The clinical significance of initial symptoms in endometriosis-associated ovarian cancer

The clinical significance of initial symptoms in endometriosis-associated ovarian cancer | 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 Article The clinical significance of initial symptoms in endometriosis-associated ovarian cancer Maaya Ono, Mayu Fukuda, Koji Yamanoi, Asuka Okunomiya, Yusuke Sagae, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2762748/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose Endometriosis is associated with various symptoms, but their severity varies widely from case to case. In this research we investigated the reality of symptoms presented by patients with clinically early-stage endometriosis-associated ovarian cancer (EAOC), and explored the relationship between symptoms and laboratory/imaging findings, pathological findings and prognosis. Methods This was a retrospective case-control study of patients who received initial surgical treatment and were diagnosed with clinically early-stage EAOC including ovarian endometrioid carcinoma (OEC), ovarian clear cell carcinoma (OCCC), and seromucinous borderline tumor (SMBT). Patients with OEC/OCCC diagnosed between 2006 and 2016, and patients with SMBT diagnosed between 2006 and 2020 were included. Chi-square and Kaplan-Meier estimates were used for statistical analyses. Results A total of 107 patients (OEC, n = 31; OCCC, n = 39; SMBT, n = 37) were included. Fifty-nine (55.1%) patients presented with symptoms, and patients with OEC who presented with symptoms was significantly higher than that of others (OEC, 77.4%; OCCC, 43.6%; SMBT, 48.6%). The details of symptoms differed significantly among pathological types (lower abdominal pain/abdominal discomfort/abnormal bleeding, OEC: 11/8/9; OCCC: 6/12/1; SMBT: 15/5/3). Only in the OEC group, symptomatic patients showed significantly higher white blood cell (WBC) count and neutrophil/lymphocyte (N/L) ratio (symptomatic vs. asymptomatic, median: WBC count: 7250 vs. 5000, p = 0.008; N/L ratio: 4.6 vs. 1.7, p = 0.013). None of the asymptomatic patients showed recurrence during follow-up. Conclusion Patients with EAOC show varying symptoms depending on the histological type of the tumor. Laboratory findings underlying symptoms also vary by histopathological type, which may reflect the difference in carcinogenesis process. ovarian clear cell carcinoma ovarian endometrioid carcinoma inflammation symptoms abnormal bleeding Figures Figure 1 What Does This Study Add To The Clinical Work The frequency and details of initial symptoms differ according to several histological types in endometriosis-associated ovarian cancer (EAOC), which may reflect differences in their carcinogenesis process. Even in early-stage EAOC, a detailed elucidation of clinical symptoms may lead to a better understanding of individual cancer biology. Introduction Endometriosis is a common gynecological disorder. In addition, it is a known precursor of malignant tumors. Endometriosis-associated ovarian cancer (EAOC) is one of the particularly ovarian cancer subtypes, which are derived from ovarian endometriosis [ 1 – 3 ]. A large proportion of EAOC cases are clinically International Federation of Gynecology and Obstetrics (FIGO) stage I cases, in which the lesions are confined to the ovaries clinically [ 4 – 6 ]. In general, FIGO stage I ovarian cancer is not considered to have a poor prognosis [ 7 ], however, there are some differences among different histopathological types. Ovarian clear cell carcinoma (OCCC) and ovarian endometrioid carcinoma (OEC) are representative histological subtypes of EAOC[ 8 , 9 ]. Seromucinous borderline tumor (SMBT), which is not strictly a cancer but a borderline malignancy, is also known to arise from endometriosis occasionally [ 10 ]. As SMBT is considered a borderline malignancy, its prognosis is basically good [ 11 ]. On the other hand, OEC and OCCC are more malignant than SMBT. Nevertheless, the omission of postoperative chemotherapy is being considered for some FIGO stage I OEC cases [ 12 ]. As for OCCC, it is particularly known to have a poor prognosis that is associated with platinum resistance[ 9 ]. Aggressive surgical procedures, such as combined resection of the tumor with other organs, may be considered for pathological complete resection of the tumor. It is interesting to note that from the same endometriosis, a variety of tumors can arise that differ greatly in their phenotype. Recently, there are several reports that have examined the differences in terms of genetic alteration among various histologic types of EAOC. Whereas, to our knowledge, few studies have focused on the differences in clinical symptoms due to differences in histology. Ovarian cancer has long been generally believed that it would not present symptoms until advanced stages so far [ 13 ]. However, a recent report indicated that 72% of patients with high-risk early-stage ovarian cancer show physical symptoms at the time of initial presentation[ 14 ]. Originally, endometriosis is associated with various symptoms, such as dysmenorrhea, which sometimes reduces daily quality of life[ 15 ]. However, the severity of symptoms varies widely from case to case, and asymptomatic cases do arise[ 16 ]. Therefore, we hypothesized that symptoms of the patients with EAOC can also vary from patient to patient, which may be reflected in the histological differences. Although several epidemiological studies have indicated that a history of severe menstrual pain[ 17 , 18 ], suggesting the presence of endometriosis, may increase the risk of ovarian cancer, there are few studies that investigated the initial symptoms of patients with EAOC in detail. Thus, the aim of this study was to investigate the clinical significance of the initial symptoms of OEC, OCCC, and SMBT, which are frequently encountered EAOC subtypes, in FIGO stage I cases with lesions confined to the ovaries. In addition, we sought to identify the symptoms that are present at the time of the initial examination and explored the relationship between these symptoms and laboratory, imaging, and pathological findings and prognosis. Materials And Methods Patients This was a case-control study of patients with OEC, OCCC, and SMBT, who underwent initial treatment at our institution. For OEC and OCCC, patients with a preoperative FIGO[ 19 ] stage I disease who were initially treated between 2006 and 2016 were included. For SMBT, we included patients with a preoperative FIGO stage I disease who received initial treatment between 2006 and 2020. Evaluation of clinical symptoms and outcomes Clinical data were extracted from the patients’ medical records and collected through in-person interview questionnaires. First, we investigated whether the patients reported symptoms or not. If they did, we investigated the details of the symptoms reported and categorized them into several groups according to frequency. Thereafter, we examined the correlation between the symptoms, the clinical course of the disease, and the laboratory and imaging findings of the patients. Information on clinical, laboratory, and imaging findings extracted from the patients’ medical records included age at the time of initial treatment, white blood cell (WBC) count in the peripheral blood immediately before initial treatment, neutrophil/lymphocyte ratio (N/L-R), serum CA125 level, and maximum tumor diameter. The CA125 values were log-transformed (log-CA125) and used for analysis. Maximum tumor diameter was measured using imaging findings. All patients underwent surgical treatment, and FIGO stage, assigned based on intraoperative and pathological findings, was evaluated as well. Tumor progression was classified into two groups: the capsuled group (C group; FIGO stages IA, IB, and IC1), which comprised of patients whose tumors had not reached the ovarian serosa at the start of surgery, and the un-capsuled group (un-C group; FIGO stages IC2, IC3, and IIIA1), which included patients whose tumors had progressed beyond the ovarian surface. Data regarding recurrence and death from the primary disease were also extracted and analyzed. Statistical analysis The differences in continuous and categorical variables between two groups were compared using the unpaired t-test and Fisher's exact test or chi-square test, respectively. The differences in continuous and categorical variables among more than three groups were compared using one-way analysis of variance and Fisher's exact test, respectively. When significant differences were observed between the groups, post-hoc pairwise comparisons were performed using the t-test with Bonferroni correction. P < 0.05 was considered statistically significant in each analysis, except for the variables analyzed using Bonferroni correction. Kaplan-Meier survival plots based on presenting symptoms were calculated and compared using log-rank test. All statistical analyses were performed using PRISM version 9.0 (GraphPad Software, San Diego, CA, USA). Results Symptoms of stage I endometriosis-associated ovarian cancer A total of 107 patients with EAOC were included in this study. Of these, 31 patients had OEC, 39 had OCCC, and 37 had SMBT. The age distribution of the patients according to histological type, FIGO classification based on pathological findings, and the presence of endometrial disorders are shown in Table 1 . Regarding patients’ symptoms, 59 of the 107 patients experienced at least one symptom. In the remaining 48 patients, OEC, OCCC, or SMBT were detected incidentally or during follow-up of endometriosis. A detailed review of the 59 patients who showed symptoms revealed that the symptoms could be divided into three categories: abdominal pain, abdominal discomfort (fullness or increased abdominal girth), and abnormal bleeding. Abdominal pain was the most common symptom (32 patients), followed by abdominal discomfort (25 patients) and abnormal bleeding (13 patients). Forty-eight of the 59 patients had only one of these symptoms, whereas 11 patients had multiple symptoms (Table 2 A). OEC OCCC SMBT Table 1 Demographic and pathological characteristics of participants Number 31 39 37 Age 50.0(41.0–58.0) 52.0(44.0–64.0) 42.0(34.5–52.5) FIGO-stage IA 8 15 30 IB 1 0 2 IC1 13 13 5 IC2 5 6 0 IC3 4 4 0 IIIA1 0 1 0 Neoplasm in Endometrium 10 0 0 Num Distribution (%) 95%CI* Table 2 The analyses about the frequency of symptoms and their background The frequency of the presence of symptoms and its details No. of symptoms 0 (No symptoms) 48 44.9 35–55 1 (1 symptom) 48 44.9 35–55 More than 1 (multiple symptoms) 11 10.3 5–18 Symptom description Abdominal pain 32 29.9 21–40 Abdominal discomfort 25 23.4 16–33 Abnormal bleeding 13 12.1 7–20 *Calculated by Clopper-Pearson exact method Symptoms were not statistically associated with age; however, they were associated with histological subtype. Presentation of symptoms was most common in the OEC group, with 24 (77.4%) of the 31 patients presenting with any of the three above-mentioned symptoms. Eighteen (48.6%) of the 37 patients in the SMBT group presented with symptoms, whereas 17 (43.6%) of the 39 patients in the OCCC group showed symptoms (Table 2 B). Analysis of the symptoms showed that lower abdominal pain was the most common symptom in the OEC group (11 patients). However, nine patients in the OEC group also presented with abnormal bleeding, whereas eight patients reported lower abdominal discomfort, indicating that the frequency of each symptom in the OEC group was almost equal. In the OCCC group, the most common symptom was lower abdominal discomfort (12 patients), followed by lower abdominal pain (six patients) and abnormal bleeding (one patient). In the SMBT group, the most common symptom was lower abdominal pain (15 patients), followed by lower abdominal discomfort (five patients) and abdominal bleeding (three patients). There was a significant difference in the distribution of symptoms among the three groups (Table 2 C). The OEC group showed an even distribution of symptoms. Contrastingly, the OCCC group showed a tendency toward lower abdominal discomfort, whereas the SMBT group showed a tendency toward lower abdominal pain. Differences in physical symptoms among patients with stage I OEC, OCCC, and SMBT We further examined the details of the symptoms of patients in each disease group (Figure). For this analysis, the patients were divided into two age groups: <50 years old and ≥ 50 years old. The results showed that in the OEC group, 11 of the 15 patients aged < 50 years and 13 of the 16 patients aged ≥ 50 years experienced some symptoms. There was no difference in the frequency of symptoms, however, there were differences in the symptom distribution between the two age groups. Patients younger than 50 years mainly reported a single symptom, with lower abdominal pain being the most common symptom (eight patients), followed by lower abdominal discomfort (four patients) and abnormal bleeding (two patients). On the other hand, patients older than 50 years most frequently reported abnormal bleeding (seven patients), followed by lower abdominal discomfort (four patients) and abdominal pain (three patients). In the OCCC group, lower abdominal discomfort was the most common complaint in both the < 50 years and ≥ 50 years age groups. However, the frequency of symptoms differed significantly between the two age groups. Only 4 of 17 patients aged < 50 years presented symptoms, while 13 of 22 patients aged ≥ 50 years presented with symptoms. The SMBT group showed the highest frequency of complaints of lower abdominal pain for those both younger and older than 50 years. However, 15 of the 26 patients aged < 50 years presented with symptoms, whereas only three of 11 patients aged ≥ 50 years showed symptoms. The OEC, OCCC, and SMBT groups differed in terms of the frequency of symptoms, age, and distribution of symptoms. The clinical significance of physical symptoms of OEC, OCCC, and SMBT The correlation between the presence of symptoms and laboratory, imaging, and pathological findings for each histologic subtype of EAOC was analyzed. The results are presented in Table 3 . In the OEC group, symptomatic patients showed significantly higher WBC count, N/L-R, and log-CA125 than asymptomatic patients (symptomatic vs. asymptomatic [median]: WBC count: 7.25 vs. 5.00, p = 0.008; N/L-R: 4.6 vs. 1.7, p = 0.013; log-CA125: 8.8 vs. 5.8, p = 0.0014, respectively, Table 3 A). Symptomatic patients tended to show slightly larger maximum tumor diameter than asymptomatic patients; however, the difference was not significant (median: 11.0 cm vs. 6.4 cm for symptomatic and asymptomatic patients, respectively; p = 0.15, Table 3 A). Regarding tumor progression, more symptomatic patients (eight of 24) than asymptomatic patients (one of seven) were in the un-C group; however, this difference was not significant (p = 0.64). The symptomatic patients were divided into an abnormal bleeding group and a non-abnormal bleeding group (lower abdominal pain or lower abdominal discomfort) for further analysis (Supplementary Table). The results showed that there was no difference between the abnormal and non-abnormal bleeding groups. Regarding the frequency of endometrial disorders, four of nine patients in the abnormal bleeding group and in five of 15 patients in the non-abnormal bleeding group had endometrial disorders. In the OCCC group, there were no differences in WBC count or N/L-R between symptomatic and asymptomatic patients (symptomatic vs. asymptomatic [median]: WBC count: 6.80 vs. 5.88, p = 0.17; N/L-R: 2.5 vs. 2.4, p = 0.23, respectively, Table 3 B). However, the symptomatic patients showed significantly higher log-CA125 and larger maximum tumor diameter than asymptomatic patients (symptomatic vs. asymptomatic [median]: log-CA125: 5.3 vs. 4.3, p = 0.033; maximum tumor diameter: 15.0 vs. 7.9, p = 0.0013; respectively, Table 3 B). Regarding tumor progression, nine of 17 symptomatic patients and two of 22 asymptomatic patients were in the un-C group. The difference in the frequency of tumor progression between symptomatic and asymptomatic patients was significant (p = 0.0098, Table 3 B). In the SMBT group, the only significant difference between symptomatic and asymptomatic patients was maximum tumor diameter (symptomatic vs. asymptomatic [median]: 9.7 vs. 4.9, p = 0.0011, Table 3 C). As all patients in the SMBT group had stage IC1 disease or lower, the presence or absence of intraoperative tumor rupture was examined; however, there was no significant difference in the presence or absence of intraoperative tumor rupture between the symptomatic and asymptomatic patients (1 of 18 symptomatic patients vs. 4 of 19 asymptomatic patients, p = 0.17, Table 3 C). Then we examined whether the presence or absence of symptoms was a predictor of poor prognosis in OEC and OCCC. The results showed that all asymptomatic patients in both OEC and OCCC group survived without recurrence (Supplementary Figure). Three of 24 symptomatic patients with OEC and four of 17 symptomatic patients with OCCC died of the disease after recurrence. Most of deceased cases were un-capsule status, however, one of deceased cases in OCCC group was pathologically confirmed to have stage IA disease after systematic lymph node dissection was performed (Supplementary Figure). Discussion In this study, we examined the presence and details of physical symptoms at the time of initial diagnosis of EAOC, which is often diagnosed in patients with diseases confined to the ovary. The results showed that among patients with EAOCs, those with OEC presented with symptoms most frequently (77%). One reason for this is that the symptoms presented by the patients with OEC were more diverse than those presented by patients with OCCC and SMBT. Especially, abnormal bleeding was the most common initial symptom in older patients with OEC. Postmenopausal patients are thought to be more likely to notice abnormal bleeding, even in small amounts, which may have resulted in a higher incidence of initial symptoms of patients with OEC. The fact that abnormal bleeding was particularly common among patients with OEC in this study is a prominent finding. Galina L, et al. reported that patients with endometrioid carcinoma were three times more likely to present abnormal bleeding compared to patients with serous carcinoma [ 20 ]. Lurie G, et al. also reported that patient with localized endometrioid carcinoma were more likely to present abnormal bleeding compared to patients with localized clear cell carcinoma [ 21 ]. In cases of a suspected ovarian malignancy with a background of endometriosis, OEC should be considered if the patient presents with abnormal bleeding. Several studies have demonstrated that when endometriosis is present, synchronous tumors often develop in the endometrium and ovaries, with endometrioid carcinoma being the most common histological type[ 1 , 22 ]. In the present study, endometrial disorders were detected in 10 of 31 patients with OEC but not in patients with OCCC and SMBT, which may be one cause of abnormal bleeding in patients with OEC. However, not all cases of abnormal bleeding had endometrial disorders, suggesting the possibility of other reasons. In this study, we further analyzed details of the symptoms presented by patients with OEC, OCCC, and SMBT. We found that symptomatic patients with OCCC and SMBT had significantly larger tumors than asymptomatic patients, whereas there was no significant difference in tumor size between symptomatic and asymptomatic patients with OEC. John KC, et al. reported that approximately 72% of patients with early-stage high-grade tumors, including OCCC but not OEC, confined to the ovary were symptomatic, and their symptoms were associated with tumor size[ 14 ]. The results of the present study are comparable to these findings. For OEC, however, the correlation between the presence of symptoms and tumor size was not as strong as that for OCCC or SMBT. Instead, WBC count and N/L-R were strongly associated with the absence of any symptoms, including abnormal bleeding, in patients with OEC. The elevation of both WBC count and N/L-R in patients with OEC suggests a correlation between inflammation and a variety of their physical symptoms including abdominal pain, abdominal discomfort and abnormal bleeding. We speculate that these differences in symptom background may reflect differences in the nature of the tumors. In recent years, research on genetic alterations that occur in cancer cells has progressed rapidly, and several genetic pathways that are characteristic of SMBT, OCCC, and OEC have been reported. OEC has been reported to be associated with many genetic changes that are strongly correlated with inflammation[ 23 , 24 ]. Considering the strong correlation between elevated WBC count and N/L-R and the presence of physical symptoms in patients with OEC, it is possible that a persistent inflammatory state is closely related to the development of OEC and presence of symptoms. The various physical symptoms and high frequencies associated with OEC may reflect a persistent inflammatory response between ectopic endometrial tissue and the surrounding tissue, which is also a factor in carcinogenesis. Regarding OCCC, several studies have demonstrated that the tumor is associated with specific oncogenic alterations, such as strong involvement of HNF1B and the SWI/SNF complex, including ARID1A[ 25 ]. For SMBT, KRAS, a known oncogene, is known to be involved in almost all cases of SMBT[ 26 ]. Considering that in the present study, the frequency of symptoms among patients with OCCC and SMBT increased with increasing tumor size, it is likely that patients with OCCC and SMBT are symptomatic only when malignant tumors grow sufficiently as a result of signal changes, rather than being symptomatic as a result of interactions in the microenvironment. Evaluation of the prognostic value of the presence of symptoms in the present study revealed that all asymptomatic patients with OEC and OCCC survived without recurrence, whereas all patients who showed recurrence and died of the disease presented with symptoms. Although tumor progression rather than symptomatology seems to be a major factor in their poor prognoses, some reported that prediagnosis high inflammation associated with decreased ovarian cancer survival, which may be compatible with our results[ 27 , 28 ]. The presence of symptoms may be a prognostic factor; however, the bias that asymptomatic cases receive early treatment cannot be denied. Thus, further studies are needed to confirm whether the presence of symptoms is a prognostic factor for OCCC/OEC. In conclusion, approximately 55% of patients with early-stage EAOC in this study presented with physical symptoms. The frequency and characteristics of these symptoms varied widely according to the histological type of the tumor, which may reflect the different carcinogenesis mechanisms of OEC, OCCC and SMBT. Patients with clinically early-stage OEC and OCCC without physical symptoms may have excellent prognosis. Thus, regular long-term regular checkups for patients with endometriosis for EAOC identification before they become symptomatic may lead to an excellent prognosis. Declarations Funding The authors declare that no funds, grants, or other support were received during the preparation of this manuscript. Competing Interests The authors have no relevant financial or non-financial interests to disclose. Author Contributions All authors contributed to the study conception and design. Data collection and analysis were performed by Maaya Ono, Mayu Fukuda and Koji Yamanoi. The first draft of the manuscript was written by Maaya Ono, Mayu Fukuda and Koji Yamanoi and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Ethics approval and Consent to participate This study was approved by the Kyoto University Graduate School and Faculty of Medicine Ethics Committee (reference number G531) and conforms to the Declaration of Helsinki. Informed consent was obtained from all participants via an opt-in approach (wherein participants signed a printed informed consent document) or an opt-out approach (wherein participants were informed about the study through the website). 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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-2762748","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":191818876,"identity":"6d437336-206d-4f7a-9f44-88d4e9f9b369","order_by":0,"name":"Maaya Ono","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Maaya","middleName":"","lastName":"Ono","suffix":""},{"id":191818877,"identity":"70e41811-363d-43b9-8adc-c25dc2be6068","order_by":1,"name":"Mayu Fukuda","email":"","orcid":"https://orcid.org/0009-0002-9703-8680","institution":"Kyoto University Hospital: Kyoto Daigaku Igakubu Fuzoku Byoin","correspondingAuthor":false,"prefix":"","firstName":"Mayu","middleName":"","lastName":"Fukuda","suffix":""},{"id":191818878,"identity":"845551b7-a037-4749-a9e8-e19ac3c482c3","order_by":2,"name":"Koji Yamanoi","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0002-1240-5422","institution":"","correspondingAuthor":true,"prefix":"","firstName":"Koji","middleName":"","lastName":"Yamanoi","suffix":""},{"id":191818879,"identity":"dfaec2a7-13ef-4986-a6ca-c3016a39fc30","order_by":3,"name":"Asuka Okunomiya","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Asuka","middleName":"","lastName":"Okunomiya","suffix":""},{"id":191818880,"identity":"b37b8b01-962b-41a8-870e-cbc9c23079bc","order_by":4,"name":"Yusuke Sagae","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Yusuke","middleName":"","lastName":"Sagae","suffix":""},{"id":191818881,"identity":"ae950644-4452-47a3-a669-589a08ffd6c4","order_by":5,"name":"Masumi Sunada","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Masumi","middleName":"","lastName":"Sunada","suffix":""},{"id":191818882,"identity":"63c665ef-16d1-48df-8bf7-8d23d85af763","order_by":6,"name":"Sachiko Kitamura","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Sachiko","middleName":"","lastName":"Kitamura","suffix":""},{"id":191818883,"identity":"d22cabf4-427f-48ea-b77a-991c838e9ebe","order_by":7,"name":"Mana Taki","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Mana","middleName":"","lastName":"Taki","suffix":""},{"id":191818884,"identity":"20d2162a-422b-497e-87d0-8ee447d29815","order_by":8,"name":"Yoko Furutake","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Yoko","middleName":"","lastName":"Furutake","suffix":""},{"id":191818885,"identity":"f4b4c001-dd49-4baa-b0bf-2f276d4e4386","order_by":9,"name":"Akihito Horie","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Akihito","middleName":"","lastName":"Horie","suffix":""},{"id":191818886,"identity":"52736803-ddeb-4ad3-95fd-bafcc1bb1d1d","order_by":10,"name":"Ken Yamaguchi","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Ken","middleName":"","lastName":"Yamaguchi","suffix":""},{"id":191818887,"identity":"818e4674-67a3-4205-b92c-8fbbf85c8ddf","order_by":11,"name":"Junzo Hamanishi","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Junzo","middleName":"","lastName":"Hamanishi","suffix":""},{"id":191818888,"identity":"eedab956-7e84-4f03-9599-e07fe285f6be","order_by":12,"name":"Masaki Mandai","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Masaki","middleName":"","lastName":"Mandai","suffix":""}],"badges":[],"createdAt":"2023-03-31 18:55:29","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2762748/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2762748/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":35962342,"identity":"a7b5dbd5-4a18-46d7-9826-75feecd05ee8","added_by":"auto","created_at":"2023-04-18 21:51:25","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":73006,"visible":true,"origin":"","legend":"\u003cp\u003eDistribution of clinical symptoms in each case.\u003c/p\u003e\n\u003cp\u003eOEC: ovarian endometrioid carcinoma, OCCC: ovarian clear cell carcinoma, SMBT: seromucinous borderline tumor.\u003c/p\u003e","description":"","filename":"Figure.png","url":"https://assets-eu.researchsquare.com/files/rs-2762748/v1/38d02c0f23150c1bf4691ecf.png"},{"id":36626875,"identity":"8c569ae4-5c78-4441-99d9-5db50161236b","added_by":"auto","created_at":"2023-05-04 20:19:20","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":417273,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2762748/v1/bfe7ab20-33ac-4a11-8dbe-2175b1f51a9e.pdf"}],"financialInterests":"","formattedTitle":"\u003cp\u003eThe clinical significance of initial symptoms in endometriosis-associated ovarian cancer\u003c/p\u003e","fulltext":[{"header":"What Does This Study Add To The Clinical Work","content":"\u003cp\u003eThe frequency and details of initial symptoms differ according to several histological types in endometriosis-associated ovarian cancer (EAOC), which may reflect differences in their carcinogenesis process. Even in early-stage EAOC, a detailed elucidation of clinical symptoms may lead to a better understanding of individual cancer biology.\u003c/p\u003e"},{"header":"Introduction","content":"\u003cp\u003eEndometriosis is a common gynecological disorder. In addition, it is a known precursor of malignant tumors. Endometriosis-associated ovarian cancer (EAOC) is one of the particularly ovarian cancer subtypes, which are derived from ovarian endometriosis [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. A large proportion of EAOC cases are clinically International Federation of Gynecology and Obstetrics (FIGO) stage I cases, in which the lesions are confined to the ovaries clinically [\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. In general, FIGO stage I ovarian cancer is not considered to have a poor prognosis [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], however, there are some differences among different histopathological types. Ovarian clear cell carcinoma (OCCC) and ovarian endometrioid carcinoma (OEC) are representative histological subtypes of EAOC[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Seromucinous borderline tumor (SMBT), which is not strictly a cancer but a borderline malignancy, is also known to arise from endometriosis occasionally [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAs SMBT is considered a borderline malignancy, its prognosis is basically good [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. On the other hand, OEC and OCCC are more malignant than SMBT. Nevertheless, the omission of postoperative chemotherapy is being considered for some FIGO stage I OEC cases [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. As for OCCC, it is particularly known to have a poor prognosis that is associated with platinum resistance[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Aggressive surgical procedures, such as combined resection of the tumor with other organs, may be considered for pathological complete resection of the tumor. It is interesting to note that from the same endometriosis, a variety of tumors can arise that differ greatly in their phenotype.\u003c/p\u003e \u003cp\u003eRecently, there are several reports that have examined the differences in terms of genetic alteration among various histologic types of EAOC. Whereas, to our knowledge, few studies have focused on the differences in clinical symptoms due to differences in histology. Ovarian cancer has long been generally believed that it would not present symptoms until advanced stages so far [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. However, a recent report indicated that 72% of patients with high-risk early-stage ovarian cancer show physical symptoms at the time of initial presentation[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Originally, endometriosis is associated with various symptoms, such as dysmenorrhea, which sometimes reduces daily quality of life[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. However, the severity of symptoms varies widely from case to case, and asymptomatic cases do arise[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Therefore, we hypothesized that symptoms of the patients with EAOC can also vary from patient to patient, which may be reflected in the histological differences. Although several epidemiological studies have indicated that a history of severe menstrual pain[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], suggesting the presence of endometriosis, may increase the risk of ovarian cancer, there are few studies that investigated the initial symptoms of patients with EAOC in detail.\u003c/p\u003e \u003cp\u003eThus, the aim of this study was to investigate the clinical significance of the initial symptoms of OEC, OCCC, and SMBT, which are frequently encountered EAOC subtypes, in FIGO stage I cases with lesions confined to the ovaries. In addition, we sought to identify the symptoms that are present at the time of the initial examination and explored the relationship between these symptoms and laboratory, imaging, and pathological findings and prognosis.\u003c/p\u003e"},{"header":"Materials And Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cp\u003eThis was a case-control study of patients with OEC, OCCC, and SMBT, who underwent initial treatment at our institution. For OEC and OCCC, patients with a preoperative FIGO[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] stage I disease who were initially treated between 2006 and 2016 were included. For SMBT, we included patients with a preoperative FIGO stage I disease who received initial treatment between 2006 and 2020.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eEvaluation of clinical symptoms and outcomes\u003c/h2\u003e \u003cp\u003eClinical data were extracted from the patients\u0026rsquo; medical records and collected through in-person interview questionnaires. First, we investigated whether the patients reported symptoms or not. If they did, we investigated the details of the symptoms reported and categorized them into several groups according to frequency. Thereafter, we examined the correlation between the symptoms, the clinical course of the disease, and the laboratory and imaging findings of the patients.\u003c/p\u003e \u003cp\u003eInformation on clinical, laboratory, and imaging findings extracted from the patients\u0026rsquo; medical records included age at the time of initial treatment, white blood cell (WBC) count in the peripheral blood immediately before initial treatment, neutrophil/lymphocyte ratio (N/L-R), serum CA125 level, and maximum tumor diameter. The CA125 values were log-transformed (log-CA125) and used for analysis. Maximum tumor diameter was measured using imaging findings. All patients underwent surgical treatment, and FIGO stage, assigned based on intraoperative and pathological findings, was evaluated as well. Tumor progression was classified into two groups: the capsuled group (C group; FIGO stages IA, IB, and IC1), which comprised of patients whose tumors had not reached the ovarian serosa at the start of surgery, and the un-capsuled group (un-C group; FIGO stages IC2, IC3, and IIIA1), which included patients whose tumors had progressed beyond the ovarian surface. Data regarding recurrence and death from the primary disease were also extracted and analyzed.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eThe differences in continuous and categorical variables between two groups were compared using the unpaired t-test and Fisher's exact test or chi-square test, respectively. The differences in continuous and categorical variables among more than three groups were compared using one-way analysis of variance and Fisher's exact test, respectively. When significant differences were observed between the groups, post-hoc pairwise comparisons were performed using the t-test with Bonferroni correction. P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant in each analysis, except for the variables analyzed using Bonferroni correction. Kaplan-Meier survival plots based on presenting symptoms were calculated and compared using log-rank test. All statistical analyses were performed using PRISM version 9.0 (GraphPad Software, San Diego, CA, USA).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv class=\"Section2\" id=\"Sec7\"\u003e\n \u003ch2\u003eSymptoms of stage I endometriosis-associated ovarian cancer\u003c/h2\u003e\n \u003cp\u003eA total of 107 patients with EAOC were included in this study. Of these, 31 patients had OEC, 39 had OCCC, and 37 had SMBT. The age distribution of the patients according to histological type, FIGO classification based on pathological findings, and the presence of endometrial disorders are shown in Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. Regarding patients\u0026rsquo; symptoms, 59 of the 107 patients experienced at least one symptom. In the remaining 48 patients, OEC, OCCC, or SMBT were detected incidentally or during follow-up of endometriosis. A detailed review of the 59 patients who showed symptoms revealed that the symptoms could be divided into three categories: abdominal pain, abdominal discomfort (fullness or increased abdominal girth), and abnormal bleeding. Abdominal pain was the most common symptom (32 patients), followed by abdominal discomfort (25 patients) and abnormal bleeding (13 patients). Forty-eight of the 59 patients had only one of these symptoms, whereas 11 patients had multiple symptoms (Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eA).\u0026nbsp;\u003c/p\u003e\u0026nbsp;\u003ctable border=\"1\" id=\"Tab1\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eOEC\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eOCCC\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSMBT\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eDemographic and pathological characteristics of participants\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ctbody\u003e\u003c/tbody\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNumber\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e37\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e50.0(41.0\u0026ndash;58.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e52.0(44.0\u0026ndash;64.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e42.0(34.5\u0026ndash;52.5)\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 \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \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\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIC1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIC2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIC3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIIIA1\u003c/p\u003e\n \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\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNeoplasm in Endometrium\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \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\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003ctable border=\"1\" id=\"Tab2\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eNum\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eDistribution (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e95%CI*\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eThe analyses about the frequency of symptoms and their background The frequency of the presence of symptoms and its details\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo. of 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 \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (No symptoms)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e44.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e35\u0026ndash;55\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (1 symptom)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e44.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e35\u0026ndash;55\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMore than 1 (multiple symptoms)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e10.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5\u0026ndash;18\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSymptom description\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 \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAbdominal pain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e29.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e21\u0026ndash;40\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAbdominal discomfort\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e23.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16\u0026ndash;33\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAbnormal bleeding\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e12.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7\u0026ndash;20\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\"\u003e*Calculated by Clopper-Pearson exact method\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e\u003cimg src=\"https://myfiles.space/user_files/122228_c8a1650c59388082/122228_custom_files/img1681765332.png\"\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003eSymptoms were not statistically associated with age; however, they were associated with histological subtype. Presentation of symptoms was most common in the OEC group, with 24 (77.4%) of the 31 patients presenting with any of the three above-mentioned symptoms. Eighteen (48.6%) of the 37 patients in the SMBT group presented with symptoms, whereas 17 (43.6%) of the 39 patients in the OCCC group showed symptoms (Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eB). Analysis of the symptoms showed that lower abdominal pain was the most common symptom in the OEC group (11 patients). However, nine patients in the OEC group also presented with abnormal bleeding, whereas eight patients reported lower abdominal discomfort, indicating that the frequency of each symptom in the OEC group was almost equal. In the OCCC group, the most common symptom was lower abdominal discomfort (12 patients), followed by lower abdominal pain (six patients) and abnormal bleeding (one patient). In the SMBT group, the most common symptom was lower abdominal pain (15 patients), followed by lower abdominal discomfort (five patients) and abdominal bleeding (three patients). There was a significant difference in the distribution of symptoms among the three groups (Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eC). The OEC group showed an even distribution of symptoms. Contrastingly, the OCCC group showed a tendency toward lower abdominal discomfort, whereas the SMBT group showed a tendency toward lower abdominal pain.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv class=\"Section2\" id=\"Sec8\"\u003e\n \u003ch2\u003eDifferences in physical symptoms among patients with stage I OEC, OCCC, and SMBT\u003c/h2\u003e\n \u003cp\u003eWe further examined the details of the symptoms of patients in each disease group (Figure). For this analysis, the patients were divided into two age groups: \u0026lt;50 years old and \u0026ge;\u0026thinsp;50 years old. The results showed that in the OEC group, 11 of the 15 patients aged\u0026thinsp;\u0026lt;\u0026thinsp;50 years and 13 of the 16 patients aged\u0026thinsp;\u0026ge;\u0026thinsp;50 years experienced some symptoms. There was no difference in the frequency of symptoms, however, there were differences in the symptom distribution between the two age groups. Patients younger than 50 years mainly reported a single symptom, with lower abdominal pain being the most common symptom (eight patients), followed by lower abdominal discomfort (four patients) and abnormal bleeding (two patients). On the other hand, patients older than 50 years most frequently reported abnormal bleeding (seven patients), followed by lower abdominal discomfort (four patients) and abdominal pain (three patients). In the OCCC group, lower abdominal discomfort was the most common complaint in both the \u0026lt;\u0026thinsp;50 years and \u0026ge;\u0026thinsp;50 years age groups. However, the frequency of symptoms differed significantly between the two age groups. Only 4 of 17 patients aged\u0026thinsp;\u0026lt;\u0026thinsp;50 years presented symptoms, while 13 of 22 patients aged\u0026thinsp;\u0026ge;\u0026thinsp;50 years presented with symptoms. The SMBT group showed the highest frequency of complaints of lower abdominal pain for those both younger and older than 50 years. However, 15 of the 26 patients aged\u0026thinsp;\u0026lt;\u0026thinsp;50 years presented with symptoms, whereas only three of 11 patients aged\u0026thinsp;\u0026ge;\u0026thinsp;50 years showed symptoms. The OEC, OCCC, and SMBT groups differed in terms of the frequency of symptoms, age, and distribution of symptoms.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv class=\"Section2\" id=\"Sec9\"\u003e\n \u003ch2\u003eThe clinical significance of physical symptoms of OEC, OCCC, and SMBT\u003c/h2\u003e\n \u003cp\u003eThe correlation between the presence of symptoms and laboratory, imaging, and pathological findings for each histologic subtype of EAOC was analyzed. The results are presented in Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e. In the OEC group, symptomatic patients showed significantly higher WBC count, N/L-R, and log-CA125 than asymptomatic patients (symptomatic vs. asymptomatic [median]: WBC count: 7.25 vs. 5.00, p\u0026thinsp;=\u0026thinsp;0.008; N/L-R: 4.6 vs. 1.7, p\u0026thinsp;=\u0026thinsp;0.013; log-CA125: 8.8 vs. 5.8, p\u0026thinsp;=\u0026thinsp;0.0014, respectively, Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eA). Symptomatic patients tended to show slightly larger maximum tumor diameter than asymptomatic patients; however, the difference was not significant (median: 11.0 cm vs. 6.4 cm for symptomatic and asymptomatic patients, respectively; p\u0026thinsp;=\u0026thinsp;0.15, Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eA). Regarding tumor progression, more symptomatic patients (eight of 24) than asymptomatic patients (one of seven) were in the un-C group; however, this difference was not significant (p\u0026thinsp;=\u0026thinsp;0.64). The symptomatic patients were divided into an abnormal bleeding group and a non-abnormal bleeding group (lower abdominal pain or lower abdominal discomfort) for further analysis (Supplementary Table). The results showed that there was no difference between the abnormal and non-abnormal bleeding groups. Regarding the frequency of endometrial disorders, four of nine patients in the abnormal bleeding group and in five of 15 patients in the non-abnormal bleeding group had endometrial disorders.\u003c/p\u003e\n \u003cp\u003e\u003cimg src=\"https://myfiles.space/user_files/122228_c8a1650c59388082/122228_custom_files/img1681765410.png\"\u003e\u003c/p\u003e\n \u003cp\u003eIn the OCCC group, there were no differences in WBC count or N/L-R between symptomatic and asymptomatic patients (symptomatic vs. asymptomatic [median]: WBC count: 6.80 vs. 5.88, p\u0026thinsp;=\u0026thinsp;0.17; N/L-R: 2.5 vs. 2.4, p\u0026thinsp;=\u0026thinsp;0.23, respectively, Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eB). However, the symptomatic patients showed significantly higher log-CA125 and larger maximum tumor diameter than asymptomatic patients (symptomatic vs. asymptomatic [median]: log-CA125: 5.3 vs. 4.3, p\u0026thinsp;=\u0026thinsp;0.033; maximum tumor diameter: 15.0 vs. 7.9, p\u0026thinsp;=\u0026thinsp;0.0013; respectively, Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eB). Regarding tumor progression, nine of 17 symptomatic patients and two of 22 asymptomatic patients were in the un-C group. The difference in the frequency of tumor progression between symptomatic and asymptomatic patients was significant (p\u0026thinsp;=\u0026thinsp;0.0098, Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eB).\u003c/p\u003e\n \u003cp\u003eIn the SMBT group, the only significant difference between symptomatic and asymptomatic patients was maximum tumor diameter (symptomatic vs. asymptomatic [median]: 9.7 vs. 4.9, p\u0026thinsp;=\u0026thinsp;0.0011, Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eC). As all patients in the SMBT group had stage IC1 disease or lower, the presence or absence of intraoperative tumor rupture was examined; however, there was no significant difference in the presence or absence of intraoperative tumor rupture between the symptomatic and asymptomatic patients (1 of 18 symptomatic patients vs. 4 of 19 asymptomatic patients, p\u0026thinsp;=\u0026thinsp;0.17, Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eC).\u003c/p\u003e\n \u003cp\u003eThen we examined whether the presence or absence of symptoms was a predictor of poor prognosis in OEC and OCCC. The results showed that all asymptomatic patients in both OEC and OCCC group survived without recurrence (Supplementary Figure). Three of 24 symptomatic patients with OEC and four of 17 symptomatic patients with OCCC died of the disease after recurrence. Most of deceased cases were un-capsule status, however, one of deceased cases in OCCC group was pathologically confirmed to have stage IA disease after systematic lymph node dissection was performed (Supplementary Figure).\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this study, we examined the presence and details of physical symptoms at the time of initial diagnosis of EAOC, which is often diagnosed in patients with diseases confined to the ovary. The results showed that among patients with EAOCs, those with OEC presented with symptoms most frequently (77%). One reason for this is that the symptoms presented by the patients with OEC were more diverse than those presented by patients with OCCC and SMBT. Especially, abnormal bleeding was the most common initial symptom in older patients with OEC. Postmenopausal patients are thought to be more likely to notice abnormal bleeding, even in small amounts, which may have resulted in a higher incidence of initial symptoms of patients with OEC.\u003c/p\u003e \u003cp\u003eThe fact that abnormal bleeding was particularly common among patients with OEC in this study is a prominent finding. Galina L, et al. reported that patients with endometrioid carcinoma were three times more likely to present abnormal bleeding compared to patients with serous carcinoma [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Lurie G, et al. also reported that patient with localized endometrioid carcinoma were more likely to present abnormal bleeding compared to patients with localized clear cell carcinoma [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. In cases of a suspected ovarian malignancy with a background of endometriosis, OEC should be considered if the patient presents with abnormal bleeding. Several studies have demonstrated that when endometriosis is present, synchronous tumors often develop in the endometrium and ovaries, with endometrioid carcinoma being the most common histological type[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. In the present study, endometrial disorders were detected in 10 of 31 patients with OEC but not in patients with OCCC and SMBT, which may be one cause of abnormal bleeding in patients with OEC. However, not all cases of abnormal bleeding had endometrial disorders, suggesting the possibility of other reasons.\u003c/p\u003e \u003cp\u003eIn this study, we further analyzed details of the symptoms presented by patients with OEC, OCCC, and SMBT. We found that symptomatic patients with OCCC and SMBT had significantly larger tumors than asymptomatic patients, whereas there was no significant difference in tumor size between symptomatic and asymptomatic patients with OEC. John KC, et al. reported that approximately 72% of patients with early-stage high-grade tumors, including OCCC but not OEC, confined to the ovary were symptomatic, and their symptoms were associated with tumor size[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. The results of the present study are comparable to these findings. For OEC, however, the correlation between the presence of symptoms and tumor size was not as strong as that for OCCC or SMBT. Instead, WBC count and N/L-R were strongly associated with the absence of any symptoms, including abnormal bleeding, in patients with OEC. The elevation of both WBC count and N/L-R in patients with OEC suggests a correlation between inflammation and a variety of their physical symptoms including abdominal pain, abdominal discomfort and abnormal bleeding. We speculate that these differences in symptom background may reflect differences in the nature of the tumors.\u003c/p\u003e \u003cp\u003eIn recent years, research on genetic alterations that occur in cancer cells has progressed rapidly, and several genetic pathways that are characteristic of SMBT, OCCC, and OEC have been reported. OEC has been reported to be associated with many genetic changes that are strongly correlated with inflammation[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Considering the strong correlation between elevated WBC count and N/L-R and the presence of physical symptoms in patients with OEC, it is possible that a persistent inflammatory state is closely related to the development of OEC and presence of symptoms. The various physical symptoms and high frequencies associated with OEC may reflect a persistent inflammatory response between ectopic endometrial tissue and the surrounding tissue, which is also a factor in carcinogenesis. Regarding OCCC, several studies have demonstrated that the tumor is associated with specific oncogenic alterations, such as strong involvement of HNF1B and the SWI/SNF complex, including ARID1A[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. For SMBT, KRAS, a known oncogene, is known to be involved in almost all cases of SMBT[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Considering that in the present study, the frequency of symptoms among patients with OCCC and SMBT increased with increasing tumor size, it is likely that patients with OCCC and SMBT are symptomatic only when malignant tumors grow sufficiently as a result of signal changes, rather than being symptomatic as a result of interactions in the microenvironment.\u003c/p\u003e \u003cp\u003eEvaluation of the prognostic value of the presence of symptoms in the present study revealed that all asymptomatic patients with OEC and OCCC survived without recurrence, whereas all patients who showed recurrence and died of the disease presented with symptoms. Although tumor progression rather than symptomatology seems to be a major factor in their poor prognoses, some reported that prediagnosis high inflammation associated with decreased ovarian cancer survival, which may be compatible with our results[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. The presence of symptoms may be a prognostic factor; however, the bias that asymptomatic cases receive early treatment cannot be denied. Thus, further studies are needed to confirm whether the presence of symptoms is a prognostic factor for OCCC/OEC.\u003c/p\u003e \u003cp\u003eIn conclusion, approximately 55% of patients with early-stage EAOC in this study presented with physical symptoms. The frequency and characteristics of these symptoms varied widely according to the histological type of the tumor, which may reflect the different carcinogenesis mechanisms of OEC, OCCC and SMBT. Patients with clinically early-stage OEC and OCCC without physical symptoms may have excellent prognosis. Thus, regular long-term regular checkups for patients with endometriosis for EAOC identification before they become symptomatic may lead to an excellent prognosis.\u003c/p\u003e "},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that no funds, grants, or other support were received during the preparation of this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no relevant financial or non-financial interests to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors contributed to the study conception and design. Data collection and analysis were performed by Maaya Ono, Mayu Fukuda and Koji Yamanoi. The first draft of the manuscript was written by Maaya Ono, Mayu Fukuda and Koji Yamanoi and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and Consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Kyoto University Graduate School and Faculty of Medicine Ethics Committee (reference number G531) and conforms to the Declaration of Helsinki. Informed consent was obtained from all participants via an opt-in approach (wherein participants signed a printed informed consent document) or an opt-out approach (wherein participants were informed about the study through the website).\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eDahiya A, Sebastian A, Thomas A, George R, Thomas V, Peedicayil A (2021) Endometriosis and malignancy: The intriguing relationship. Int J Gynaecol Obstet 155:72-78. https://doi.org/10.1002/ijgo.13585\u003c/li\u003e\n\u003cli\u003eSamartzis EP, Labidi-Galy SI, MoschettaM, Uccello M, Kalaitzopoulos DR, Perez-Fidalgo JA, Boussios S (2020) Endometriosis-associated ovarian carcinomas: insights into pathogenesis, diagnostics, and therapeutic targets-a narrative review. Ann Transl Med 8:1712. https://doi.org/10.21037/atm-20-3022a\u003c/li\u003e\n\u003cli\u003eSo KA, Hong SR, Kim NR, Yang EJ, Shim SH, Lee SJ et al (2021) Association between atypical endometriosis and ovarian malignancies in the real world. J Ovarian Res 14:110. https://doi.org/10.1186/s13048-021-00865-2\u003c/li\u003e\n\u003cli\u003eLi Q, Sun Y, Zhang X, Wang L, Wu W, Wu M et al (2019) Endometriosis-associated ovarian cancer is a single entity with distinct clinicopathological characteristics. 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Obstet Gynecol Sci 63:709-718. https://doi.org/10.5468/ogs.20117\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Supplementary Material","content":"\u003cp\u003eSupplementary Material is not available with this version.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"ovarian clear cell carcinoma, ovarian endometrioid carcinoma, inflammation, symptoms, abnormal bleeding","lastPublishedDoi":"10.21203/rs.3.rs-2762748/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2762748/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003ePurpose\u003c/b\u003e\u003c/p\u003e \u003cp\u003eEndometriosis is associated with various symptoms, but their severity varies widely from case to case. In this research we investigated the reality of symptoms presented by patients with clinically early-stage endometriosis-associated ovarian cancer (EAOC), and explored the relationship between symptoms and laboratory/imaging findings, pathological findings and prognosis.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThis was a retrospective case-control study of patients who received initial surgical treatment and were diagnosed with clinically early-stage EAOC including ovarian endometrioid carcinoma (OEC), ovarian clear cell carcinoma (OCCC), and seromucinous borderline tumor (SMBT). Patients with OEC/OCCC diagnosed between 2006 and 2016, and patients with SMBT diagnosed between 2006 and 2020 were included. Chi-square and Kaplan-Meier estimates were used for statistical analyses.\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults\u003c/b\u003e\u003c/p\u003e \u003cp\u003eA total of 107 patients (OEC, n\u0026thinsp;=\u0026thinsp;31; OCCC, n\u0026thinsp;=\u0026thinsp;39; SMBT, n\u0026thinsp;=\u0026thinsp;37) were included. Fifty-nine (55.1%) patients presented with symptoms, and patients with OEC who presented with symptoms was significantly higher than that of others (OEC, 77.4%; OCCC, 43.6%; SMBT, 48.6%). The details of symptoms differed significantly among pathological types (lower abdominal pain/abdominal discomfort/abnormal bleeding, OEC: 11/8/9; OCCC: 6/12/1; SMBT: 15/5/3). Only in the OEC group, symptomatic patients showed significantly higher white blood cell (WBC) count and neutrophil/lymphocyte (N/L) ratio (symptomatic vs. asymptomatic, median: WBC count: 7250 vs. 5000, p\u0026thinsp;=\u0026thinsp;0.008; N/L ratio: 4.6 vs. 1.7, p\u0026thinsp;=\u0026thinsp;0.013). None of the asymptomatic patients showed recurrence during follow-up.\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusion\u003c/b\u003e\u003c/p\u003e \u003cp\u003ePatients with EAOC show varying symptoms depending on the histological type of the tumor. Laboratory findings underlying symptoms also vary by histopathological type, which may reflect the difference in carcinogenesis process.\u003c/p\u003e","manuscriptTitle":"The clinical significance of initial symptoms in endometriosis-associated ovarian cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-04-18 21:51:20","doi":"10.21203/rs.3.rs-2762748/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"2853c48b-202e-481a-8348-ec484bdb9b4c","owner":[],"postedDate":"April 18th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2023-05-04T20:19:13+00:00","versionOfRecord":[],"versionCreatedAt":"2023-04-18 21:51:20","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-2762748","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2762748","identity":"rs-2762748","version":["v1"]},"buildId":"B-jG_2CBjPDmsCi4Wdhf-","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}