Impact of lymphovascular space invasion on lymph node metastasis in low-grade endometrial cancer with shallow myometrial invasion and negative imaging.

Impact of lymphovascular space invasion on lymph node metastasis in low-grade endometrial cancer with shallow myometrial invasion and negative imaging. | 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 Impact of lymphovascular space invasion on lymph node metastasis in low-grade endometrial cancer with shallow myometrial invasion and negative imaging. Teruyuki Yoshimitsu, Hidetaka Nomura, Toshiaki Watanabe, Satoki Misaka, and 13 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9122530/v1 This work is licensed under a CC BY 4.0 License Status: Under Revision Version 1 posted 5 You are reading this latest preprint version Abstract Background: This study aimed to determine the frequency of lymph node metastasis in endometrioid carcinomas of grades 1 or 2 with shallow myometrial invasion and lymphovascular space invasion (LVSI). Methods: After obtaining institutional review board approval, we retrospectively reviewed the medical records of 133 patients with endometrial cancer who were treated at our hospital between January 2007 and December 2022. These patients met the following criteria: endometrioid carcinoma grade 1 or 2, myometrial invasion less than 50%, and preoperative CT showing regional lymph nodes with a short diameter less than 10 mm. All patients underwent pelvic and para-aortic lymphadenectomies. Results: Lymph node metastasis was identified in 10 (8%) cases. LVSI was significantly associated with lymph node metastasis (odds ratio 8.278, 95% CI 2.239–32.035, P-value: 0.002). LVSI was present in 32 (24%) of the 133 cases, and among these, 7 (22%) had lymph node metastasis. Of the patients with lymph node involvement, 3 (44%) had only pelvic metastases, 2 (28%) had only para-aortic metastases, and 2 (28%) had both pelvic and para-aortic metastases. All patients received postoperative adjuvant chemotherapy, and there were no recurrences or deaths during the study period among those with lymph node involvement. Conclusion: Even in endometrioid carcinoma grade 1–2 with shallow myometrial invasion, where lymph node metastasis is not suspected on imaging, the presence of LVSI may be a crucial factor in deciding whether to perform subsequent lymphadenectomy. endometrial cancer lymphovascular space invasion lymphadenectomy lymph node metastasis Figures Figure 1 Synopsis In low-grade endometrioid carcinoma with shallow invasion, nodal metastasis occurred in 8%. LVSI significantly predicted nodal spread (OR 8.278). LVSI-positive cases may warrant lymphadenectomy despite negative imaging. Introduction As initial treatment for endometrial cancer, total hysterectomy and bilateral salpingo-oophorectomy are standard procedures, often complemented by retroperitoneal lymphadenectomy and omentectomy [ 1 , 2 ]. The therapeutic significance of regional lymphadenectomy, however, remains a matter of controversy. In Japan, the Japan Clinical Oncology Group (JCOG) 1412 clinical trial is currently investigating the therapeutic value of para-aortic lymphadenectomy in intermediate- to high-risk uterine cancer recurrence, with results eagerly anticipated. Nonetheless, lymph node metastasis is a known poor prognostic factor for endometrial cancer. In Japan, pelvic lymphadenectomy is generally recommended, and para-aortic lymphadenectomy is proposed for staging and to determine the need for adjuvant therapy in patients presumed to be at intermediate- to high-risk of recurrence preoperatively. Conversely, the omission of regional lymphadenectomy has been suggested for patients with low-risk disease [ 3 ]. Several risk factors for lymph node metastasis in endometrial cancer have been reported, including tumor diameter ≥ 2 cm [ 4 ], myometrial invasion ≥ 50% [ 5 ], grade 3 histology [ 6 ], lymphovascular space invasion (LVSI) [ 5 ], and cervical stromal invasion [ 7 ]. Conversely, patients without these factors are presumed to have a low risk of regional lymph node metastasis. The Mayo criteria, for instance, suggest a low risk of lymph node metastasis when the histological type is grade 1–2, myometrial invasion is less than 50%, and tumor diameter is ≤ 2 cm [ 8 ]. Among these risk factors, most can be estimated preoperatively through imaging and histological examination, except for LVSI, which can only be definitively determined by histopathological examination after surgery. Currently, regional lymphadenectomy is often omitted when preoperative MRI and CT findings, along with initial histological results, suggest a low risk of lymph node metastasis. However, when LVSI is subsequently identified postoperatively, there is no consensus on whether to proceed with a two-stage surgery for complete staging or to initiate chemotherapy despite inadequate staging. This dilemma arises due to concerns about the burden of two surgeries and potential delays in commencing additional treatment. In this study, we investigated the relationship between the presence of LVSI and lymph node metastasis in endometrioid carcinoma grade 1 or 2 with shallow myometrial invasion. Patients and Methods Patients We retrospectively included patients treated for endometrial cancer at our hospital between January 2007 and December 2023 who underwent total hysterectomy with pelvic and para-aortic lymphadenectomy. Our study focused on endometrioid carcinoma grade 1–2, excluding grade 3 endometrioid carcinoma and other non-endometrioid high-grade histological types based on postoperative histopathological examination. All included patients had < 50% myometrial invasion on postoperative pathology, and preoperative CT scans showed regional lymph nodes with a short-axis diameter < 10 mm, indicating no preoperative suspicion of lymph node metastasis. Lymphadenectomy was performed as a one- or two-stage procedure using laparotomy, laparoscopic, or robot-assisted surgical approaches. The cephalic extent of lymphadenectomy reached the level of the left renal vein. LVSI was evaluated using both hematoxylin and eosin (HE) staining and immunohistochemical staining with D2-40. Based on postoperative histopathological examination, patients at high risk of recurrence were treated with adjuvant chemotherapy; those at low risk were omitted; and those at intermediate risk were treated with or without adjuvant chemotherapy, depending on the case. The chemotherapy regimen typically consisted of paclitaxel (175 mg/m2) and carboplatin (AUC6), with a target of 6 cycles. For patients in whom regional lymphadenectomy was initially omitted and only hysterectomy was performed, if pelvic lymph node metastasis was confirmed at initial surgery, we recommended additional para-aortic lymphadenectomy to complete surgical staging. Furthermore, if postoperative pathology revealed LVSI, we advised additional pelvic and para-aortic lymphadenectomy. Statistical analysis The relationship between lymph node metastasis risk factors and lymph node metastasis was investigated. Risk factors for lymph node metastasis were LVSI, ≥ 50% myometrial invasion, and a maximum tumor diameter of ≥ 2 cm on preoperative imaging. Associations between lymph node metastasis and these risk factors were tested using Fisher’s exact test. A P-value of < 0.05 was considered statistically significant unless otherwise indicated. All statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria). More precisely, EZR is a modified version of R Commander designed to add statistical functions frequently used in biostatistics. Results Patient characteristics are summarized in Table 1 . A total of 133 patients met our inclusion criteria. The median age was 53 years. Primary surgery was performed in 96% of patients, with 4% undergoing secondary surgery. The initial decision to perform one-stage surgery, including para-aortic lymphadenectomy, was typically based on preoperative suspicion of Stage IB or higher or on histological grade 3 or non-endometrioid high-grade carcinoma. Some reasons for this decision overlapped. For two-stage surgeries, one patient had positive pelvic lymph node metastasis on initial histopathological examination, and four patients had positive LVSI. Table 1 Patient characteristics (n = 133) Characteristic Age, years 53 (49–59) BMI, kg/m 2 21.8 (19.8–24.2) One-stage or two-stage surgery One-stage surgery 128 (96%) Two-stage surgery 5 (4%) Reasons for one-stage surgery* Estimated stage is ⅠB or more 89 Preoperative pathological classification; high grade carcinoma 14 Others 27 Reasons for two-stage surgery Pelvic lymph node metastasis 1 Lymphovascular space invasion 4 Dates are presented as median(inter-quartile range) or n (%). BMI, body mass index * There are duplicate selections. Results are presented in Table 2 . Of the 133 patients, 123 (92%) had no regional lymph node metastasis, while 10 (8%) had confirmed lymph node metastasis. Among those with metastasis, 6 (5%) had metastasis only in the pelvic lymph nodes, and 4 (3%) had metastasis to para-aortic lymph nodes. LVSI was positive in 32 patients (24%). Vascular invasion (as a broader category) was observed in 12 (10%) patients. Myometrial invasion was less than one-half in 115 patients (86%) and absent in 18 (14%). The median diameter of the largest tumor on preoperative imaging was 42 mm. The median number of pelvic lymph nodes removed was 32, and the median number of para-aortic lymph nodes removed was 22. Table 2 Postoperative results Characteristics Lymphovascular space invasion Positive 32 (24%) Negative 101 (76%) Vascular space invasion Positive 12 (10%) Negative 121 (90%) Myometrial invasion (less than 1/2) Positive 115 (86%) Negative 18 (14%) Tumor diameter Less than 2cm 20 (15%) Over 2cm 113 (85%) Lymph node metastasis None 123 (92%) Pelvic only 6 (5%) Para-aortic 4 (3%) The median number of removed lymph nodes Pelvic 32 (26–39.75) Para-aortic 22 (17.75–29.25) Dates are presented as median (inter-quartile range) or n (%). A univariate analysis of the association between each lymph node metastasis risk factor and lymph node metastasis is presented in Table 3 . For LVSI, the odds ratio (OR) was 8.278 (95% confidence interval [CI]: 2.239–32.035, P-value: 0.002), indicating a significant association. The OR for myometrial invasion of < 1/2 was 1.041 (95% CI: 0.166–6.541, P-value: 0.966), and the OR for tumor size ≥ 2 cm was 1.182 (95% CI: 0.19–7.352, P-value: 0.858). Neither myometrial invasion nor tumor size showed a statistically significant association with lymph node metastasis in this analysis. Multivariate analysis was not performed due to the small number of events. Table 3 Relationship between lymph node metastasis and clinical prognostic factors Characteristics No LM LM OR 95% CI p-value LVSI 8.278 2.139–32.035 0.002 Negative 98 (73.6%) 3 (2.2%) Positive 25 (19.0%) 7 (5.2%) MI 1.041 0.166–6.541 0.966 Negative 17 (12.8%) 1 (0.75%) Positive 106 (79.7%) 9 (6.75%) TD 1.182 0.19–7.352 0.858 < 2cm 19 (14.2%) 1 (0.75%) ≥ 2cm 104 (78.3%) 9 (6.75%) LM, lymph node metastasis; LVSI, lymphovascular space invasion; MI, myometrial invasion; TD, tumor diameter The relationship between LVSI and lymph node metastasis is further illustrated in Fig. 1 . Of the 133 eligible patients, 32 (24%) had positive LVSI, and 7 (22%) of those had positive lymph node metastasis. Details of cases with positive regional lymph nodes are presented in Table 4 , and all patients received adjuvant chemotherapy. Although the number of cases was small, 2 of 7 (28%) had metastasis confined to the para-aortic lymph nodes. Importantly, none of the patients with regional lymph node metastasis experienced recurrence or death during a median observation period of approximately 4 years. Table 4 The details of lymph node metastatic cases Status of LM Recurrence case Death case Only PL 6 (60%) 0 0 Only PAN 2 (20%) 0 0 PL and PAN 2 (20%) 0 0 LM, lymph node metastasis; PL, pelvic lymph node metastasis; PAN, para-aortic lymph node metastasis Dates are presented as n (%). Discussion This study shows that among patients with endometrioid carcinoma grade 1–2, shallow myometrial invasion, and no preoperative imaging suspicion of lymph node metastasis, 22% with LVSI had confirmed nodal metastases. Various reports have established LVSI as an independent risk factor for lymph node metastasis in endometrial cancer [ 9 , 10 ]. Watanabe et al. reported that LVSI is an independent predictor of lymph node metastasis in so-called low-risk recurrent uterine cancers, defined as less than one-half myometrial invasion and endometrioid carcinoma grade 1–2 [ 11 ]. However, there are differences in background and results between existing studies and our present study. In the first two studies, histology included not only low-grade carcinoma, such as endometrioid carcinoma grade 1–2, but also high-grade carcinoma, including carcinosarcoma and endometrioid carcinoma grade 3. Furthermore, in the latter study, lymph node metastasis was limited to pelvic lymph nodes. A key strength of our study is that the histological type was strictly limited to low-grade carcinoma (grade 1–2 endometrioid carcinoma), and we investigated the relationship between LVSI and metastasis in both pelvic and para-aortic lymph nodes. Although the association between LVSI and lymph node metastasis could be demonstrated only by univariate analysis in this study due to the small number of events, our findings indicate that some patients who initially appear to have no suspicion of lymph node metastasis (e.g., grade 1–2 endometrioid carcinoma with shallow myometrial invasion and negative imaging) may still have positive LVSI. Crucially, 22% of patients with positive LVSI had lymph node metastasis, even in these seemingly low-risk cases. In conclusion, even in patients with grade 1–2 endometrioid carcinoma and shallow myometrial invasion, where lymph node metastasis was not suspected on imaging, positive LVSI may be a valuable indicator when considering lymphadenectomy extending to the para-aortic region to accurately determine the stage of progression. However, it is important to acknowledge the reported increases in operative time, blood loss, and overall perioperative complications, as well as the impact on postoperative intestinal peristalsis, associated with extending lymphadenectomy to the para-aortic region [ 12 – 14 ]. Therefore, the optimal extent of lymphadenectomy remains a critical question. In our study, among 133 cases of endometrioid carcinoma grade 1–2 with less than one-half myometrial invasion, 6 cases (60%) had metastasis solely to pelvic lymph nodes, 2 cases (20%) had metastasis to both pelvic and para-aortic lymph nodes, and 2 cases (20%) had metastasis only to para-aortic lymph nodes. The relatively high rate of isolated para-aortic lymph node metastasis (20%) in our cohort suggests that para-aortic lymph node dissection should still be considered even in the absence of pelvic lymph node metastasis. Other reports, however, report differing rates of para-aortic lymph node metastasis. Ulas et al. reported that among 67 cases of lymph node metastasis, 37 (56%) had only pelvic lymph node metastasis, 26 (39%) had both pelvic and para-aortic lymph node metastasis, and 4 (5%) had only para-aortic lymph node metastasis [ 10 ]. Mariani et al. reported that among 281 cases of endometrioid carcinoma with grade 1–2, less than one-half myometrial invasion, and tumor diameter less than 2 cm, 33% had only pelvic lymph node metastasis, 51% had both pelvic and para-aortic lymph node metastasis, and 16% had only para-aortic lymph node metastasis [ 15 ]. In comparison with these studies, although our overall number of cases was smaller, the rate of para-aortic lymph node metastasis was notably higher. One hypothesis for this higher rate in our study is more thorough lymph node retrieval. The median number of para-aortic lymph nodes removed in the SEPAL study was 23, and at least 10 are considered therapeutically necessary [ 16 ]. Furthermore, the UICC 6th edition defines dissection as the removal of 11 or more lymph nodes, and the 7th edition defines it as 6 or more [ 17 ]. In the LAP-2 study, the median number of lymph nodes removed was 7 (range: 4–11), but their para-aortic lymphadenectomy was limited to the area below the inferior mesenteric artery [ 18 ]. The median number of para-aortic lymph nodes removed at our hospital was 22 (range: 18–29), which we consider sufficient by any standard. We believe this thorough removal contributed to the higher observed para-aortic lymph node metastasis rate compared with other reports. Notably, no cases of recurrence or death were observed among patients with lymph node metastases in this study during the observation period. It's crucial to clarify that this study did not examine the therapeutic significance of lymph node dissection, which would require a comparison of prognosis with patients who did not undergo lymph node dissection. Nevertheless, the absence of recurrence or death in our lymph node metastasis- positive cohort is an important finding. Sriram Venigalla et al. conducted a retrospective study of 7, 250 patients with Stage I endometrial cancer (excluding endometrioid carcinoma) and reported that lymphadenectomy improved prognosis, especially when lymph nodes were dissected up to the para- aortic region and when more than 15 nodes were removed [ 19 ]. Similarly, Brandon- Luke L. Seagle et al., in a study of 152, 152,702 cases of Stage I- IIIB (FIGO 2008) endometrial cancer (encompassing endometrioid carcinoma grade 1–3, serous carcinoma, and carcinosarcoma) without lymph node metastasis, found that prognosis improved with the removal of 15 or more lymph nodes, and with every 5 additional lymph nodes removed, even in the absence of lymph node metastasis. However, significant differences in differentiation and the advanced stage were noted [ 20 ]. In the first two reports, it was inferred that lymphadenectomy contributed to improved prognosis by enabling accurate staging and appropriate postoperative adjuvant therapy. In the latter report, it was suggested that a reduction in the risk of lymph node recurrence contributed to the improved prognosis despite the absence of lymph node metastasis. On the other hand, Lily Tran et al. focused on the size of uterine cancer lymph node metastasis, reporting that the prognosis of isolated tumor cells (ITCs) with a diameter of less than 0. 2 mm was not significantly different from that of patients with negative lymph nodes [ 21 ]. The reason none of the patients with lymph node metastases in this study experienced recurrence or death may be attributed to the accurate determination of the stage of progression and appropriate postoperative adjuvant therapy. Additionally, since our study was limited to cases where all lymph nodes had a short diameter of less than 10 mm on preoperative imaging, we speculate that the small size of the metastases may not have been a poor prognostic factor. This study has several limitations. It is a single-center, retrospective study, and the number of cases is limited. Interpretation of LVSI also requires caution. Although LVSI was previously excluded from the FIGO staging of endometrial cancer and often used as a recurrence risk factor in Japanese guidelines, the FIGO 2023 staging classification now incorporates LVSI. The absence of LVSI or fewer than five invasions is classified as advanced Stage I, whereas five or more invasions are defined as advanced Stage II [22]. Although this advanced staging has not yet been adopted in Japan, it suggests a future possibility of evaluating patients based on the degree of LVSI. Declarations Conflict of interest: The authors have no competing interests to declare that are relevant to the content of this article. Ethics approval: This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Institutional Review Board of the Cancer Institute Hospital (Approval No. 2023-GB-079). Consent to participate: As this was a retrospective study, the Institutional Review Board waived the requirement for informed consent. Patients were allowed to opt out via the hospital's website. Consent for publication: Not applicable. Funding: This study was partially supported by the Supporting Fund of Gynecology of Cancer Institute Hospital. The authors declare that no other specific funding was received for this work. Authors' contributions: All authors contributed to the study's conception and design. Material preparation, data collection, and analysis were performed by Teruyuki Yoshimitsu, Hidetaka Nomura, Toshiaki Watanabe, Satoki Misaka, Yusuke Butsuhara, Shogo Nishino, Mayumi Kamata, Motoko Kanno, Akiko Abe, Atsushi Fusegi, Makiko Omi, Yoichi Aoki, Sachiho Netsu, Terumi Tanigawa, Sanshiro Okamoto, Mayu Yunokawa, and Hiroyuki Kanao. The first draft of the manuscript was written by Teruyuki Yoshimitsu, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Acknowledgements: The Supporting Fund of Gynecology of Cancer Institute Hospital partially supported this study. We thank Editage ( www.editage.com ) for its English language editing services. Availability of data and materials: The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. References Triada Doulgeraki S, Vagios E, Kavoura P, Yiannou I, Messini A, Nonni et al Mismatch repair status in high-grade endometrial carcinoma of endometrioid and non-endometrioid type. J BUON 2019 Sep-Oct ;24(5):2020–2027 Yeh C, Lee S, Lheureux, Amit M, Oza (2017) Treatment strategies for endometrial cancer: current practice and perspective. Curr Opin Obstet Gynecol 29(1):47–58 Sari ME, Yalcin İbrahim, Sahin H, Meydanli MM (2017) Tayfun Gungor. Risk factors for paraaortic lymph node metastasis in endometrial cancer. Int J Clin Oncol 22(5):937–944 Chirag Shah EB, Johnson E, Everett H, Tamimi B, Greer E, Swisher et al (2005) Does size matter? Tumor size and morphology as predictors of nodal status and recurrence in endometrial cancer. Gynecol Oncol 99(3):564–570 Srinivas Kondalsamy-Chennakesavan, van Vugt S, Sanday K, Nicklin J, Land R, Perrin L et al (2010) Evaluation of tumor-free distance and depth of myometrial invasion as prognostic factors for lymph node metastases in endometrial cancer. Int J Gynecol Cancer 20(7):1217–1221 Chi DS, Barakat RR, Palayekar MJ, Levine DA, Sonoda Y, Alektiar K et al (2008 Mar-Apr) The incidence of pelvic lymph node metastasis by FIGO staging for patients with adequately surgically staged endometrial adenocarcinoma of endometrioid histology. Int J Gynecol Cancer 18(2):269–273 Kamura T, Yahata H, Shigematsu T, Ogawa S, Amada S, Kaku T et al (1999) Predicting pelvic lymph node metastasis in endometrial carcinoma. Gynecol Oncol 72(3):387–391 Mariani A, Webb MJ, Keeney GL, Haddock MG, Calori G, Podratz KC (2000) Low-risk corpus cancer: is lymphadenectomy or radiotherapy necessary? Am J Obstet Gynecol 182(6):1506–1519 Gilani S, Anderson I, Fathallah L, Mazzara P (2014) Factors predicting nodal metastasis in endometrial cancer. Arch Gynecol Obstet 290(6):1187–1193 Ulas Solmaz E, Mat ML, Dereli V, Turan G, Tosun A, Dogan et al (2015 Mar) Lymphovascular space invasion and positive pelvic lymph nodes are independent risk factors for para-aortic nodal metastasis in endometrioid endometrial cancer. Eur J Obstet Gynecol Reprod Biol 186:63–67 Watanabe M, Aoki Y, Kase H, Fujita K, Tanaka K Low risk endometrial cancer: a study of pelvic lymph node metastasis Marcus Q, Bernardini, Joan K, Murphy (2009) Issues surrounding lymphadenectomy in the management of endometrial cancer. J Surg Oncol 99(4):232–241 Yosuke Konno Y, Todo S, Minobe H, Kato K, Okamoto S, Sudo et al (2011) A retrospective analysis of postoperative complications with or without para-aortic lymphadenectomy in endometrial cancer. Int J Gynecol Cancer 21(2):385–390 Fagotti A, Fanfani F, Ercoli A, Giordano MA, Sallustio G, Scambia G (2007) Postoperative ileus after para-aortic lymphadenectomy: a prospective study. Gynecol Oncol 104(1):46–51 Andrea Mariani SC, Dowdy WA, Cliby BS, Gostout MB, Jones, Timothy O, Wilson, Karl C, Podratz (2008) Prospective assessment of lymphatic dissemination in endometrial cancer: a paradigm shift in surgical staging. Gynecol Oncol 109(1):11–18 Yukiharu Todo H, Kato M, Kaneuchi H, Watari M, Takeda N, Sakuragi (2010) Survival effect of para-aortic lymphadenectomy in endometrial cancer (SEPAL study): a retrospective cohort analysis. Lancet 375(9721):1165–1172 Joan L, Walker MR, Piedmonte, Nick M, Spirtos SM, Eisenkop JB, Schlaerth, Robert S, Mannel et al (2009) Laparoscopy compared with laparotomy for comprehensive surgical staging of uterine cancer: Gynecologic Oncology Group Study LAP2. J Clin Oncol 27(32):5331–5336 Sriram Venigalla, Amit K, Chowdhry (2018) David I Shalowitz. Survival implications of staging lymphadenectomy for non-endometrioid endometrial cancers. Gynecol Oncol 149(3):531–538 Brandon-Luke L, Seagle D, Gilchrist-Scott S, Graves AE, Strohl Wilberto Nieves-Neira, Shohreh Shahabi. Association of Lymph Node Count and Overall Survival in Node-Negative Endometrial Cancers. JCO Clin Cancer Inf. 2017:1: 10.1200/CCI.16.00064 Lily Tran P, Christensen JE, Barroeta K, Hunter J, Sookram, Stephanie M, McGregor et al (2023) Prognostic Significance of Size, Location, and Number of Lymph Node Metastases in Endometrial Carcinoma. Int J Gynecol Pathol 42(4):376–389 Jonathan S, Berek X, Matias-Guiu C, Creutzberg C, Fotopoulou D, Gaffney S, Kehoe et al (2023) Endometrial Cancer Staging Subcommittee, FIGO Women's Cancer Committee. FIGO staging of endometrial cancer: 2023. Int J Gynaecol Obstet 162(2):383 Cite Share Download PDF Status: Under Revision Version 1 posted Editorial decision: Major revisions 14 Apr, 2026 Reviewers agreed at journal 19 Mar, 2026 Reviewers invited by journal 19 Mar, 2026 Editor assigned by journal 16 Mar, 2026 First submitted to journal 14 Mar, 2026 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. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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Institute Hospital of Japanese Fundation for Cancer Reserch","correspondingAuthor":false,"prefix":"","firstName":"Makiko","middleName":"","lastName":"Omi","suffix":""},{"id":608705392,"identity":"864053a1-e02b-48e3-89e8-9694d86fe249","order_by":11,"name":"Yoichi Aoki","email":"","orcid":"","institution":"Cancer Institute Hospital of Japanese Fundation for Cancer Reserch","correspondingAuthor":false,"prefix":"","firstName":"Yoichi","middleName":"","lastName":"Aoki","suffix":""},{"id":608705393,"identity":"e79be782-0423-4c45-a859-d21add093a72","order_by":12,"name":"Sachiho Netsu","email":"","orcid":"","institution":"Cancer Institute Hospital of Japanese Fundation for Cancer Reserch","correspondingAuthor":false,"prefix":"","firstName":"Sachiho","middleName":"","lastName":"Netsu","suffix":""},{"id":608705394,"identity":"43ba9466-117b-4e95-a545-05fbd640b13c","order_by":13,"name":"Terumi Tanigawa","email":"","orcid":"","institution":"Cancer Institute Hospital of Japanese Fundation for Cancer Reserch","correspondingAuthor":false,"prefix":"","firstName":"Terumi","middleName":"","lastName":"Tanigawa","suffix":""},{"id":608705395,"identity":"3fe1b2ae-226c-4da4-949f-d7d39589bab0","order_by":14,"name":"Sacshiro Okamoto","email":"","orcid":"","institution":"Cancer Institute Hospital of Japanese Fundation for Cancer Reserch","correspondingAuthor":false,"prefix":"","firstName":"Sacshiro","middleName":"","lastName":"Okamoto","suffix":""},{"id":608705396,"identity":"dc452692-795c-455e-8ed5-71669968ebba","order_by":15,"name":"Mayu Yunokawa","email":"","orcid":"","institution":"Cancer Institute Hospital of Japanese Fundation for Cancer Reserch","correspondingAuthor":false,"prefix":"","firstName":"Mayu","middleName":"","lastName":"Yunokawa","suffix":""},{"id":608705397,"identity":"6cd374e4-4ba5-445b-9305-8dd1c77030a3","order_by":16,"name":"Hiroyuki Kanao","email":"","orcid":"","institution":"Cancer Institute Hospital of Japanese Fundation for Cancer Reserch","correspondingAuthor":false,"prefix":"","firstName":"Hiroyuki","middleName":"","lastName":"Kanao","suffix":""}],"badges":[],"createdAt":"2026-03-14 12:29:53","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9122530/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9122530/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":105297259,"identity":"48c105c4-6eca-4501-aa3b-c5854fa8fad6","added_by":"auto","created_at":"2026-03-24 13:18:21","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":166627,"visible":true,"origin":"","legend":"\u003cp\u003eThe relationship between LVSI and lymph node metastasis\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-9122530/v1/b9488e6f1028ff326c669ee6.jpeg"},{"id":105297274,"identity":"43028d99-d2fc-418a-8d7f-dd3a96fd3a00","added_by":"auto","created_at":"2026-03-24 13:18:26","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":803627,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9122530/v1/8e4aa9fb-7fbf-4726-b0d4-a0182105d54e.pdf"}],"financialInterests":"","formattedTitle":"Impact of lymphovascular space invasion on lymph node metastasis in low-grade endometrial cancer with shallow myometrial invasion and negative imaging.","fulltext":[{"header":"Synopsis","content":"\u003cp\u003eIn low-grade endometrioid carcinoma with shallow invasion, nodal metastasis occurred in 8%. LVSI significantly predicted nodal spread (OR 8.278). LVSI-positive cases may warrant lymphadenectomy despite negative imaging. \u003c/p\u003e"},{"header":"Introduction","content":"\u003cp\u003eAs initial treatment for endometrial cancer, total hysterectomy and bilateral salpingo-oophorectomy are standard procedures, often complemented by retroperitoneal lymphadenectomy and omentectomy [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The therapeutic significance of regional lymphadenectomy, however, remains a matter of controversy. In Japan, the Japan Clinical Oncology Group (JCOG) 1412 clinical trial is currently investigating the therapeutic value of para-aortic lymphadenectomy in intermediate- to high-risk uterine cancer recurrence, with results eagerly anticipated. Nonetheless, lymph node metastasis is a known poor prognostic factor for endometrial cancer. In Japan, pelvic lymphadenectomy is generally recommended, and para-aortic lymphadenectomy is proposed for staging and to determine the need for adjuvant therapy in patients presumed to be at intermediate- to high-risk of recurrence preoperatively. Conversely, the omission of regional lymphadenectomy has been suggested for patients with low-risk disease [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSeveral risk factors for lymph node metastasis in endometrial cancer have been reported, including tumor diameter\u0026thinsp;\u0026ge;\u0026thinsp;2 cm [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], myometrial invasion\u0026thinsp;\u0026ge;\u0026thinsp;50% [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], grade 3 histology [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], lymphovascular space invasion (LVSI) [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], and cervical stromal invasion [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Conversely, patients without these factors are presumed to have a low risk of regional lymph node metastasis. The Mayo criteria, for instance, suggest a low risk of lymph node metastasis when the histological type is grade 1\u0026ndash;2, myometrial invasion is less than 50%, and tumor diameter is \u0026le;\u0026thinsp;2 cm [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAmong these risk factors, most can be estimated preoperatively through imaging and histological examination, except for LVSI, which can only be definitively determined by histopathological examination after surgery. Currently, regional lymphadenectomy is often omitted when preoperative MRI and CT findings, along with initial histological results, suggest a low risk of lymph node metastasis. However, when LVSI is subsequently identified postoperatively, there is no consensus on whether to proceed with a two-stage surgery for complete staging or to initiate chemotherapy despite inadequate staging. This dilemma arises due to concerns about the burden of two surgeries and potential delays in commencing additional treatment. In this study, we investigated the relationship between the presence of LVSI and lymph node metastasis in endometrioid carcinoma grade 1 or 2 with shallow myometrial invasion.\u003c/p\u003e"},{"header":"Patients and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cp\u003eWe retrospectively included patients treated for endometrial cancer at our hospital between January 2007 and December 2023 who underwent total hysterectomy with pelvic and para-aortic lymphadenectomy. Our study focused on endometrioid carcinoma grade 1\u0026ndash;2, excluding grade 3 endometrioid carcinoma and other non-endometrioid high-grade histological types based on postoperative histopathological examination. All included patients had\u0026thinsp;\u0026lt;\u0026thinsp;50% myometrial invasion on postoperative pathology, and preoperative CT scans showed regional lymph nodes with a short-axis diameter\u0026thinsp;\u0026lt;\u0026thinsp;10 mm, indicating no preoperative suspicion of lymph node metastasis.\u003c/p\u003e \u003cp\u003eLymphadenectomy was performed as a one- or two-stage procedure using laparotomy, laparoscopic, or robot-assisted surgical approaches. The cephalic extent of lymphadenectomy reached the level of the left renal vein. LVSI was evaluated using both hematoxylin and eosin (HE) staining and immunohistochemical staining with D2-40. Based on postoperative histopathological examination, patients at high risk of recurrence were treated with adjuvant chemotherapy; those at low risk were omitted; and those at intermediate risk were treated with or without adjuvant chemotherapy, depending on the case. The chemotherapy regimen typically consisted of paclitaxel (175 mg/m2) and carboplatin (AUC6), with a target of 6 cycles. For patients in whom regional lymphadenectomy was initially omitted and only hysterectomy was performed, if pelvic lymph node metastasis was confirmed at initial surgery, we recommended additional para-aortic lymphadenectomy to complete surgical staging. Furthermore, if postoperative pathology revealed LVSI, we advised additional pelvic and para-aortic lymphadenectomy.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eThe relationship between lymph node metastasis risk factors and lymph node metastasis was investigated. Risk factors for lymph node metastasis were LVSI, \u0026ge;\u0026thinsp;50% myometrial invasion, and a maximum tumor diameter of \u0026ge;\u0026thinsp;2 cm on preoperative imaging. Associations between lymph node metastasis and these risk factors were tested using Fisher\u0026rsquo;s exact test. A P-value of \u0026lt;\u0026thinsp;0.05 was considered statistically significant unless otherwise indicated. All statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria). More precisely, EZR is a modified version of R Commander designed to add statistical functions frequently used in biostatistics.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003ePatient characteristics are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. A total of 133 patients met our inclusion criteria. The median age was 53 years. Primary surgery was performed in 96% of patients, with 4% undergoing secondary surgery. The initial decision to perform one-stage surgery, including para-aortic lymphadenectomy, was typically based on preoperative suspicion of Stage IB or higher or on histological grade 3 or non-endometrioid high-grade carcinoma. Some reasons for this decision overlapped. For two-stage surgeries, one patient had positive pelvic lymph node metastasis on initial histopathological examination, and four patients had positive LVSI.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatient characteristics (n\u0026thinsp;=\u0026thinsp;133)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristic\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e53 (49\u0026ndash;59)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI, kg/m\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21.8 (19.8\u0026ndash;24.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOne-stage or two-stage surgery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOne-stage surgery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e128 (96%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTwo-stage surgery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eReasons for one-stage surgery*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEstimated stage is ⅠB or more\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e89\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePreoperative pathological classification; high grade carcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOthers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eReasons for two-stage surgery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePelvic lymph node metastasis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLymphovascular space invasion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eDates are presented as median(inter-quartile range) or n (%).\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eBMI, body mass index\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003e* There are duplicate selections.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eResults are presented in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Of the 133 patients, 123 (92%) had no regional lymph node metastasis, while 10 (8%) had confirmed lymph node metastasis. Among those with metastasis, 6 (5%) had metastasis only in the pelvic lymph nodes, and 4 (3%) had metastasis to para-aortic lymph nodes. LVSI was positive in 32 patients (24%). Vascular invasion (as a broader category) was observed in 12 (10%) patients. Myometrial invasion was less than one-half in 115 patients (86%) and absent in 18 (14%). The median diameter of the largest tumor on preoperative imaging was 42 mm. The median number of pelvic lymph nodes removed was 32, and the median number of para-aortic lymph nodes removed was 22.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePostoperative results\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLymphovascular space invasion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32 (24%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e101 (76%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVascular space invasion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (10%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e121 (90%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMyometrial invasion (less than 1/2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e115 (86%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18 (14%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor diameter\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLess than 2cm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20 (15%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOver 2cm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e113 (85%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLymph node metastasis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e123 (92%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePelvic only\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePara-aortic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThe median number of removed lymph nodes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePelvic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32 (26\u0026ndash;39.75)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePara-aortic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22 (17.75\u0026ndash;29.25)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eDates are presented as median (inter-quartile range) or n (%).\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eA univariate analysis of the association between each lymph node metastasis risk factor and lymph node metastasis is presented in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. For LVSI, the odds ratio (OR) was 8.278 (95% confidence interval [CI]: 2.239\u0026ndash;32.035, P-value: 0.002), indicating a significant association. The OR for myometrial invasion of \u0026lt;\u0026thinsp;1/2 was 1.041 (95% CI: 0.166\u0026ndash;6.541, P-value: 0.966), and the OR for tumor size\u0026thinsp;\u0026ge;\u0026thinsp;2 cm was 1.182 (95% CI: 0.19\u0026ndash;7.352, P-value: 0.858). Neither myometrial invasion nor tumor size showed a statistically significant association with lymph node metastasis in this analysis. Multivariate analysis was not performed due to the small number of events.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eRelationship between lymph node metastasis and clinical prognostic factors\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo LM\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLM\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eOR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLVSI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8.278\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2.139\u0026ndash;32.035\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e98 (73.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3 (2.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e25 (19.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7 (5.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.041\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.166\u0026ndash;6.541\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.966\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e17 (12.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1 (0.75%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e106 (79.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e9 (6.75%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.182\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.19\u0026ndash;7.352\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.858\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt; 2cm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e19 (14.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1 (0.75%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge; 2cm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e104 (78.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e9 (6.75%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003eLM, lymph node metastasis; LVSI, lymphovascular space invasion; MI, myometrial invasion; TD, tumor diameter\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe relationship between LVSI and lymph node metastasis is further illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Of the 133 eligible patients, 32 (24%) had positive LVSI, and 7 (22%) of those had positive lymph node metastasis.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eDetails of cases with positive regional lymph nodes are presented in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e, and all patients received adjuvant chemotherapy. Although the number of cases was small, 2 of 7 (28%) had metastasis confined to the para-aortic lymph nodes. Importantly, none of the patients with regional lymph node metastasis experienced recurrence or death during a median observation period of approximately 4 years.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eThe details of lymph node metastatic cases\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStatus of LM\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRecurrence case\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDeath case\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOnly PL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (60%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOnly PAN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (20%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePL and PAN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (20%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eLM, lymph node metastasis; PL, pelvic lymph node metastasis; PAN, para-aortic lymph node metastasis\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eDates are presented as n (%).\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study shows that among patients with endometrioid carcinoma grade 1\u0026ndash;2, shallow myometrial invasion, and no preoperative imaging suspicion of lymph node metastasis, 22% with LVSI had confirmed nodal metastases.\u003c/p\u003e \u003cp\u003eVarious reports have established LVSI as an independent risk factor for lymph node metastasis in endometrial cancer [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Watanabe et al. reported that LVSI is an independent predictor of lymph node metastasis in so-called low-risk recurrent uterine cancers, defined as less than one-half myometrial invasion and endometrioid carcinoma grade 1\u0026ndash;2 [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. However, there are differences in background and results between existing studies and our present study. In the first two studies, histology included not only low-grade carcinoma, such as endometrioid carcinoma grade 1\u0026ndash;2, but also high-grade carcinoma, including carcinosarcoma and endometrioid carcinoma grade 3. Furthermore, in the latter study, lymph node metastasis was limited to pelvic lymph nodes. A key strength of our study is that the histological type was strictly limited to low-grade carcinoma (grade 1\u0026ndash;2 endometrioid carcinoma), and we investigated the relationship between LVSI and metastasis in both pelvic and para-aortic lymph nodes.\u003c/p\u003e \u003cp\u003eAlthough the association between LVSI and lymph node metastasis could be demonstrated only by univariate analysis in this study due to the small number of events, our findings indicate that some patients who initially appear to have no suspicion of lymph node metastasis (e.g., grade 1\u0026ndash;2 endometrioid carcinoma with shallow myometrial invasion and negative imaging) may still have positive LVSI. Crucially, 22% of patients with positive LVSI had lymph node metastasis, even in these seemingly low-risk cases. In conclusion, even in patients with grade 1\u0026ndash;2 endometrioid carcinoma and shallow myometrial invasion, where lymph node metastasis was not suspected on imaging, positive LVSI may be a valuable indicator when considering lymphadenectomy extending to the para-aortic region to accurately determine the stage of progression.\u003c/p\u003e \u003cp\u003eHowever, it is important to acknowledge the reported increases in operative time, blood loss, and overall perioperative complications, as well as the impact on postoperative intestinal peristalsis, associated with extending lymphadenectomy to the para-aortic region [\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Therefore, the optimal extent of lymphadenectomy remains a critical question. In our study, among 133 cases of endometrioid carcinoma grade 1\u0026ndash;2 with less than one-half myometrial invasion, 6 cases (60%) had metastasis solely to pelvic lymph nodes, 2 cases (20%) had metastasis to both pelvic and para-aortic lymph nodes, and 2 cases (20%) had metastasis only to para-aortic lymph nodes. The relatively high rate of isolated para-aortic lymph node metastasis (20%) in our cohort suggests that para-aortic lymph node dissection should still be considered even in the absence of pelvic lymph node metastasis.\u003c/p\u003e \u003cp\u003eOther reports, however, report differing rates of para-aortic lymph node metastasis. Ulas et al. reported that among 67 cases of lymph node metastasis, 37 (56%) had only pelvic lymph node metastasis, 26 (39%) had both pelvic and para-aortic lymph node metastasis, and 4 (5%) had only para-aortic lymph node metastasis [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Mariani et al. reported that among 281 cases of endometrioid carcinoma with grade 1\u0026ndash;2, less than one-half myometrial invasion, and tumor diameter less than 2 cm, 33% had only pelvic lymph node metastasis, 51% had both pelvic and para-aortic lymph node metastasis, and 16% had only para-aortic lymph node metastasis [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. In comparison with these studies, although our overall number of cases was smaller, the rate of para-aortic lymph node metastasis was notably higher. One hypothesis for this higher rate in our study is more thorough lymph node retrieval. The median number of para-aortic lymph nodes removed in the SEPAL study was 23, and at least 10 are considered therapeutically necessary [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Furthermore, the UICC 6th edition defines dissection as the removal of 11 or more lymph nodes, and the 7th edition defines it as 6 or more [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. In the LAP-2 study, the median number of lymph nodes removed was 7 (range: 4\u0026ndash;11), but their para-aortic lymphadenectomy was limited to the area below the inferior mesenteric artery [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. The median number of para-aortic lymph nodes removed at our hospital was 22 (range: 18\u0026ndash;29), which we consider sufficient by any standard. We believe this thorough removal contributed to the higher observed para-aortic lymph node metastasis rate compared with other reports.\u003c/p\u003e \u003cp\u003eNotably, no cases of recurrence or death were observed among patients with lymph node metastases in this study during the observation period. It's crucial to clarify that this study did not examine the therapeutic significance of lymph node dissection, which would require a comparison of prognosis with patients who did not undergo lymph node dissection. Nevertheless, the absence of recurrence or death in our lymph node metastasis- positive cohort is an important finding. Sriram Venigalla et al. conducted a retrospective study of 7, 250 patients with Stage I endometrial cancer (excluding endometrioid carcinoma) and reported that lymphadenectomy improved prognosis, especially when lymph nodes were dissected up to the para- aortic region and when more than 15 nodes were removed [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Similarly, Brandon- Luke L. Seagle et al., in a study of 152, 152,702 cases of Stage I- IIIB (FIGO 2008) endometrial cancer (encompassing endometrioid carcinoma grade 1\u0026ndash;3, serous carcinoma, and carcinosarcoma) without lymph node metastasis, found that prognosis improved with the removal of 15 or more lymph nodes, and with every 5 additional lymph nodes removed, even in the absence of lymph node metastasis. However, significant differences in differentiation and the advanced stage were noted [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. In the first two reports, it was inferred that lymphadenectomy contributed to improved prognosis by enabling accurate staging and appropriate postoperative adjuvant therapy. In the latter report, it was suggested that a reduction in the risk of lymph node recurrence contributed to the improved prognosis despite the absence of lymph node metastasis. On the other hand, Lily Tran et al. focused on the size of uterine cancer lymph node metastasis, reporting that the prognosis of isolated tumor cells (ITCs) with a diameter of less than 0. 2 mm was not significantly different from that of patients with negative lymph nodes [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. The reason none of the patients with lymph node metastases in this study experienced recurrence or death may be attributed to the accurate determination of the stage of progression and appropriate postoperative adjuvant therapy. Additionally, since our study was limited to cases where all lymph nodes had a short diameter of less than 10 mm on preoperative imaging, we speculate that the small size of the metastases may not have been a poor prognostic factor.\u003c/p\u003e \u003cp\u003eThis study has several limitations. It is a single-center, retrospective study, and the number of cases is limited. Interpretation of LVSI also requires caution. Although LVSI was previously excluded from the FIGO staging of endometrial cancer and often used as a recurrence risk factor in Japanese guidelines, the FIGO 2023 staging classification now incorporates LVSI. The absence of LVSI or fewer than five invasions is classified as advanced Stage I, whereas five or more invasions are defined as advanced Stage II [22]. Although this advanced staging has not yet been adopted in Japan, it suggests a future possibility of evaluating patients based on the degree of LVSI.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eConflict of interest:\u003c/h2\u003e \u003cp\u003eThe authors have no competing interests to declare that are relevant to the content of this article.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eEthics approval:\u003c/strong\u003e \u003cp\u003e This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Institutional Review Board of the Cancer Institute Hospital (Approval No. 2023-GB-079).\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eConsent to participate:\u003c/strong\u003e \u003cp\u003e As this was a retrospective study, the Institutional Review Board waived the requirement for informed consent. Patients were allowed to opt out via the hospital's website.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eConsent for publication:\u003c/strong\u003e \u003cp\u003eNot applicable.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding:\u003c/h2\u003e \u003cp\u003eThis study was partially supported by the Supporting Fund of Gynecology of Cancer Institute Hospital. The authors declare that no other specific funding was received for this work.\u003c/p\u003e\u003ch2\u003eAuthors' contributions:\u003c/h2\u003e \u003cp\u003eAll authors contributed to the study's conception and design. Material preparation, data collection, and analysis were performed by Teruyuki Yoshimitsu, Hidetaka Nomura, Toshiaki Watanabe, Satoki Misaka, Yusuke Butsuhara, Shogo Nishino, Mayumi Kamata, Motoko Kanno, Akiko Abe, Atsushi Fusegi, Makiko Omi, Yoichi Aoki, Sachiho Netsu, Terumi Tanigawa, Sanshiro Okamoto, Mayu Yunokawa, and Hiroyuki Kanao. The first draft of the manuscript was written by Teruyuki Yoshimitsu, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgements:\u003c/h2\u003e \u003cp\u003eThe Supporting Fund of Gynecology of Cancer Institute Hospital partially supported this study. We thank Editage (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ewww.editage.com\u003c/a\u003e\u003c/span\u003e\u003cspan address=\"http://www.editage.com\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) for its English language editing services.\u003c/p\u003e\u003ch2\u003eAvailability of data and materials:\u003c/h2\u003e \u003cp\u003eThe datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eTriada Doulgeraki S, Vagios E, Kavoura P, Yiannou I, Messini A, Nonni et al Mismatch repair status in high-grade endometrial carcinoma of endometrioid and non-endometrioid type. J BUON 2019 Sep-Oct ;24(5):2020\u0026ndash;2027\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYeh C, Lee S, Lheureux, Amit M, Oza (2017) Treatment strategies for endometrial cancer: current practice and perspective. Curr Opin Obstet Gynecol 29(1):47\u0026ndash;58\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSari ME, Yalcin İbrahim, Sahin H, Meydanli MM (2017) Tayfun Gungor. Risk factors for paraaortic lymph node metastasis in endometrial cancer. Int J Clin Oncol 22(5):937\u0026ndash;944\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChirag Shah EB, Johnson E, Everett H, Tamimi B, Greer E, Swisher et al (2005) Does size matter? Tumor size and morphology as predictors of nodal status and recurrence in endometrial cancer. Gynecol Oncol 99(3):564\u0026ndash;570\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSrinivas Kondalsamy-Chennakesavan, van Vugt S, Sanday K, Nicklin J, Land R, Perrin L et al (2010) Evaluation of tumor-free distance and depth of myometrial invasion as prognostic factors for lymph node metastases in endometrial cancer. Int J Gynecol Cancer 20(7):1217\u0026ndash;1221\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChi DS, Barakat RR, Palayekar MJ, Levine DA, Sonoda Y, Alektiar K et al (2008 Mar-Apr) The incidence of pelvic lymph node metastasis by FIGO staging for patients with adequately surgically staged endometrial adenocarcinoma of endometrioid histology. Int J Gynecol Cancer 18(2):269\u0026ndash;273\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKamura T, Yahata H, Shigematsu T, Ogawa S, Amada S, Kaku T et al (1999) Predicting pelvic lymph node metastasis in endometrial carcinoma. Gynecol Oncol 72(3):387\u0026ndash;391\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMariani A, Webb MJ, Keeney GL, Haddock MG, Calori G, Podratz KC (2000) Low-risk corpus cancer: is lymphadenectomy or radiotherapy necessary? Am J Obstet Gynecol 182(6):1506\u0026ndash;1519\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGilani S, Anderson I, Fathallah L, Mazzara P (2014) Factors predicting nodal metastasis in endometrial cancer. Arch Gynecol Obstet 290(6):1187\u0026ndash;1193\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eUlas Solmaz E, Mat ML, Dereli V, Turan G, Tosun A, Dogan et al (2015 Mar) Lymphovascular space invasion and positive pelvic lymph nodes are independent risk factors for para-aortic nodal metastasis in endometrioid endometrial cancer. Eur J Obstet Gynecol Reprod Biol 186:63\u0026ndash;67\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWatanabe M, Aoki Y, Kase H, Fujita K, Tanaka K Low risk endometrial cancer: a study of pelvic lymph node metastasis\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMarcus Q, Bernardini, Joan K, Murphy (2009) Issues surrounding lymphadenectomy in the management of endometrial cancer. J Surg Oncol 99(4):232\u0026ndash;241\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYosuke Konno Y, Todo S, Minobe H, Kato K, Okamoto S, Sudo et al (2011) A retrospective analysis of postoperative complications with or without para-aortic lymphadenectomy in endometrial cancer. Int J Gynecol Cancer 21(2):385\u0026ndash;390\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFagotti A, Fanfani F, Ercoli A, Giordano MA, Sallustio G, Scambia G (2007) Postoperative ileus after para-aortic lymphadenectomy: a prospective study. Gynecol Oncol 104(1):46\u0026ndash;51\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAndrea Mariani SC, Dowdy WA, Cliby BS, Gostout MB, Jones, Timothy O, Wilson, Karl C, Podratz (2008) Prospective assessment of lymphatic dissemination in endometrial cancer: a paradigm shift in surgical staging. Gynecol Oncol 109(1):11\u0026ndash;18\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYukiharu Todo H, Kato M, Kaneuchi H, Watari M, Takeda N, Sakuragi (2010) Survival effect of para-aortic lymphadenectomy in endometrial cancer (SEPAL study): a retrospective cohort analysis. Lancet 375(9721):1165\u0026ndash;1172\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJoan L, Walker MR, Piedmonte, Nick M, Spirtos SM, Eisenkop JB, Schlaerth, Robert S, Mannel et al (2009) Laparoscopy compared with laparotomy for comprehensive surgical staging of uterine cancer: Gynecologic Oncology Group Study LAP2. J Clin Oncol 27(32):5331\u0026ndash;5336\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSriram Venigalla, Amit K, Chowdhry (2018) David I Shalowitz. Survival implications of staging lymphadenectomy for non-endometrioid endometrial cancers. Gynecol Oncol 149(3):531\u0026ndash;538\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBrandon-Luke L, Seagle D, Gilchrist-Scott S, Graves AE, Strohl Wilberto Nieves-Neira, Shohreh Shahabi. Association of Lymph Node Count and Overall Survival in Node-Negative Endometrial Cancers. JCO Clin Cancer Inf. 2017:1:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1200/CCI.16.00064\u003c/span\u003e\u003cspan address=\"10.1200/CCI.16.00064\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLily Tran P, Christensen JE, Barroeta K, Hunter J, Sookram, Stephanie M, McGregor et al (2023) Prognostic Significance of Size, Location, and Number of Lymph Node Metastases in Endometrial Carcinoma. Int J Gynecol Pathol 42(4):376\u0026ndash;389\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJonathan S, Berek X, Matias-Guiu C, Creutzberg C, Fotopoulou D, Gaffney S, Kehoe et al (2023) Endometrial Cancer Staging Subcommittee, FIGO Women's Cancer Committee. FIGO staging of endometrial cancer: 2023. Int J Gynaecol Obstet 162(2):383\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":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-clinical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijco","sideBox":"Learn more about [International Journal of Clinical Oncology](http://link.springer.com/journal/10147)","snPcode":"10147","submissionUrl":"https://www.editorialmanager.com/ijco/default2.aspx","title":"International Journal of Clinical Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"endometrial cancer, lymphovascular space invasion, lymphadenectomy, lymph node metastasis","lastPublishedDoi":"10.21203/rs.3.rs-9122530/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9122530/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground:\u003c/h2\u003e \u003cp\u003eThis study aimed to determine the frequency of lymph node metastasis in endometrioid carcinomas of grades 1 or 2 with shallow myometrial invasion and lymphovascular space invasion (LVSI).\u003c/p\u003e\u003ch2\u003eMethods:\u003c/h2\u003e \u003cp\u003e After obtaining institutional review board approval, we retrospectively reviewed the medical records of 133 patients with endometrial cancer who were treated at our hospital between January 2007 and December 2022. These patients met the following criteria: endometrioid carcinoma grade 1 or 2, myometrial invasion less than 50%, and preoperative CT showing regional lymph nodes with a short diameter less than 10 mm. All patients underwent pelvic and para-aortic lymphadenectomies.\u003c/p\u003e\u003ch2\u003eResults:\u003c/h2\u003e \u003cp\u003eLymph node metastasis was identified in 10 (8%) cases. LVSI was significantly associated with lymph node metastasis (odds ratio 8.278, 95% CI 2.239\u0026ndash;32.035, P-value: 0.002). LVSI was present in 32 (24%) of the 133 cases, and among these, 7 (22%) had lymph node metastasis. Of the patients with lymph node involvement, 3 (44%) had only pelvic metastases, 2 (28%) had only para-aortic metastases, and 2 (28%) had both pelvic and para-aortic metastases. All patients received postoperative adjuvant chemotherapy, and there were no recurrences or deaths during the study period among those with lymph node involvement.\u003c/p\u003e\u003ch2\u003eConclusion:\u003c/h2\u003e \u003cp\u003eEven in endometrioid carcinoma grade 1\u0026ndash;2 with shallow myometrial invasion, where lymph node metastasis is not suspected on imaging, the presence of LVSI may be a crucial factor in deciding whether to perform subsequent lymphadenectomy.\u003c/p\u003e","manuscriptTitle":"Impact of lymphovascular space invasion on lymph node metastasis in low-grade endometrial cancer with shallow myometrial invasion and negative imaging.","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-24 13:18:16","doi":"10.21203/rs.3.rs-9122530/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revisions","date":"2026-04-14T07:27:37+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2026-03-19T08:25:08+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-03-19T07:40:01+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-03-16T17:47:09+00:00","index":"","fulltext":""},{"type":"submitted","content":"International Journal of Clinical Oncology","date":"2026-03-14T08:29:48+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-clinical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijco","sideBox":"Learn more about [International Journal of Clinical Oncology](http://link.springer.com/journal/10147)","snPcode":"10147","submissionUrl":"https://www.editorialmanager.com/ijco/default2.aspx","title":"International Journal of Clinical Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"3ac5056e-20e4-485b-a31b-b1f894787f96","owner":[],"postedDate":"March 24th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"in-revision","subjectAreas":[],"tags":[],"updatedAt":"2026-04-14T11:28:11+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-24 13:18:16","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9122530","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9122530","identity":"rs-9122530","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}