2019\u003c/span\u003e). As a benign disease behaving like a malignant tumor, endometriosis can invade tissues and spread elsewhere. With abnormal secretion of immune regulatory factors and abnormal activation of the complement system(J\u0026uacute;lia et al., \u003cspan class=\"CitationRef\"\u003e2019\u003c/span\u003e), immune escape occurs and creates a favorable environment for recurrence. This is a reminder that a history of endometriosis in ovarian cancer patients should be taken seriously and that long-term management and close follow-up are necessary.\u003c/p\u003e\n\u003cp\u003eTo our knowledge, this is the largest retrospectively collected pure and mixed ovarian clear cell and EC set in China. We have discussed the relationship between endometriosis and EC or CCC, aiming to provide some guidance for clinical work. Attention should be paid to ovarian cancer patients with a history of endometriosis and those with concurrent endometriosis in pathological sections. This study also has some limitations. Multicenter, large-sample prospective clinical research is necessary in the future.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eEthics approval and consent to participate\u003c/h2\u003e\n\u003cp\u003eThe study was conducted in accordance with the principles of the Declaration of Helsinki and was approved by the Institute Research Medical Ethics Committee of Peking University People\u0026rsquo;s Hospital (No. 2020PHB212-01). Informed written consents were obtained from all patients prior to their enrollment in this study.\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eConsent for publication\u003c/h2\u003e\n\u003cp\u003eNot applicable.\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eAcknowledgements\u003c/h2\u003e\n\u003cp\u003eWe thank the members of the Department of pathology, Peking University People\u0026rsquo;s Hospital for their help with the pathological reviews in this study.\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eAuthors\u0026rsquo; contributions\u003c/h2\u003e\n\u003cp\u003eLing Zhou - undertook collection, analysis and interpretation of the data and wrote the manuscript drafts.\u003c/p\u003e\n\u003cp\u003eLiqing Yao- undertook collection, helped designing the indicators and programs.\u003c/p\u003e\n\u003cp\u003eLin Dai- be of assistance to many aspects of pathology.\u003c/p\u003e\n\u003cp\u003eXue Ye, Shang Wang, Ruiqiong Ma and Hongyan Chen - data collection.\u003c/p\u003e\n\u003cp\u003eHuiping Liu-data collection and data analysis.\u003c/p\u003e\n\u003cp\u003eHonglan Zhu- contributed to data analysis and interpretation, and critically revised the manuscript.\u003c/p\u003e\n\u003cp\u003eXiaohong Chang - responsible for the conception, design and performing of the whole study.\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eDeclaration of competing interests\u003c/h2\u003e\n\u003cp\u003eThe authors declare no conflict of interest.\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eFunding\u003c/h2\u003e\n\u003cp\u003eThis work was financially supported by the National Natural Science Foundation of China (No.81971360; No.81671431) and the Beijing Municipal Natural Science Foundation (No.7182173).\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eAvailability of data and materials\u003c/h2\u003e\n\u003cp\u003eThe dataset supporting the conclusions of this article is included within the article and its additional files.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAnglesio MS, Kan WY, Madlen M, Horlings HM, Ali B, Janine S,.. . 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Synchronous primary ovarian and endometrial cancers: a population-based assessment of survival. Obstetrics Gynecology. 2009;113(4):783\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWinter WE, Maxwell GL, Tian C, Carlson JW, Ozols RF, Rose PG,.. . Mcguire WP. Prognostic factors for stage III epithelial ovarian cancer: a Gynecologic Oncology Group Study. Journal of Clinical Oncology Official Journal of the American Society of Clinical Oncology. 2007;25(24):3621\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYasuhito T, Yoshihiko Y, Hiroshi S, Hirotaka K, Akira O, Yoriko Y,.. . Toshiyuki S. Modulation of estrogenic action in clear cell carcinoma of the ovary (Review). Experimental Therapeutic Medicine. 2012;3(1):18\u0026ndash;24.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYoshikawa H, Jimbo H, Okada S, Matsumoto K, Taketani Y. Prevalence of Endometriosis in Ovarian Cancer. 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Suppl 1 ).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-ovarian-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jovr","sideBox":"Learn more about [Journal of Ovarian Research](http://ovarianresearch.biomedcentral.com)","snPcode":"13048","submissionUrl":"https://submission.nature.com/new-submission/13048/3","title":"Journal of Ovarian Research","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Ovarian Endometrioid Carcinoma, Ovarian Clear Cell Carcinoma, Endometriosis, Prognosis","lastPublishedDoi":"10.21203/rs.3.rs-115365/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-115365/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjective\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eThis study aimed to identify the clinical characteristics of Chinese patients with ovarian endometrioid carcinoma (EC) and clear cell carcinoma (CCC) and to assess the impact of concurrent endometriosis on this group.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eThe present study reviewed the medical records of patients who received initial treatment and a postoperative pathological diagnosis of EC or CCC at our center in China between 1998 and 2018. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eOf 211 patients, 73 had pure EC, and 91 had pure CCC, and the remaining 47 had mixed cancer. The proportion of EC and CCC remained stable over past 21 years. The proportion of EC declined with aging and the age of EC onset to incline to the young. And the age of CCC onset had two peaks, namely, 36 and 77 years. After review by the pathologist, the number of endometriosis cases found in the pathological section of the analysis increased to 114, accounting for 54% of patients. As the stage progressed, the appearance of endometriosis became increasingly scarce in pathological sections(p=0.001). \u003c/p\u003e\u003cp\u003eCompared with CCC, EC had a higher frequency of concurrent endometrial cancer (independent endometrial lesions) and estrogen and progesterone receptor expression(p=0.000). And more patients were in premenopausal state in EC group(p=0.040). \u003c/p\u003e\u003cp\u003eIn the pure group, multivariate analysis showed that correlation existed between relevance to endometriosis and worse outcomes(p=0.041). In patients with mixed cancer, mixed endometrioid histology was associated with better survival than other subtypes, even with stage III or poorly differentiated tumors(p=0.001). \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eCCC and EC which are common in ovarian cancer patients who have associated with endometriosis have distinct clinicopathological characteristics. Attention should be paid to ovarian cancer patients with a history of endometriosis and those with concurrent endometriosis in pathological sections.\u0026nbsp;\u003c/p\u003e","manuscriptTitle":"Ovarian Endometrioid Carcinoma and Clear Cell Carcinoma: A 21-year Retrospective Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2020-12-01 18:31:10","doi":"10.21203/rs.3.rs-115365/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Minor revision","date":"2021-02-19T00:00:00+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2020-12-22T00:00:00+00:00","index":1,"fulltext":"Recommendation: Reviewer's comments unavailable due to the journal's policy.\n"},{"type":"reviewerAgreed","content":"","date":"2020-12-10T00:00:00+00:00","index":2,"fulltext":""},{"type":"reviewerAgreed","content":"","date":"2020-12-09T00:00:00+00:00","index":1,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2020-11-27T00:00:00+00:00","index":"","fulltext":""},{"type":"submitted","content":"","date":"2020-11-24T00:00:00+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2020-11-24T00:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2020-11-23T23:00:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2020-11-23T23:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-ovarian-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jovr","sideBox":"Learn more about [Journal of Ovarian Research](http://ovarianresearch.biomedcentral.com)","snPcode":"13048","submissionUrl":"https://submission.nature.com/new-submission/13048/3","title":"Journal of Ovarian Research","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"38f41214-fd4b-4519-aa08-b20c9fafce22","owner":[],"postedDate":"December 1st, 2020","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":1236187,"name":"Sexual \u0026 Reproductive Medicine"},{"id":1236188,"name":"Cancer Biology"}],"tags":[],"updatedAt":"2021-05-29T13:37:29+00:00","versionOfRecord":[],"versionCreatedAt":"2020-12-01 18:31:10","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-115365","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-115365","identity":"rs-115365","version":["v1"]},"buildId":"B-jG_2CBjPDmsCi4Wdhf-","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}