Fertility-sparing treatment for low-grade endometrial stromal sarcoma

Fertility-sparing treatment for low-grade endometrial stromal sarcoma | 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 Fertility-sparing treatment for low-grade endometrial stromal sarcoma Baolin Xu, Yan You, Huanwen Wu, Lei Li This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7098205/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 05 Jan, 2026 Read the published version in European Journal of Medical Research → Version 1 posted 9 You are reading this latest preprint version Abstract Background Little is known about the oncologic results of patients with low-grade endometrial stromal sarcoma (LGESS) with fertility preservation. This study investigated the prognosis of fertility-sparing surgeries and relevant obstetrical outcomes. Methods All eligible patients in the study center were retrospectively reviewed if they consented to surgical treatment for primary LGESS from February 2012 to June 2019 in the study center. Follow-up of fertility and oncologic outcomes wascarried out until June 1, 2020. Results Among 135 patients who underwent surgical therapy for primary uterine LGESS, 21 (15.6%) and 42 (31.1%) underwent fertility-sparing surgery and ovarian preservation, respectively. After a median follow-up of 38.5 (range 5–98) months, differences were detected in the recurrence rates among patients with and without fertility-sparing surgery (47.6% versus 15.8%, p =0.002) or with and without ovarian preservation (42.9% versus 10.8%, p <0.001). Fertility-sparing surgery and ovarian preservation significantly increased the risk of recurrence in the entire cohort (hazard ratio [HR] 3.5 and 5.2, 95% confidence interval [CI] 1.6-7.6 and 2.4-11.3, p =0.002 and <0.001) and in stage I patients (HR 2.6 and 3.1, 95% CI 1.0-6.4 and 1.3-7.4, p =0.041 and 0.011). No factor was found to be associated with increased mortality risk. Among the 9 patients who attempted pregnancy, 7 (77.8%) achieved 8 live births. All three advanced-stage patients who underwentfertility-sparing surgery experienced recurrence without successful conception. Conclusion Fertility-sparing surgery for LGESS results in a significantly increased risk of recurrence but not mortality and has promising results in terms of live births in stage I patients. Low-grade endometrial stromal sarcoma fertility-sparing surgery ovarian preservation recurrence mortality Figures Figure 1 Figure 2 INTRODUCTION Low-grade endometrial stromal sarcoma (LGESS) is a malignant tumor composed of cells resembling stromal cells of the proliferative-phase endometrium, displaying permeative, infiltrative growth into the myometrium and/or Iymphovascular spaces [1]. LGESS represents <1% of all uterine malignancies but is the second most common uterine malignant mesenchymal tumor and has a favorable prognosis [2]. The five-year disease-specific survival rates are 90% for stage I or stage II disease and 50% for stage III or IV disease [3]. Hysterectomy with salpingo-oophorectomy is the standard treatment for LGESS. Ovary-sparing procedures and myomectomy are adverse factors for relapse [4]. However, the age range at diagnosis of LGESS is broad, and many patients are of reproductive age and desire pregnancy. For primary uterine LGESS, the fertility and oncological outcomes of fertility-sparing procedures remain ambiguous since fertility-sparing treatment has been reported only in case reports [5, 6]. In addition, these reports did not compare patients who did not undergo fertility-sparing procedures and had no specific information on subsequent obstetric outcomes. These limitations restrict effective decision-making for young patients who desire fertility preservation after the diagnosis of LGESS, especially early-stage patients. In this retrospective cohort study, we reviewed all LGESS cases diagnosed and treated in the last 7 years at the study center to explore the prognostic role of fertility preservation in these patients. The primary objectives were to explore the disease-free survival (DFS) and overall survival (OS) rates after surgery for LGESS, and the secondary objective was to explore the fertility outcomes of these patients. METHODS Ethical approval The Institutional Review Board of the study center approved this retrospective study (No. SK-1289). All procedures performed in the study involving human participants were in accordance with the ethical standards of the institutional and National Research Committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Study design This was a retrospective cohort study. Patients who were diagnosed with and treated for primary LGESS at the study center from February 2012 to June 2019 were reviewed. Follow-up of fertility and oncologic outcomes was carried out up to June 1, 2020. The pathological diagnoses were reviewed and confirmed by pathologists of this study. The margin status of resected tumors was given special attention. Patients were excluded if they had repeated LGESS, had an ambiguous diagnosis or misdiagnosis of LGESS, or if they did not accept surgical treatment. Detailed epidemiological information, including age at diagnosis, menopausal status, gravidity, parity, and personal and family history of cancer, was collected by reviewing case reports and by interviewing patients via email and/or telephone. Interventions All patients underwent surgical treatment, with or without adjuvant chemotherapy, radiotherapy, and/or hormone therapy. Patients were divided into groups according to surgical entity: those with or without fertility-sparing surgery and those with hysterectomy with or without ovarian preservation. In this study, fertility-sparing surgery involves preservation of the uterus and at least one ovary. Patients who underwent fertility-sparing surgery also had records of regular menstruation in this study after all relevant treatments. Ovarian preservation refers to the preservation of at least one ovary with or without an intact uterus. However, not all patients undergo evaluations of the ovarian reserve after ovarian preservation. Data on surgical treatment, including surgical routes, retroperitoneal lymphadenectomy, and pathological results (FIGO staging, lymphovascular space invasion [LVSI], estrogen and progesterone receptor status, mitotic activity, and metastasis to lymph nodes), were also collected from the case and pathology reports. Ambiguous or missing pathological information was supplemented by pathologists of this study. The same attention was given to the chemotherapy regimens and courses, hormone therapy regimens and courses, and radiotherapy. For patients who undergo pelvic radiotherapy after the diagnosis of LGESS, treatment is not regarded as fertility sparing even if their ovaries are not resected by surgery. Measures Oncologic outcomes consisted of DFS and OS, which were followed up during the study period. All recurrences were confirmed via histological diagnosis via biopsy and/or repeated surgeries. All deaths were confirmed by certification of death. The fertility outcomes consisted of conception rates and birth rates in the same follow-up periods. For patients who underwent fertility-sparing surgery, the trend in pregnancy attempts and reasons for not attempting pregnancy were confirmed by telephone and/or outpatient clinical interviews. Data on the interval from last treatment to conception, conception methods, pregnancy weeks and complications were recorded in detail. Statistics Comparisons of continuous variables were conducted with parametric methods if assumptions of normal distribution were confirmed. Nonnormally distributed variables and categorical data were compared between various groups with and without fertility-sparing surgery or ovarian preservation via nonparametric tests. Survival curves were generated via the Kaplan‒Meier method, and proportional hazards models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (95% CIs) for the effects of fertility-sparing surgery and ovarian preservation on DFS and OS. Unless otherwise stated, all analyses were performed with a two-sided significance level of 0.05 and were conducted with the use of the software Statistical Product and Service Solutions (SPSS) Statistics 20.0 (IBM Corporation, Armonk, NY, USA). RESULTS Patient characteristics The flow diagram is presented in Figure 1 . In total, 143 eligible patients with a definite diagnosis of LGESS were reviewed, and 135 patients with primary uterine LGESS were included in the study. The raw data of this study are shown in Supplementary Table S1 .One hundred and two (75.6%) patients had stage I disease. Hormone treatment was utilized by 61 (45.2%) patients. Twenty-one (15.6%) and 114 (84.4%) patients accepted fertility-sparing and nonfertility-sparing surgery, respectively, and 42 (31.1%) and 93 (68.9%) patients accepted ovarian preservation and no ovarian preservation, respectively. The baseline characteristics of the patients in the various groups are summarized in Table 1 . Patients who underwent fertility-sparing surgery or ovarian preservation were significantly younger (both p <0.001) and had lower gravidity or parity (all p values <0.005). Eighteen patients underwent retroperitoneal lymphadenectomy, and only one (5.6%) had lymph node metastasis. Ten patients in the fertility-sparing groups underwent only hysteroscopy to remove the lesions. Hormone treatment was utilized by 12 of 21 (57.1%) patients who underwent fertility-sparing surgery and 23 of 42 (54.8%) patients who underwent ovarian preservation. Three patients selected the LNG-IUS for long-term treatment. A review of histological pathology revealed similar proportions of patients with advanced FIGO stages (III/IV), estrogen or progesterone receptor status, and mitotic activity and similar tumor diameters between patients with and without fertility-sparing treatment or ovarian preservation ( Table 1 ). However, nonfertility-sparing patients had a greater proportion of positive LVSI than fertility-sparing patients did ( p =0.035). Among the 21 fertility-sparing patients, marginal status was available for evaluation in 16 patients and was negative. Five patients had no available margin status for evaluation because fractured tissue was resected by hysteroscopy ( Table 2 ). Oncological outcomes and relevant risk factors in the whole cohort Comparisons of survival outcomes across various groups are presented in Figure 2 and Supplementary Figure S1 . The HRs calculated via proportional hazards models are listed in Supplementary Table S2 . After a median follow-up time of 38.5 (range 5–98) months, no patient was lost to follow-up during the study period; 10 (47.6%) and 18 (15.8%) recurrences occurred in the fertility-sparing and nonfertility-sparing groups ( p =0.002), and 18 (42.9%) and 10 (10.8%) recurrences occurred in the ovarian preservation and nonovarian preservation groups ( p <0.001), respectively. According to the Kaplan‒Meier analysis, fertility-sparing surgery ( Figure 2A and 2B ) or ovarian preservation ( Figure 2D and 2E ) resulted in a significantly increased recurrence risk in the whole cohort (HR 3.5 and 5.2, 95% CI 1.6–7.6 and 2.4–11.3, p =0.002 and <0.001, respectively) and in stage I patients (HR 2.6 and 3.1, 95% CI 1.0–6.4 and 1.3–7.4, p =0.041 and 0.011, respectively). No other factors, including age group, menopausal status, FIGO stage, pathological characteristics, retroperitoneal lymphadenectomy, or adjuvant therapy, were significantly associated with recurrence risk ( Figure S1 ). As a continuous variable, age at diagnosis was not significantly associated with recurrence (HR 0.8, 95% CI 0.4–1.6; p =0.576). Menopausal status seemed to have a protective effect against recurrence, but the effect was marginal ( p =0.100). Notably, three patients utilized the LNG-IUS and remained free of disease during the follow-up periods. Three of the 5 patients without available margins experienced recurrences. No factor was found to be associated with increased mortality risk. In particular, neither fertility-sparing surgery ( Figure 2C , HR 0.04 [95% CI 0.0-not available], p =0.626) nor ovarian preservation ( Figure 2F , HR 1.1 [95% CI 0.1-12.4], p =0.922) increased mortality. Among patients who underwent ovarian preservation, fertility-sparing surgery was not associated with increased recurrence or mortality ( p =0.810 and 0.285, respectively; Supplementary Figure S2 and Supplementary Figure S3 ). Multivariate analysis was not performed because of the limited number of endpoint events and meaningful statistical power. Fertility and oncological outcomes of patients receiving fertility-sparing treatment The specific fertility and oncologic outcomes of the patients who underwent fertility-sparing surgery are listed in Table 2 . The mean age of the patients who underwent fertility-sparing surgery was 29.1 (±7.5) years. Twelve out of 21 (57.1%) patients did not attempt pregnancy after their surgeries, since 6 patients had no fertility requirement due to being unmarried, 2 were still undergoing treatment, and 4 wanted only fertility spared. Among the 9 patients who attempted pregnancy, 7 achieved 8 live births, and 2 did not. No miscarriage occurred. Seven births were achieved by natural conception, and one live birth was achieved by in vitro fertilization and embryo transfer. The median interval from the last treatment to conception was 11 months (range 10–20 months). Severe complications during pregnancy included preterm birth (36 weeks) and hypertensive disease in two patients. No death occurred and no other severe adverse events occurred during the pregnancy puerperium in mothers and infants. Ten patients experienced recurrence after fertility-sparing treatment, 4 (40.0%) had distant metastasis beyond the pelvic cavity, and only 3 (30.0%) cases of recurrence were limited to the uterus. All three patients with Stage III disease experienced recurrence without successful conception. Postrecurrence treatments for patients who underwent fertility-sparing surgery are listed in Supplementary Table S3 . After recurrence, seven patients underwent nonfertility-sparing surgeries and remained free of disease, and 3 patients who underwent repeated fertility-sparing surgeries experienced disease relapse and underwent nonfertility-sparing surgeries again, after which they all remained disease free during the follow-up period. No patients who underwent fertility-sparing surgery died during the follow-up period. Unfortunately, among the 6 single (unmarried) patients who underwent fertility-sparing surgery, 3 experienced local recurrences within the uterus and underwent nonfertility-sparing surgeries. Specifically, one patient ( Supplementary Table S3 ) was diagnosed with first recurrence during her cesarean section for the second live birth, when metastasis to retroperitoneal lymph nodes was noticed. She subsequently underwent repeated fertility-sparing surgeries (resection of metastatic lymph nodes) without adjuvant therapy. However, five months after the surgery, recurrence in the uterus was noticed, and the patient underwent nonfertility-sparing surgeries and remained disease free during the follow-up period. DISCUSSION In this study, we report the fertility and oncological outcomes of LGESS patients with and without fertility-sparing surgery or ovarian preservation. To our knowledge, this is the largest cohort to address fertility-sparing surgery in LGESS patients. The evidence in our study suggests that either fertility-sparing surgery or ovarian preservation significantly increases the recurrence risk of LGESS. Among the 9 patients who attempted pregnancy, 7 achieved 8 live births. The results are promising for patients desiring fertility. However, patients should be informed of the 3.5-fold increased risk of recurrence and that recurrence would occur in nearly half of patients with or without successful live births, although fertility-sparing treatment was not associated with an increased mortality risk. Owing to the infrequency of LGESS, very few studies have explored the risk factors for recurrence in this population, and none have specified the prognostic role of fertility-sparing treatment. For the first time, we found that fertility-sparing treatment significantly increased the risk of recurrence. The potential reasons may be related to ovarian preservation in this population. Despite these controversies [2, 7, 8], ovarian preservation has been proven to increase the risk of LGESS recurrence [9], which is further supported by the findings of a systematic review [10]. Both estrogen and tamoxifen treatment are contraindicated in patients with LGESS since they also increase the risk of recurrence [11, 12]. Menopause is a protective factor associated with improved progression-free survival among patients with LGESS [13]. In addition, numerous reports have revealed the role of endometriosis in the pathogenesis of extrauterine LGESS [14]. These findings suggest that LGESS is a highly estrogen-dependent disease, and this knowledge is essential for decision-making before surgical therapies. For patients not desiring fertility, ovarian preservation leads to a greater risk of recurrence and therefore is not practical in terms of effectiveness, especially for older patients or patients not desiring fertility. Owing to the limited sample size, currently, no evidence exists regarding the quality of life after oophorectomy in premenopausal patients. However, it is prudent not to offer estrogen therapy to survivors of LGESS and women with granulosa cell tumors of the ovaries [15]. In our study, neither ovarian preservation nor fertility-sparing treatment had an adverse effect on OS. This finding has been confirmed by other studies [10], including a National Cancer Database analysis [16]. The lack of survival difference could be explained by the good prognosis of patients with isolated tumor relapse and the strict follow-up in such a cohort. A currently published report suggested that age and marital status are important parameters in the nomogram for predicting the OS of patients with LGESS. In their study, ovarian preservation was associated with an even lower risk of mortality than no ovarian preservation [17]. The discrepancy in the recurrence and mortality risks led to different recommendations in the relevant guidelines [18-20]. In our view, ovarian preservation is safe in terms of long-term survival and is appropriate for patients requiring fertility preservation. However, we suggest that once a patient achieves a live birth, salpingo-oophorectomy could be a practical recommendation to decrease further potential recurrence. Strengths and limitations Our study supports hysteroscopy as an effective fertility-sparing treatment modality for LGESS. In the fertility-sparing treatment cohort in our study, ten patients had their lesions removed only by hysteroscopy. Among these 10 patients, 7 (70%) remained disease free after surgery, and 4 of 5 (80%) successfully achieved live births. Previous case reports have also supported the diagnostic and treatment role of hysteroscopy for LGESS [6, 21-23]. The selection of eligible patients with comprehensive imaging and pathological evaluation is critical for the successful management of fertility-sparing treatment by hysteroscopy. However, hysteroscopy has the limitation of being unable to evaluate margin status because of the presence of fractured tissues, while a positive resection margin is an independent adverse factor for relapse [4]. Half of the patients who underwent hysteroscopy had no available margin status for evaluation, and 3 of the 5 patients experienced recurrence, which was likely associated with positive margins. Unfortunately, three of the six single (unmarried) patients (50.0%) in our study experienced recurrence after fertility-sparing surgeries. Effective sustained treatment is urgently needed for such situations. Adjuvant hormonal treatment has been considered a feasible adjuvant therapy for reducing the recurrence risk of patients with LGESS while bearing little benefit to OS [24]. In our study, three patients utilized the LNG-IUS and remained free of disease. The LNG-IUS design can achieve long-term local control by slowly releasing levonorgestrel, which is effective in the conservative treatment of adenomyosis [25], leiomyoma [26], and endometrial precancerous or cancerous diseases [27]. It may have protective effects on ovarian cancer [28]. Most adverse events associated with the LNG-IUS are mild and acceptable [25]. However, its use in the treatment of LGESS has not been reported in the English-language literature. Our study is the first to report the possible effectiveness of sustained therapy in this population, which has provided a promising method for LGESS patients desiring fertility sparing but unable to be conceptive. The retrospective design and limited sample size of our study are its main limitations. The prognostic roles of other important clinicopathological parameters, including age, menopausal status, stages, and adjuvant therapies, are undetermined. We could not perform multivariate analysis to investigate the prognostic role of fertility-sparing treatment because of the limited number of endpoint events and meaningful statistical power. As described previously,[8] long-term follow-up is essential for LGESS, a rare and indolent disease. Most importantly, how to select eligible patients for fertility-sparing treatment remains unresolved. As shown in our study, advanced-stage patients all experienced relapse without successful conception. However, other conditions had little supportive evidence due to the limited sample sizes. The conclusions regarding overall survival/mortality are based on only 3 deaths that occurred in the entire cohort during the follow-up period, which would limit the ability to make statistically robust conclusions about overall survival or mortality, or at least that any conclusions here should be interpreted with caution given the small number of deaths that occurred. CONCLUSION In this retrospective cohort study, fertility-sparing surgery or ovarian preservation in patients with LGESS resulted in a significantly increased risk of recurrence but had no impact on mortality. Fertility-sparing treatment had promising results in terms of live births. Hysteroscopy and the LNG-IUS may provide less invasive and sustained treatment for LGESS. Declarations Disclosure All the authors declare that they have no conflicts of interest to disclose. Author contributions LL conceived of the original idea for the study, interpreted results, carried out the statistical analysis, edited the paper and was overall guarantor. BX obtained ethical approval, contributed to the preparation of the data set, interpreted results and contributed to drafts of the paper. HW conducted the pathological evaluation. All authors have approved the final version of the manuscript. Acknowledgments None Funding This study is supported by the Independent Research Fund of State Key Laboratory of Complex, Severe and Rare Diseases in Peking Union Medical College Hospital (2025-I-ZD-001 and 2025-O-ZD-003), by the Key Research Project of Beijing Natural Science Foundation (No. Z220013), by the CAMS Innovation Fund for Medical Sciences (CIFMS) (No. 2024-I2M-C&T-B-029), by the National High Level Hospital Clinical Research Funding (2022-PUMCH-B-083, 2022-PUMCH-C-010, 2022-PUMCH-C-022 and 2022-PUMCH-D-003), and by Peking Union Medical College Hospital Talent Cultivation Program (Category D) (No. UHB12577). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Ethics approval and registration The Institutional Review Board of Peking Union Medical College Hospital approved this study (No. SK-1289). Statement of submission The paper is not under consideration by another journal, and the results presented in this work have not been previously presented or published. Consent for publication Consent for publication has been obtained from all patients. Availability of data and material All the data used in this study are contained in the supplemental files. References Kurman, R.J., et al., eds. WHO Classification of Tumours of Female Reproductive Organs. 4 ed. World Health Organization Classification of Tumours. 2014, International Agency for Research on Cancer (IARC): Lyon. Zhou, J., et al., Influence of different treatment modalities on survival of patients with low-grade endometrial stromal sarcoma: A retrospective cohort study. Int J Surg, 2015. 23(Pt A): p. 147 – 51. Seagle, B.L., et al., Low-grade and high-grade endometrial stromal sarcoma: A National Cancer Database study. Gynecol Oncol, 2017. 146(2): p. 254–262. 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Int J Gynaecol Obstet, 2019. 146(3): p. 357–363. Kriplani, A., et al., Efficacy of the levonorgestrel-releasing intrauterine system in uterine leiomyoma. Int J Gynaecol Obstet, 2012. 116(1): p. 35–8. Chen, X., The current situation of the levonorgestrel intrauterine system (LNG-IUS) in conservative treatment for patients with early-stage endometrial cancer and atypical hyperplasia. J Gynecol Oncol, 2019. 30(4): p. e79. Jareid, M., et al., Levonorgestrel-releasing intrauterine system use is associated with a decreased risk of ovarian and endometrial cancer, without increased risk of breast cancer. Results from the NOWAC Study. Gynecol Oncol, 2018. 149(1): p. 127–132. Additional Declarations No competing interests reported. Supplementary Files SupplementaryTableS1.xlsx Legends of supplementary materials Supplementary Table S1. Raw data of this study. SupplementaryTableS3.docx Supplementary Table S2. Hazard ratios (HRs) with 95% confidence intervals (95% CIs) for recurrence or mortality in various populations. N/A, not available. SupplementaryTableS2.docx Supplementary Table S3. Postrecurrent treatment for patients with fertility-sparing surgery. SupplementaryFigureS1.tif Supplementary Figure S1. Disease-free survival (DFS) of patients with characteristics other than fertility-sparing surgery or ovarian preservation by Kaplan‒Meier analysis. (A) DFS of patients in various age groups ( p =0.187). (B) DFS of patients with various menopausal statuses ( p =0.100). (C) DFS of patients with early- and advanced-stage disease ( p =0.988). (D) DFS of patients with positive and negative lymphovascular space invasion ( p =0.593). (E) DFS of patients who received various surgical routes ( p =0.373). (F) DFS of patients with and without retroperitoneal lymphadenectomy ( p =0.233). (G) DFS of patients with and without hormone treatment ( p =0.685). (H) DFS of patients with and without chemotherapy ( p =0.523). SupplementaryFigureS2.tif Supplementary Figure S2. Disease-free survival (DFS) with and without fertility-sparing surgeries in patients with ovarian preservation. SupplementaryFigureS3.tif Supplementary Figure S3. Overall survival (OS) with and without fertility-sparing surgery in patients with ovarian preservation. Cite Share Download PDF Status: Published Journal Publication published 05 Jan, 2026 Read the published version in European Journal of Medical Research → Version 1 posted Editorial decision: Revision requested 01 Oct, 2025 Reviews received at journal 08 Sep, 2025 Reviews received at journal 01 Sep, 2025 Reviewers agreed at journal 18 Aug, 2025 Reviewers agreed at journal 15 Aug, 2025 Reviewers invited by journal 15 Aug, 2025 Editor assigned by journal 11 Jul, 2025 Submission checks completed at journal 11 Jul, 2025 First submitted to journal 11 Jul, 2025 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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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-7098205","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":501905981,"identity":"fe0eb225-0f91-4612-ac93-98b1a1ed819f","order_by":0,"name":"Baolin Xu","email":"","orcid":"","institution":"Peking Union Medical College Hospital","correspondingAuthor":false,"prefix":"","firstName":"Baolin","middleName":"","lastName":"Xu","suffix":""},{"id":501905982,"identity":"e99a3eff-2d88-4481-acdc-4f16fc424599","order_by":1,"name":"Yan You","email":"","orcid":"","institution":"Peking Union Medical College Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yan","middleName":"","lastName":"You","suffix":""},{"id":501905983,"identity":"fb31add7-0e2b-4c00-adeb-f4ce5efe67fc","order_by":2,"name":"Huanwen Wu","email":"","orcid":"","institution":"Peking Union Medical College Hospital","correspondingAuthor":false,"prefix":"","firstName":"Huanwen","middleName":"","lastName":"Wu","suffix":""},{"id":501905984,"identity":"729b275f-154c-4973-8143-949f56aa1ed2","order_by":3,"name":"Lei Li","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAtklEQVRIiWNgGAWjYBACPmbmBoYEhgNybOztB4jTwsbMCNZizMdzJoFILQxALQwMBxLnSTgYEKmFnbHxwYNfd9LbJICW/ajYRpTDmg0S+57ltkk3HmDsOXObKC1tEok9h3PbZA4kANnEaWn/AdSSziaRYEC0ljaGhB+HE0jS0iyR2HDYsA0YyAeJ8gs//+GDH3/8OSwv395+8MGPCiK0gAHQbWBwgEj1IPCHBLWjYBSMglEw8gAA9iQ8ix3Q718AAAAASUVORK5CYII=","orcid":"","institution":"Peking Union Medical College Hospital","correspondingAuthor":true,"prefix":"","firstName":"Lei","middleName":"","lastName":"Li","suffix":""}],"badges":[],"createdAt":"2025-07-11 06:08:41","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7098205/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7098205/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s40001-025-03830-7","type":"published","date":"2026-01-05T15:56:56+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":89974381,"identity":"9261d46d-a396-4376-a8c7-924734dc0201","added_by":"auto","created_at":"2025-08-27 05:53:54","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":140496,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFlow diagram of the study.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLGESS, low-grade endometrial stromal sarcoma.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7098205/v1/8f0ba4e007e6072206bdbdd3.png"},{"id":89976324,"identity":"277f2048-7918-482f-9188-735f59cc13be","added_by":"auto","created_at":"2025-08-27 06:01:55","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":289157,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSurvival outcomes of patients with and without fertility-sparing surgery or ovarian preservation according to Kaplan‒Meier analysis.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(A) Disease-free survival (DFS) of patients with and without fertility-sparing surgery (\u003cem\u003ep\u003c/em\u003e=0.001).\u003c/p\u003e\n\u003cp\u003e(B) DFS of stage I patients with and without fertility-sparing surgery (\u003cem\u003ep\u003c/em\u003e=0.034).\u003c/p\u003e\n\u003cp\u003e(C) Overall survival (OS) of patients with and without fertility-sparing surgery (\u003cem\u003ep\u003c/em\u003e=0.440).\u003c/p\u003e\n\u003cp\u003e(D) DFS of patients with and without ovarian preservation (\u003cem\u003ep\u003c/em\u003e\u0026lt;0.001).\u003c/p\u003e\n\u003cp\u003e(E) DFS of stage I patients with and without ovarian preservation (\u003cem\u003ep\u003c/em\u003e=0.007).\u003c/p\u003e\n\u003cp\u003e(F) OS of patients with and without ovarian preservation (\u003cem\u003ep\u003c/em\u003e=0.922).\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7098205/v1/bdd315fd1996d4083163bf18.png"},{"id":100069080,"identity":"ee99ddf8-f6a4-453b-8096-6ec6a71e1176","added_by":"auto","created_at":"2026-01-12 16:08:26","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1034067,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7098205/v1/0d840b52-16ef-4e1f-80cf-af01e83f4d29.pdf"},{"id":89976323,"identity":"cf86b756-ec8c-4245-a8a5-cbb92194ed0f","added_by":"auto","created_at":"2025-08-27 06:01:55","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":37902,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eLegends of supplementary materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSupplementary Table S1. Raw data of this study.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"SupplementaryTableS1.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-7098205/v1/7ac610661b57362497a33c03.xlsx"},{"id":89974400,"identity":"44dc6c76-ac35-467d-bb91-8bd63236ef17","added_by":"auto","created_at":"2025-08-27 05:53:55","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":12417,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplementary Table S2. Hazard ratios (HRs) with 95% confidence intervals (95% CIs) for recurrence or mortality in various populations.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eN/A, not available.\u003c/p\u003e","description":"","filename":"SupplementaryTableS3.docx","url":"https://assets-eu.researchsquare.com/files/rs-7098205/v1/f75f7202127a0bafac003f81.docx"},{"id":89974412,"identity":"2b8ef44b-6d22-43e4-9321-d6a71e6478cc","added_by":"auto","created_at":"2025-08-27 05:53:56","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":13207,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplementary Table S3. Postrecurrent treatment for patients with fertility-sparing surgery.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"SupplementaryTableS2.docx","url":"https://assets-eu.researchsquare.com/files/rs-7098205/v1/aa7c114a93c8374d71414bbd.docx"},{"id":89974403,"identity":"4fa7ac57-ae07-4e0f-ae7b-6130ba583cd2","added_by":"auto","created_at":"2025-08-27 05:53:55","extension":"tif","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":635866,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplementary Figure S1. Disease-free survival (DFS) of patients with characteristics other than fertility-sparing surgery or ovarian preservation by Kaplan‒Meier analysis.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(A) DFS of patients in various age groups (\u003cem\u003ep\u003c/em\u003e=0.187).\u003c/p\u003e\n\u003cp\u003e(B) DFS of patients with various menopausal statuses (\u003cem\u003ep\u003c/em\u003e=0.100).\u003c/p\u003e\n\u003cp\u003e(C) DFS of patients with early- and advanced-stage disease (\u003cem\u003ep\u003c/em\u003e=0.988).\u003c/p\u003e\n\u003cp\u003e(D) DFS of patients with positive and negative lymphovascular space invasion (\u003cem\u003ep\u003c/em\u003e=0.593).\u003c/p\u003e\n\u003cp\u003e(E) DFS of patients who received various surgical routes (\u003cem\u003ep\u003c/em\u003e=0.373).\u003c/p\u003e\n\u003cp\u003e(F) DFS of patients with and without retroperitoneal lymphadenectomy (\u003cem\u003ep\u003c/em\u003e=0.233).\u003c/p\u003e\n\u003cp\u003e(G) DFS of patients with and without hormone treatment (\u003cem\u003ep\u003c/em\u003e=0.685).\u003c/p\u003e\n\u003cp\u003e(H) DFS of patients with and without chemotherapy (\u003cem\u003ep\u003c/em\u003e=0.523).\u003c/p\u003e","description":"","filename":"SupplementaryFigureS1.tif","url":"https://assets-eu.researchsquare.com/files/rs-7098205/v1/b0c96fca0b715865fc12ab69.tif"},{"id":89974418,"identity":"bcb20a6a-2ddd-48a7-a8ca-1807655f60d2","added_by":"auto","created_at":"2025-08-27 05:53:56","extension":"tif","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":172468,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplementary Figure S2. Disease-free survival (DFS) with and without fertility-sparing surgeries in patients with ovarian preservation.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"SupplementaryFigureS2.tif","url":"https://assets-eu.researchsquare.com/files/rs-7098205/v1/2fc2b749291ee7a5ec4a1396.tif"},{"id":89974410,"identity":"36172394-348b-4b91-bb3a-f3c05b563937","added_by":"auto","created_at":"2025-08-27 05:53:56","extension":"tif","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":158076,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplementary Figure S3. Overall survival (OS) with and without fertility-sparing surgery in patients with ovarian preservation.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"SupplementaryFigureS3.tif","url":"https://assets-eu.researchsquare.com/files/rs-7098205/v1/87930cca80b5c3055426aeb2.tif"}],"financialInterests":"No competing interests reported.","formattedTitle":"Fertility-sparing treatment for low-grade endometrial stromal sarcoma","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eLow-grade endometrial stromal sarcoma (LGESS) is a malignant tumor composed of cells resembling stromal cells of the proliferative-phase endometrium, displaying permeative, infiltrative growth into the myometrium and/or Iymphovascular spaces [1]. LGESS represents \u0026lt;1% of all uterine malignancies but is the second most common uterine malignant mesenchymal tumor and has a favorable prognosis [2]. The five-year disease-specific survival rates are 90% for stage I or stage II disease and 50% for stage III or IV disease [3]. Hysterectomy with salpingo-oophorectomy is the standard treatment for LGESS. Ovary-sparing procedures and myomectomy are adverse factors for relapse [4]. However, the age range at diagnosis of LGESS is broad, and many patients are of reproductive age and desire pregnancy. For primary uterine LGESS, the fertility and oncological outcomes of fertility-sparing procedures remain ambiguous since fertility-sparing treatment has been reported only in case reports [5, 6]. In addition, these reports did not compare patients who did not undergo fertility-sparing procedures and had no specific information on subsequent obstetric outcomes. These limitations restrict effective decision-making for young patients who desire fertility preservation after the diagnosis of LGESS, especially early-stage patients.\u003c/p\u003e\n\u003cp\u003eIn this retrospective cohort study, we reviewed all LGESS cases diagnosed and treated in the last 7 years at the study center to explore the prognostic role of fertility preservation in these patients. The primary objectives were to explore the disease-free survival (DFS) and overall survival (OS) rates after surgery for LGESS, and the secondary objective was to explore the fertility outcomes of these patients.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cp\u003e\u003cstrong\u003eEthical approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe Institutional Review Board of the study center approved this retrospective study (No. SK-1289). All procedures performed in the study involving human participants were in accordance with the ethical standards of the institutional and National Research Committee and with the 1964 \u003cem\u003eDeclaration of Helsinki\u003c/em\u003e and its later amendments or comparable ethical standards.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy design\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis was a retrospective cohort study. Patients who were diagnosed with and treated for primary LGESS at the study center from February 2012 to June 2019 were reviewed. Follow-up of fertility and oncologic outcomes was carried out up to June 1, 2020. The pathological diagnoses were reviewed and confirmed by pathologists of this study. The margin status of resected tumors was given special attention. Patients were excluded if they had repeated LGESS, had an ambiguous diagnosis or misdiagnosis of LGESS, or if they did not accept surgical treatment. Detailed epidemiological information, including age at diagnosis, menopausal status, gravidity, parity, and personal and family history of cancer, was collected by reviewing case reports and by interviewing patients via email and/or telephone.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInterventions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll patients underwent surgical treatment, with or without adjuvant chemotherapy, radiotherapy, and/or hormone therapy. Patients were divided into groups according to surgical entity: those with or without fertility-sparing surgery and those with hysterectomy with or without ovarian preservation. In this study, fertility-sparing surgery involves preservation of the uterus and at least one ovary. Patients who underwent fertility-sparing surgery also had records of regular menstruation in this study after all relevant treatments. Ovarian preservation refers to the preservation of at least one ovary with or without an intact uterus. However, not all patients undergo evaluations of the ovarian reserve after ovarian preservation. Data on surgical treatment, including surgical routes, retroperitoneal lymphadenectomy, and pathological results (FIGO staging, lymphovascular space invasion [LVSI], estrogen and progesterone receptor status, mitotic activity, and metastasis to lymph nodes), were also collected from the case and pathology reports. Ambiguous or missing pathological information was supplemented by pathologists of this study. The same attention was given to the chemotherapy regimens and courses, hormone therapy regimens and courses, and radiotherapy. For patients who undergo pelvic radiotherapy after the diagnosis of LGESS, treatment is not regarded as fertility sparing even if their ovaries are not resected by surgery.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMeasures\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOncologic outcomes consisted of DFS and OS, which were followed up during the study period. All recurrences were confirmed via histological diagnosis via biopsy and/or repeated surgeries. All deaths were confirmed by certification of death. The fertility outcomes consisted of conception rates and birth rates in the same follow-up periods. For patients who underwent fertility-sparing surgery, the trend in pregnancy attempts and reasons for not attempting pregnancy were confirmed by telephone and/or outpatient clinical interviews. Data on the interval from last treatment to conception, conception methods, pregnancy weeks and complications were recorded in detail.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eComparisons of continuous variables were conducted with parametric methods if assumptions of normal distribution were confirmed. Nonnormally distributed variables and categorical data were compared between various groups with and without fertility-sparing surgery or ovarian preservation via nonparametric tests. Survival curves were generated via the Kaplan‒Meier method, and proportional hazards models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (95% CIs) for the effects of fertility-sparing surgery and ovarian preservation on DFS and OS. Unless otherwise stated, all analyses were performed with a two-sided significance level of 0.05 and were conducted with the use of the software Statistical Product and Service Solutions (SPSS) Statistics 20.0 (IBM Corporation, Armonk, NY, USA).\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003e\u003cstrong\u003ePatient\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe flow diagram is presented in \u003cstrong\u003eFigure 1\u003c/strong\u003e. In total, 143 eligible patients with a definite diagnosis of LGESS were reviewed, and 135 patients with primary uterine LGESS were included in the study. The raw data of this study are shown in \u003cstrong\u003eSupplementary Table S1\u003c/strong\u003e.One hundred and two (75.6%) patients had stage I disease. Hormone treatment was utilized by 61 (45.2%) patients. Twenty-one (15.6%) and 114 (84.4%) patients accepted fertility-sparing and nonfertility-sparing surgery, respectively, and 42 (31.1%) and 93 (68.9%) patients accepted ovarian preservation and no ovarian preservation, respectively. The baseline characteristics of the patients in the various groups are summarized in \u003cstrong\u003eTable 1\u003c/strong\u003e. Patients who underwent fertility-sparing surgery or ovarian preservation were significantly younger (both \u003cem\u003ep\u003c/em\u003e\u0026lt;0.001) and had lower gravidity or parity (all \u003cem\u003ep\u003c/em\u003e values \u0026lt;0.005). Eighteen patients underwent retroperitoneal lymphadenectomy, and only one (5.6%) had lymph node metastasis. Ten patients in the fertility-sparing groups underwent only hysteroscopy to remove the lesions. Hormone treatment was utilized by 12 of 21 (57.1%) patients who underwent fertility-sparing surgery and 23 of 42 (54.8%) patients who underwent ovarian preservation. Three patients selected the LNG-IUS for long-term treatment.\u003c/p\u003e\n\u003cp\u003eA review of histological pathology revealed similar proportions of patients with advanced FIGO stages (III/IV), estrogen or progesterone receptor status, and mitotic activity and similar tumor diameters between patients with and without fertility-sparing treatment or ovarian preservation (\u003cstrong\u003eTable 1\u003c/strong\u003e). However, nonfertility-sparing patients had a greater proportion of positive LVSI than fertility-sparing patients did (\u003cem\u003ep\u003c/em\u003e=0.035). Among the 21 fertility-sparing patients, marginal status was available for evaluation in 16 patients and was negative. Five patients had no available margin status for evaluation because fractured tissue was resected by hysteroscopy (\u003cstrong\u003eTable 2\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOncological outcomes and relevant risk factors in the whole cohort\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eComparisons of survival outcomes across various groups are presented in \u003cstrong\u003eFigure 2\u003c/strong\u003e and \u003cstrong\u003eSupplementary Figure S1\u003c/strong\u003e. The HRs calculated via proportional hazards models are listed in \u003cstrong\u003eSupplementary Table S2\u003c/strong\u003e. After a median follow-up time of 38.5 (range 5–98) months, no patient was lost to follow-up during the study period; 10 (47.6%) and 18 (15.8%) recurrences occurred in the fertility-sparing and nonfertility-sparing groups (\u003cem\u003ep\u003c/em\u003e=0.002), and 18 (42.9%) and 10 (10.8%) recurrences occurred in the ovarian preservation and nonovarian preservation groups (\u003cem\u003ep\u003c/em\u003e\u0026lt;0.001), respectively.\u003c/p\u003e\n\u003cp\u003eAccording to the Kaplan‒Meier analysis, fertility-sparing surgery (\u003cstrong\u003eFigure 2A\u0026nbsp;\u003c/strong\u003eand \u003cstrong\u003e2B\u003c/strong\u003e) or ovarian preservation (\u003cstrong\u003eFigure 2D\u003c/strong\u003e and \u003cstrong\u003e2E\u003c/strong\u003e) resulted in a significantly increased recurrence risk in the whole cohort (HR 3.5 and 5.2, 95% CI 1.6–7.6 and 2.4–11.3, \u003cem\u003ep\u003c/em\u003e=0.002 and \u0026lt;0.001, respectively) and in stage I patients (HR 2.6 and 3.1, 95% CI 1.0–6.4 and 1.3–7.4, \u003cem\u003ep\u003c/em\u003e=0.041 and 0.011, respectively). No other factors, including age group, menopausal status, FIGO stage, pathological characteristics, retroperitoneal lymphadenectomy, or adjuvant therapy, were significantly associated with recurrence risk (\u003cstrong\u003eFigure S1\u003c/strong\u003e). As a continuous variable, age at diagnosis was not significantly associated with recurrence (HR 0.8, 95% CI 0.4–1.6; \u003cem\u003ep\u003c/em\u003e=0.576). Menopausal status seemed to have a protective effect against recurrence, but the effect was marginal (\u003cem\u003ep\u003c/em\u003e=0.100). Notably, three patients utilized the LNG-IUS and remained free of disease during the follow-up periods. Three of the 5 patients without available margins experienced recurrences.\u003c/p\u003e\n\u003cp\u003eNo factor was found to be associated with increased mortality risk. In particular, neither fertility-sparing surgery (\u003cstrong\u003eFigure 2C\u003c/strong\u003e, HR 0.04 [95% CI 0.0-not available], \u003cem\u003ep\u003c/em\u003e=0.626) nor ovarian preservation (\u003cstrong\u003eFigure 2F\u003c/strong\u003e, HR 1.1 [95% CI 0.1-12.4], \u003cem\u003ep\u003c/em\u003e=0.922) increased mortality.\u003c/p\u003e\n\u003cp\u003eAmong patients who underwent ovarian preservation, fertility-sparing surgery was not associated with increased recurrence or mortality (\u003cem\u003ep\u003c/em\u003e=0.810 and 0.285, respectively; \u003cstrong\u003eSupplementary Figure S2\u003c/strong\u003e and \u003cstrong\u003eSupplementary Figure S3\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eMultivariate analysis was not performed because of the limited number of endpoint events and meaningful statistical power.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFertility and oncological outcomes of patients\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003ereceiving\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;fertility-sparing treatment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe specific fertility and oncologic outcomes of the patients who underwent fertility-sparing surgery are listed in \u003cstrong\u003eTable 2\u003c/strong\u003e. The mean age of the patients who underwent fertility-sparing surgery was 29.1 (±7.5) years. Twelve out of 21 (57.1%) patients did not attempt pregnancy after their surgeries, since 6 patients had no fertility requirement due to being unmarried, 2 were still undergoing treatment, and 4 wanted only fertility spared. Among the 9 patients who attempted pregnancy, 7 achieved 8 live births, and 2 did not. No miscarriage occurred. Seven births were achieved by natural conception, and one live birth was achieved by in vitro fertilization and embryo transfer. The median interval from the last treatment to conception was 11 months (range 10–20 months). Severe complications during pregnancy included preterm birth (36 weeks) and hypertensive disease in two patients. No death occurred and no other severe adverse events occurred during the pregnancy puerperium in mothers and infants.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTen patients experienced recurrence after fertility-sparing treatment, 4 (40.0%) had distant metastasis beyond the pelvic cavity, and only 3 (30.0%) cases of recurrence were limited to the uterus. All three patients with Stage III disease experienced recurrence without successful conception. Postrecurrence treatments for patients who underwent fertility-sparing surgery are listed in \u003cstrong\u003eSupplementary\u003c/strong\u003e \u003cstrong\u003eTable S3\u003c/strong\u003e. After recurrence, seven patients underwent nonfertility-sparing surgeries and remained free of disease, and 3 patients who underwent repeated fertility-sparing surgeries experienced disease relapse and underwent nonfertility-sparing surgeries again, after which they all remained disease free during the follow-up period. No patients who underwent fertility-sparing surgery died during the follow-up period. Unfortunately, among the 6 single (unmarried) patients who underwent fertility-sparing surgery, 3 experienced local recurrences within the uterus and underwent nonfertility-sparing surgeries.\u003c/p\u003e\n\u003cp\u003eSpecifically, one patient (\u003cstrong\u003eSupplementary Table S3\u003c/strong\u003e) was diagnosed with first recurrence during her cesarean section for the second live birth, when metastasis to retroperitoneal lymph nodes was noticed. She subsequently underwent repeated fertility-sparing surgeries (resection of metastatic lymph nodes) without adjuvant therapy. However, five months after the surgery, recurrence in the uterus was noticed, and the patient underwent nonfertility-sparing surgeries and remained disease free during the follow-up period.\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eIn this study, we report the fertility and oncological outcomes of LGESS patients with and without fertility-sparing surgery or ovarian preservation. To our knowledge, this is the largest cohort to address fertility-sparing surgery in LGESS patients. The evidence in our study suggests that either fertility-sparing surgery or ovarian preservation significantly increases the recurrence risk of LGESS. Among the 9 patients who attempted pregnancy, 7 achieved 8 live births. The results are promising for patients desiring fertility. However, patients should be informed of the 3.5-fold increased risk of recurrence and that recurrence would occur in nearly half of patients with or without successful live births, although fertility-sparing treatment was not associated with an increased mortality risk.\u003c/p\u003e\n\u003cp\u003eOwing to the infrequency of LGESS, very few studies have explored the risk factors for recurrence in this population, and none have specified the prognostic role of fertility-sparing treatment. For the first time, we found that fertility-sparing treatment significantly increased the risk of recurrence. The potential reasons may be related to ovarian preservation in this population. Despite these controversies [2, 7, 8], ovarian preservation has been proven to increase the risk of LGESS recurrence [9], which is further supported by the findings of a systematic review [10]. Both estrogen and tamoxifen treatment are contraindicated in patients with LGESS since they also increase the risk of recurrence [11, 12]. Menopause is a protective factor associated with improved progression-free survival among patients with LGESS [13]. In addition, numerous reports have revealed the role of endometriosis in the pathogenesis of extrauterine LGESS [14]. These findings suggest that LGESS is a highly estrogen-dependent disease, and this knowledge is essential for decision-making before surgical therapies. For patients not desiring fertility, ovarian preservation leads to a greater risk of recurrence and therefore is not practical in terms of effectiveness, especially for older patients or patients not desiring fertility. Owing to the limited sample size, currently, no evidence exists regarding the quality of life after oophorectomy in premenopausal patients. However, it is prudent not to offer estrogen therapy to survivors of LGESS and women with granulosa cell tumors of the ovaries [15]. \u003c/p\u003e\n\u003cp\u003eIn our study, neither ovarian preservation nor fertility-sparing treatment had an adverse effect on OS. This finding has been confirmed by other studies [10], including a National Cancer Database analysis [16]. The lack of survival difference could be explained by the good prognosis of patients with isolated tumor relapse and the strict follow-up in such a cohort. A currently published report suggested that age and marital status are important parameters in the nomogram for predicting the OS of patients with LGESS. In their study, ovarian preservation was associated with an even lower risk of mortality than no ovarian preservation [17]. The discrepancy in the recurrence and mortality risks led to different recommendations in the relevant guidelines [18-20]. In our view, ovarian preservation is safe in terms of long-term survival and is appropriate for patients requiring fertility preservation. However, we suggest that once a patient achieves a live birth, salpingo-oophorectomy could be a practical recommendation to decrease further potential recurrence.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStrengths and limitations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOur study supports hysteroscopy as an effective fertility-sparing treatment modality for LGESS. In the fertility-sparing treatment cohort in our study, ten patients had their lesions removed only by hysteroscopy. Among these 10 patients, 7 (70%) remained disease free after surgery, and 4 of 5 (80%) successfully achieved live births. Previous case reports have also supported the diagnostic and treatment role of hysteroscopy for LGESS [6, 21-23]. The selection of eligible patients with comprehensive imaging and pathological evaluation is critical for the successful management of fertility-sparing treatment by hysteroscopy. However, hysteroscopy has the limitation of being unable to evaluate margin status because of the presence of fractured tissues, while a positive resection margin is an independent adverse factor for relapse [4]. Half of the patients who underwent hysteroscopy had no available margin status for evaluation, and 3 of the 5 patients experienced recurrence, which was likely associated with positive margins.\u003c/p\u003e\n\u003cp\u003eUnfortunately, three of the six single (unmarried) patients (50.0%) in our study experienced recurrence after fertility-sparing surgeries. Effective sustained treatment is urgently needed for such situations. Adjuvant hormonal treatment has been considered a feasible adjuvant therapy for reducing the recurrence risk of patients with LGESS while bearing little benefit to OS [24]. In our study, three patients utilized the LNG-IUS and remained free of disease. The LNG-IUS design can achieve long-term local control by slowly releasing levonorgestrel, which is effective in the conservative treatment of adenomyosis [25], leiomyoma [26], and endometrial precancerous or cancerous diseases [27]. It may have protective effects on ovarian cancer [28]. Most adverse events associated with the LNG-IUS are mild and acceptable [25]. However, its use in the treatment of LGESS has not been reported in the English-language literature. Our study is the first to report the possible effectiveness of sustained therapy in this population, which has provided a promising method for LGESS patients desiring fertility sparing but unable to be conceptive.\u003c/p\u003e\n\u003cp\u003eThe retrospective design and limited sample size of our study are its main limitations. The prognostic roles of other important clinicopathological parameters, including age, menopausal status, stages, and adjuvant therapies, are undetermined. We could not perform multivariate analysis to investigate the prognostic role of fertility-sparing treatment because of the limited number of endpoint events and meaningful statistical power. As described previously,[8] long-term follow-up is essential for LGESS, a rare and indolent disease. Most importantly, how to select eligible patients for fertility-sparing treatment remains unresolved. As shown in our study, advanced-stage patients all experienced relapse without successful conception. However, other conditions had little supportive evidence due to the limited sample sizes. The conclusions regarding overall survival/mortality are based on only 3 deaths that occurred in the entire cohort during the follow-up period, which would limit the ability to make statistically robust conclusions about overall survival or mortality, or at least that any conclusions here should be interpreted with caution given the small number of deaths that occurred.\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eIn this retrospective cohort study, fertility-sparing surgery or ovarian preservation in patients with LGESS resulted in a significantly increased risk of recurrence but had no impact on mortality. Fertility-sparing treatment had promising results in terms of live births. Hysteroscopy and the LNG-IUS may provide less invasive and sustained treatment for LGESS.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eDisclosure\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll the authors declare that they have no conflicts of interest to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLL conceived of the original idea for the study, interpreted results, carried out the statistical analysis, edited the paper and was overall guarantor. BX obtained ethical approval, contributed to the preparation of the data set, interpreted results and contributed to drafts of the paper. HW conducted the pathological evaluation. All authors have approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study is supported by the Independent Research Fund of State Key Laboratory of Complex, Severe and Rare Diseases in Peking Union Medical College Hospital (2025-I-ZD-001 and 2025-O-ZD-003), by the Key Research Project of Beijing Natural Science Foundation (No. Z220013), by the CAMS Innovation Fund for Medical Sciences (CIFMS) (No. 2024-I2M-C\u0026amp;T-B-029), by the National High Level Hospital Clinical Research Funding (2022-PUMCH-B-083, 2022-PUMCH-C-010, 2022-PUMCH-C-022 and 2022-PUMCH-D-003), and by Peking Union Medical College Hospital Talent Cultivation Program (Category D) (No. UHB12577). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and registration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe Institutional Review Board of Peking Union Medical College Hospital approved this study (No. SK-1289).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatement of submission\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe paper is not under consideration by another journal, and the results presented in this work have not been previously presented or published.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConsent for publication has been obtained from all patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll the data used in this study are contained in the supplemental files.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eKurman, R.J., et al., eds. WHO Classification of Tumours of Female Reproductive Organs. 4 ed. World Health Organization Classification of Tumours. 2014, International Agency for Research on Cancer (IARC): Lyon.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eZhou, J., et al., Influence of different treatment modalities on survival of patients with low-grade endometrial stromal sarcoma: A retrospective cohort study. Int J Surg, 2015. 23(Pt A): p. 147\u0026thinsp;\u0026ndash;\u0026thinsp;51.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSeagle, B.L., et al., Low-grade and high-grade endometrial stromal sarcoma: A National Cancer Database study. Gynecol Oncol, 2017. 146(2): p. 254\u0026ndash;262.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBai, H., et al., Ovary and uterus-sparing procedures for low-grade endometrial stromal sarcoma: A retrospective study of 153 cases. Gynecol Oncol, 2014. 132(3): p. 654\u0026ndash;60.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMaeda, O., et al., Long-term survival in low-grade endometrial stromal sarcoma with childbirth and multidisciplinary treatment: a case report. J Med Case Rep, 2015. 9: p. 233.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLaurelli, G., et al., Fertility-sparing management of low-grade endometrial stromal sarcoma: analysis of an institutional series and review of the literature. Eur J Obstet Gynecol Reprod Biol, 2015. 195: p. 61\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNasioudis, D., et al., Safety of ovarian preservation in premenopausal women with stage I uterine sarcoma. J Gynecol Oncol, 2017. 28(4): p. e46.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eStewart, L.E., et al., Impact of oophorectomy and hormone suppression in low grade endometrial stromal sarcoma: A multicenter review. Gynecol Oncol, 2018. 149(2): p. 297\u0026ndash;300.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFeng, W., et al., Prognostic indicators in WHO 2003 low-grade endometrial stromal sarcoma. Histopathology, 2013. 62(5): p. 675\u0026ndash;87.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNasioudis, D., et al., Ovarian preservation for low-grade endometrial stromal sarcoma: a systematic review of the literature and meta-analysis. Int J Gynecol Cancer, 2019. 29(1): p. 126\u0026ndash;132.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePink, D., et al., Harm or benefit of hormonal treatment in metastatic low-grade endometrial stromal sarcoma: Single center experience with 10 cases and review of the literature. Gynecol Oncol, 2006. 101(3): p. 464\u0026ndash;469.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKashiyama, T., et al., Low-grade endometrial stromal sarcoma developing in a postmenopausal woman under toremifene treatment for breast cancer. J Obstet Gynaecol Res, 2013. 39(1): p. 424\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eZhang, Y., et al., Low-Grade Endometrial Stromal Sarcoma and Uterine Adenosarcoma: A Comparison of Clinical Manifestations and Outcomes. J Cancer, 2019. 10(15): p. 3352\u0026ndash;3360.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eOliva, E., J.F. Egger, and R.H. Young, Primary endometrioid stromal sarcoma of the ovary: a clinicopathologic study of 27 cases with morphologic and behavioral features similar to those of uterine low-grade endometrial stromal sarcoma. Am J Surg Pathol, 2014. 38(3): p. 305\u0026ndash;15.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGuidozzi, F., Estrogen therapy in gynecological cancer survivors. Climacteric, 2013. 16(6): p. 611\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNasioudis, D., et al., Effect of bilateral salpingo-oophorectomy on the overall survival of premenopausal patients with stage I low-grade endometrial stromal sarcoma; a National Cancer Database analysis. Gynecol Oncol, 2020. 157(3): p. 634\u0026ndash;638.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWu, J., et al., A nomogram for predicting overall survival in patients with low-grade endometrial stromal sarcoma: A population-based analysis. Cancer Commun (Lond), 2020. 40(7): p. 301\u0026ndash;312.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKoh, W.J., et al., Uterine Sarcoma, Version 1.2016: Featured Updates to the NCCN Guidelines. J Natl Compr Canc Netw, 2015. 13(11): p. 1321\u0026ndash;31.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSoft tissue and visceral sarcomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol, 2014. 25 Suppl 3: p. iii102-12.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAmant, F., et al., Gynecologic Cancer InterGroup (GCIG) consensus review for endometrial stromal sarcoma. Int J Gynecol Cancer, 2014. 24(9 Suppl 3): p. S67-72.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFlam, F. and A. R\u0026aring;destad, Endometrial stromal sarcoma diagnosed by operative hysteroscopy. Hum Reprod, 1996. 11(12): p. 2797\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGonzalez-Bosquet, E., et al., Hysteroscopic diagnosis of a high-grade endometrial sarcoma in a 41-year-old woman. Eur J Gynaecol Oncol, 2010. 31(5): p. 579\u0026ndash;81.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eVilos, G.A., et al., Hysteroscopic endomyometrial resection of three uterine sarcomas. J Am Assoc Gynecol Laparosc, 2001. 8(4): p. 545\u0026ndash;51.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCui, R., et al., The clinical benefits of hormonal treatment for LG-ESS: a meta-analysis. Arch Gynecol Obstet, 2019. 300(5): p. 1167\u0026ndash;1175.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLi, L., et al., Treatment of symptomatic adenomyosis with the levonorgestrel-releasing intrauterine system. Int J Gynaecol Obstet, 2019. 146(3): p. 357\u0026ndash;363.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKriplani, A., et al., Efficacy of the levonorgestrel-releasing intrauterine system in uterine leiomyoma. Int J Gynaecol Obstet, 2012. 116(1): p. 35\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eChen, X., The current situation of the levonorgestrel intrauterine system (LNG-IUS) in conservative treatment for patients with early-stage endometrial cancer and atypical hyperplasia. J Gynecol Oncol, 2019. 30(4): p. e79.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJareid, M., et al., Levonorgestrel-releasing intrauterine system use is associated with a decreased risk of ovarian and endometrial cancer, without increased risk of breast cancer. Results from the NOWAC Study. Gynecol Oncol, 2018. 149(1): p. 127\u0026ndash;132.\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":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-medical-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejmr","sideBox":"Learn more about [European Journal of Medical Research](http://eurjmedres.biomedcentral.com)","snPcode":"40001","submissionUrl":"https://submission.nature.com/new-submission/40001/3","title":"European Journal of Medical Research","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Low-grade endometrial stromal sarcoma, fertility-sparing surgery, ovarian preservation, recurrence, mortality","lastPublishedDoi":"10.21203/rs.3.rs-7098205/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7098205/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLittle is known about the oncologic results of patients with low-grade endometrial stromal sarcoma (LGESS) with fertility preservation. This study investigated the prognosis of fertility-sparing surgeries and relevant obstetrical outcomes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll eligible patients in the study center were retrospectively reviewed if they consented to surgical treatment for primary LGESS from February 2012 to June 2019 in the study center. Follow-up of fertility and oncologic outcomes wascarried out until June 1, 2020.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAmong 135 patients who underwent surgical therapy for primary uterine LGESS, 21 (15.6%) and 42 (31.1%) underwent fertility-sparing surgery and ovarian preservation, respectively. After a median follow-up of 38.5 (range 5–98) months, differences were detected in the recurrence rates among patients with and without fertility-sparing surgery (47.6% versus 15.8%, \u003cem\u003ep\u003c/em\u003e=0.002) or with and without ovarian preservation (42.9% versus 10.8%, \u003cem\u003ep\u003c/em\u003e\u0026lt;0.001). Fertility-sparing surgery and ovarian preservation significantly increased the risk of recurrence in the entire cohort (hazard ratio [HR] 3.5 and 5.2, 95% confidence interval [CI] 1.6-7.6 and 2.4-11.3, \u003cem\u003ep\u003c/em\u003e=0.002 and \u0026lt;0.001) and in stage I patients (HR 2.6 and 3.1, 95% CI 1.0-6.4 and 1.3-7.4, \u003cem\u003ep\u003c/em\u003e=0.041 and 0.011). No factor was found to be associated with increased mortality risk. Among the 9 patients who attempted pregnancy, 7 (77.8%) achieved 8 live births. All three advanced-stage patients who underwentfertility-sparing surgery experienced recurrence without successful conception.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFertility-sparing surgery for LGESS results in a significantly increased risk of recurrence but not mortality and has promising results in terms of live births in stage I patients.\u003c/p\u003e","manuscriptTitle":"Fertility-sparing treatment for low-grade endometrial stromal sarcoma","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-27 05:53:23","doi":"10.21203/rs.3.rs-7098205/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-10-02T01:34:58+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-08T14:47:46+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-01T12:43:44+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"138381878039009296639215496192454624771","date":"2025-08-18T10:56:57+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"196661723691880246083204396717993537006","date":"2025-08-15T19:54:22+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-08-15T18:58:14+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-07-11T15:10:36+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-07-11T10:50:51+00:00","index":"","fulltext":""},{"type":"submitted","content":"European Journal of Medical Research","date":"2025-07-11T06:01:42+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-medical-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejmr","sideBox":"Learn more about [European Journal of Medical Research](http://eurjmedres.biomedcentral.com)","snPcode":"40001","submissionUrl":"https://submission.nature.com/new-submission/40001/3","title":"European Journal of Medical Research","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a2b11be9-3898-4ae4-bf78-247b2b350b08","owner":[],"postedDate":"August 27th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-01-12T16:00:37+00:00","versionOfRecord":{"articleIdentity":"rs-7098205","link":"https://doi.org/10.1186/s40001-025-03830-7","journal":{"identity":"european-journal-of-medical-research","isVorOnly":false,"title":"European Journal of Medical Research"},"publishedOn":"2026-01-05 15:56:56","publishedOnDateReadable":"January 5th, 2026"},"versionCreatedAt":"2025-08-27 05:53:23","video":"","vorDoi":"10.1186/s40001-025-03830-7","vorDoiUrl":"https://doi.org/10.1186/s40001-025-03830-7","workflowStages":[]},"version":"v1","identity":"rs-7098205","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7098205","identity":"rs-7098205","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}