To begin with, direct manipulation of the uterus during surgery may cause the fragmentation of the tumor. Then fragmented tumor cells in the vaginal fornices may back-flow into the pelvic peritoneal surfaces at the time of intra-corporeal colpotomy. Furthermore, during laparoscopic procedure, the use of an intrauterine manipulator may lead to uterine perforation, which causes the direct spread of tumor. Moreover, tumor cells may be spread into the peritoneal cavity via transtubal retrograde flow. However, distant metastases are more likely driven by tumor biology (e.g., molecular subtype, LVSI) rather than UM use.

The use of UM in EC patients is thought to be associated with transtubal tumor spread and an increased rate of LVSI. Studies have documented that UM causes retrograde seeding of tumor cells into the peritoneal cavity due to the pressure effect and a higher positive peritoneal cytology [31, 32]. Krizova et al. [26] reported that in the histopathological examination of hysterectomy specimens of 160 oncological patients, the use of UM showed a higher rate of lymph vascular pseudo-invasion and positive peritoneal cytology. However, Kitahara et al. [25] suggested that pseudo-invasion results from artifacts in the gross pathological process rather than a true invasion. Therefore, there are studies showing that the use of UM increases the rate of LVSI and positive peritoneal cytology [31, 33, 34]. However, unlike these studies, Machida et al. [35] noted that the application of UM during laparoscopic hysterectomy in patients with EC was not associated with a higher frequency of LVSI. Frimer et al. [36] did not observe a relationship between the use of UM and an increase in micrometastasis and isolated tumor cells during surgical treatment in 175 EC patients. Similarly, Lee et al. [18] determined in a randomized study that the use of UM did not show an increase in peritoneal tumor cells or an increase in positive LVSI. Tinelli et al. [27] found that the use of UM did not affect peritoneal cytology and LVSI in 110 patients with stage I EC. Another recent study found that the use of UM in minimally invasive surgery for EC was not associated with LVSI [37]. In our study, LVSI was determined in 77 (65.8%) of 117 EC patients who underwent laparoscopic surgery. LVSI was observed in 81.0% of patients without UM and in 62.1% of patients with UM, but there was no significant difference between the groups. The LVSI results in this current study are consistent with previous study results showing that the use of UM in laparoscopic surgery in EC patients is not associated with LVSI, although overall observed LVSI rates in this current study were higher than in previous studies. The elevated LVSI rate (65.8%) contrasts with SEER data (LVSI ~20%-40 %) and may reflect differences in histopathological criteria, centralized pathology review, population heterogeneity, or a high-risk cohort (49.6% with deep myometrial invasion). This study also evaluated the impact of UM on survival and likelihood of recurrence. In our study, recurrence was observed in 15 (12.8%) patients and 15 (12.8%) patients died. Ten of the 15 patients with recurrence died. The recurrence rate and mortality rate in patients with UM was 12.6% and was not significantly different from the recurrence rate and mortality rate of 14.3% in patients without UM. Padilla-Iserte et al.’s [38] multicenter cohort study determined that in patients undergoing minimally invasive surgery for early-stage EC, UM exhibited a higher recurrence rate, lower recurrence-free survival, and lower overall survival rate. In a recent study, it was determined that the general recurrence rate was similar in patients with and without UM, but local vaginal recurrence rates were higher in patients using UM [37]. When researchers excluded patients who received adjuvant therapy, they observed that patients with UM showed a higher rate of vaginal vault recurrence and overall recurrence and worse disease-free survival. Researchers reported that UM demonstrated worse outcomes for the subgroup of low-risk patients who did not receive adjuvant therapy [37]. A subgroup analysis of patients who did not receive adjuvant therapy (n=35) revealed no significant difference in recurrence (14.3% vs. 15.4%, p=0.912) or survival (14.3% vs. 15.4%, p=0.912) between UM and non-UM groups. However, the small sample size limits definitive conclusions. While prior studies suggest UM may worsen outcomes in untreated subgroups, our analysis found no significant association. This discrepancy may reflect differences in risk stratification or adjuvant therapy eligibility criteria. However, contrary to these data, in a multicenter study conducted by the Italian Gynecological Endoscopy Society in which 951 EC patients were retrospectively evaluated, it was determined that there was no relationship between the use of UM in EC treatment and disease-free, disease-specific, and overall survival. [28] Gueli Alletti et al. [39], in their multicenter prospective randomized clinical study evaluating 154 patients with G1-G2 early-stage EC, noted that UM did not affect the relapse pattern or DFS. According to the results of a large meta-analysis evaluating 18 studies, the use of UM during laparoscopic surgery for EC does not increase the recurrence rate [40]. Similarly, in a recent meta-analysis evaluating 14 studies including 5019 patients, no statistically significant relationship was determined between the use of UM during hysterectomy for EC and recurrence-free and overall survival [41]. The results of our study that UM does not affect recurrence and survival are consistent with previous results. Moreover, in our study, the hospitalization period and perioperative complication rate of patients with UM were similar to patients without UM. Additionally, in patients with UM, the rate of patients with surgery time >120 minutes was less than in patients without UM.

There are possible explanations for the different results. 1. Heterogeneity in patient populations. Studies vary in baseline risk factors (e.g., grade, tumor stage, histologic subtype). For instance, populations with higher rates of advanced-stage disease or aggressive histologies (e.g., grade 3) may show a high prevalence of tumor seeding with UM use. Conversely, studies focusing on early-stage, low-grade tumors may report no significant association with recurrence or survival.

2. Differences in UM design and technique. UM devices vary in rigidity, cervical occlusion mechanisms, and intrauterine pressure creation. For example, balloon-tipped UMs (e.g., Cohen manipulator) may exert lower pressure compared to fixed-volume systems (e.g., RUMI), potentially influencing the risk of retrograde tumor spillage. Procedural differences, such as cervical sealing or minimal colpotomy, could further confound outcomes.

3. Surgical expertise and learning curves. A surgeon’s experience with UM-assisted minimally invasive surgery (MIS) may impact outcomes. Inexperienced operators may inadvertently increase intrauterine pressure or cause uterine perforation. This variability is rarely accounted for in retrospective studies.

4. Adjuvant therapy protocols. Discrepancies in adjuvant treatment (e.g., chemotherapy, brachytherapy) across institutions could mask or modify the true oncologic impact of UM use. Studies failing to control for adjuvant therapy may report conflicting survival outcomes despite similar surgical practices.

2. Methodologic limitations. Retrospective studies dominate this field, introducing selection bias and confounding. For example, studies comparing UM users to non-users may overlook inherent differences in tumor biology or surgical complexity. Additionally, short follow- up durations in some series may underestimate recurrence rates.

One limitation of our study is that it is a retrospective, single-center study with a small number of patients. The grade, stage, and histological subtype heterogeneity of EC is another limitation. This heterogeneity regarding EC may have affected the study results. According to the study, after controlling for confounders, the application of a uterine manipulator did not independently predict survival or recurrence. Deficiencies such as the type of UM used, indications for use, duration of UM placement, and the application of different treatment methods are also limitations.

In conclusions, in this retrospective study, the surgical and oncological outcomes of the use of uterine manipulators during endometrial cancer surgery were evaluated. Firstly, the HOHL type uterine manipulator with an atraumatic tip was used in all cases included in this study. This selection was based on its ergonomic design, which facilitates optimal uterine maneuver and colpotomy under direct visualization while minimizing tumor fragmentation. While other UM types (eg, Clermont- Ferrand) are available in our institution, they were not used in this cohort to maintain procedural standardization. Secondly, mitigating the risk of intraoperative tumor spillage was a critical focus of our surgical procedure. At the initiation of operation, bilateral fallopian tubes were coagulated and sealed to prevent retrograde transtubal tumor seeding. Under direct laparoscopic visualization, with careful avoidance of tumor fragmentation, the HOHL type manipulator’s colpotomy cup was employed to stabilize the cervix and ensure a circumferential, en-bloc resection. No instances of gross tumor fragmentation were documented intraoperatively. Thirdly, UM fixation is realized by experienced doctors. The HOHL manipulator was inserted transvaginally after catching the cervix with a tenaculum. Fixation was achieved using the manipulator’s adjustable cervical cup, which was tightened to occlude the cervical os and minimize retrograde tumor spillage. No additional sutures were required for stabilization. To sum up, we can give information on our routine key steps to prevent dissemination, which include:

Preoperative vaginal disinfection with povidone-iodine.

Circumferential colpotomy was performed laparoscopically using monopolar electrocautery, maintaining a 1–2 cm margin from the cervical cup.

Immediate closure of the vaginal vault following uterine extraction to isolate the surgical field.

Minimal uterine manipulation in cases with suspected fundal or adnexal tumor involvement.

For avoidance of morcellation, all specimens were extracted intact via the vagina.

Lavage of the peritoneal cavity after surgical material removal in cases with suspected microscopic spillage was carried out.

The concern that unmeasured criteria (e.g., BMI, tumor size, stage) may have influenced both the use of a uterine manipulator and oncological outcomes may occur. In the original analysis, baseline demographic and clinical characteristics of the UM and non-UM groups are presented in the table. While key variables, such as tumor stage, histology, and surgical approach, were balanced between groups, other factors, including BMI, tumor size, and surgeon preference, were not formally compared. Baseline characteristics differed between UM and non-UM groups: UM patients had higher BMI and shorter surgery duration. Our findings suggest that, within the limitations of a retrospective analysis, the use of uterine manipulators in minimally invasive endometrial cancer surgery does not appear to significantly impact lymphovascular space invasion, recurrence, or survival outcomes. While our study found no association between UM use and survival, its role in optimizing surgical precision and efficiency underscores its utility in select cases. However, due to potential confounding factors, selection bias, and variability in surgical techniques inherent to retrospective studies, these results should be interpreted with caution. Moreover, debates regarding the use of uterine manipulators seem to continue. Therefore, multicenter, randomized, prospective studies on the use of uterine manipulators during endometrial cancer surgery are needed.

We want to acknowledge the AGP editorial board for their scientific opportunity and outstanding support that was provided in this manuscript.

Author contributions

Conceptualization: [AI]; Methodology: [AI]; Formal analysis and investigation: [AI]; Writing - original draft preparation: [AI]; Writing - review and editing: [AI]; Supervision: [AI].

Competing interests

The authors have no conflict of interest in this study.

Data availability statements

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Ethics statement

Approval from the local ethics committee of the Oncology Department of the Azerbaijan Medical University (Approval № 238/2024.06.01). Since the study was retrospective and observational, the Clinical Research Ethics Committee of Azerbaijan Medical University waived the need for written informed consent.

Funding

This study was not funded by any organization.

1 01 7-33 71 2021 10.3322/caac.21654 Siegel RL Miller KD Fuchs HE Jemal A CA: a cancer journal for clinicians Cancer Statistics, 2021 Access year: 2023 American Cancer Society: Key statistics for endometrial cancer. Available from: https://www.cancer.org/cancer/endometrialcancer/about/key-statistics.html Access year: 2022 ECIS-European Cancer Information System: Estimates of cancer incidence and mortality in 2020. Available from: https://ecis.jrc.ec.europa.eu/explorer.php?$0-0$1-AEE$2-All$4-2$3-All$6-0,85$5-2020,2020$7-7$CEstByCancer$X0_8-3$CEstRelativeCanc$X1_8-3$X1_9-AE27$CEstBySexByCancer$X2_8-3$X2_-1-1 10 10 1168-1177 97 2018 10.1111/aogs.13381 Gavrilyuk O Braaten T Weiderpass E Licaj I Lund E Acta Obstetricia Et Gynecologica Scandinavica Lifetime number of years of menstruation as a risk index for postmenopausal endometrial cancer in the Norwegian Women and Cancer Study 10 1 03 130 17 2016 10.1186/s13063-016-1260-1 Koutoukidis DA Beeken RJ Manchanda R Burnell M Knobf MT Lanceley A Trials Diet and exercise in uterine cancer survivors (DEUS pilot) - piloting a healthy eating and physical activity program: study protocol for a randomized controlled trial 899262 12 2022 10.3389/fonc.2022.899262 Njoku K Agnew HJ Crosbie EJ Frontiers in Oncology Impact of Type 2 Diabetes Mellitus on Endometrial Cancer Survival: A Prospective Database Analysis 06 8 08 2195 12 2020 10.3390/cancers12082195 Tempfer CB Hilal Z Kern P Juhasz-Boess I Rezniczek GA Cancers Menopausal Hormone Therapy and Risk of Endometrial Cancer: A Systematic Review 22 15 07 3689 13 2021 10.3390/cancers13153689 Hutt S Mihaies D Karteris E Michael A Payne AM Chatterjee J Cancers Statistical Meta-Analysis of Risk Factors for Endometrial Cancer and Development of a Risk Prediction Model Using an Artificial Neural Network Algorithm 26 18 06 3385-3394 12 2024 10.12998/wjcc.v12.i18.3385 Liu Y Lu X Guo H Bao C Zhang J Jin Y World Journal of Clinical Cases Development and validation of a circulating tumor DNA-based optimization-prediction model for short-term postoperative recurrence of endometrial cancer 18 07 rs.3.rs-2917380 2023 10.21203/rs.3.rs-2917380/v1 Tran DN Rozen V Hunter MI Kim TH Jeong JW Research Square ARG1 is a potential prognostic marker in metastatic and recurrent endometrial cancer 2 03 e11 32 2021 10.3802/jgo.2021.32.e11 Tortorella L Restaino S Zannoni GF Vizzielli G Chiantera V Cappuccio S Gioè A et al Journal of Gynecologic Oncology Substantial lymph-vascular space invasion (LVSI) as predictor of distant relapse and poor prognosis in low-risk early-stage endometrial cancer 762329 11 2021 10.3389/fonc.2021.762329 Wang J Xu P Yang X Yu Q Xu X Zou G Zhang X Frontiers in Oncology Association of Myometrial Invasion With Lymphovascular Space Invasion, Lymph Node Metastasis, Recurrence, and Overall Survival in Endometrial Cancer: A Meta-Analysis of 79 Studies With 68,870 Patients 01 1 01 232-237 20 2024 10.4103/jcrt.jcrt_888_22 Çakır İ Gülseren V Özdemir IA Abacı H Talu ECK Çakır ZE Ata Can et al Journal of Cancer Research and Therapeutics Characteristics of patients with late recurrence endometrial cancer 2 05 224-228 117 2010 10.1016/j.ygyno.2010.01.009 Cardenas-Goicoechea J Adams S Bhat SB Randall TC Gynecologic Oncology Surgical outcomes of robotic-assisted surgical staging for endometrial cancer are equivalent to traditional laparoscopic staging at a minimally invasive surgical center 11 10 3561-3567 20 2013 10.1245/s10434-013-3064-9 Leitao MM Malhotra V Briscoe G Suidan R Dholakiya P Santos K Jewell EL et al Annals of Surgical Oncology Postoperative pain medication requirements in patients undergoing computer-assisted (“Robotic”) and standard laparoscopic procedures for newly diagnosed endometrial cancer 10 32 11 5331-5336 27 2009 10.1200/JCO.2009.22.3248 Walker JL Piedmonte MR Spirtos NM Eisenkop SM Schlaerth JB Mannel RS Spiegel G et al Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology Laparoscopy compared with laparotomy for comprehensive surgical staging of uterine cancer: Gynecologic Oncology Group Study LAP2 2 184-188 18 2011 10.1016/j.jmig.2010.11.007 Fanfani F. Gagliardi M. L. Zannoni G. F. Gallotta V. Vizzielli G. Lecca A. Scambia G. Fagotti A. Journal of Minimally Invasive Gynecology Total laparoscopic hysterectomy in early-stage endometrial cancer using an intrauterine manipulator: is it a bias for frozen section analysis? Case-control study 2 02 372-379 23 2013 10.1097/IGC.0b013e3182788485 Lee M Kim YT Kim SW Kim S Kim JH Nam EJ International Journal of Gynecological Cancer: Official Journal of the International Gynecological Cancer Society Effects of uterine manipulation on surgical outcomes in laparoscopic management of endometrial cancer: a prospective randomized clinical trial 1 07 131-134 286 2012 10.1007/s00404-012-2249-y Mebes I Diedrich K Banz-Jansen C Archives of Gynecology and Obstetrics Total laparoscopic hysterectomy without uterine manipulator at big uterus weight (>280 g) 12 9 09 CD006655 2012 10.1002/14651858.CD006655.pub2 Galaal K Bryant A Fisher AD Al-Khaduri M Kew F Lopes AD The Cochrane Database of Systematic Reviews Laparoscopy versus laparotomy for the management of early stage endometrial cancer 2 02 239-244 80 2001 10.1006/gyno.2000.6069 Malur S. Possover M. Michels W. Schneider A. Gynecologic Oncology Laparoscopic-assisted vaginal versus abdominal surgery in patients with endometrial cancer--a prospective randomized trial 1 01 126-133 112 2009 10.1016/j.ygyno.2008.08.019 Malzoni M Tinelli R Cosentino F Perone Ci Rasile M Iuzzolino D Malzoni C Reich H Gynecologic Oncology Total laparoscopic hysterectomy versus abdominal hysterectomy with lymphadenectomy for early-stage endometrial cancer: a prospective randomized study 4 376-381 33 2012 Perrone A. M. Di Marcoberardino B. Rossi M. Pozzati F. Pellegrini A. Procaccini M. Santini D. De Iaco P. European Journal of Gynaecological Oncology Laparoscopic versus laparotomic approach to endometrial cancer 5 05 2497-2502 34 2014 Tinelli R Litta P Meir Y Surico D Leo L Fusco A Angioni S Cicinelli E Anticancer Research Advantages of laparoscopy versus laparotomy in extremely obese women (BMI>35) with early-stage endometrial cancer: a multicenter study 2 02 298-303 33 2009 10.1097/PAS.0b013e31818a01bf Kitahara S Walsh C Frumovitz M Malpica A Silva EG The American Journal of Surgical Pathology Vascular pseudoinvasion in laparoscopic hysterectomy specimens for endometrial carcinoma: a grossing artifact? 1 01 115-126 35 2011 10.1097/PAS.0b013e31820273dc Krizova A Clarke BA Bernardini MQ James S Kalloger SE Boerner SL Mulligan AM The American Journal of Surgical Pathology Histologic artifacts in abdominal, vaginal, laparoscopic, and robotic hysterectomy specimens: a blinded, retrospective review 2 06 98-103 25 2016 10.1016/j.suronc.2016.03.005 Tinelli R Cicinelli E Tinelli A Bettocchi S Angioni S Litta P Surgical Oncology Laparoscopic treatment of early-stage endometrial cancer with and without uterine manipulator: Our experience and review of literature 6 06 592.e1-592.e11 216 2017 10.1016/j.ajog.2017.01.027 Uccella S Bonzini M Malzoni M Fanfani F Palomba S Aletti G Corrado Gi et al American Journal of Obstetrics and Gynecology The effect of a uterine manipulator on the recurrence and mortality of endometrial cancer: a multi-centric study by the Italian Society of Gynecological Endoscopy 10 225-231 20 2010 Nassif J Wattiez A Surgical Technology International Clermont Ferrand uterine manipulator 01 5 03 1950 12 2023 10.3390/jcm12051950 Eoh KJ Kim Y Nam EJ Kim SW Kim YT Journal of Clinical Medicine Clinical Relevance of Uterine Manipulation on Oncologic Outcome in Robot-Assisted versus Open Surgery in the Management of Endometrial Cancer 5 1145-1149 18 2008 10.1111/j.1525-1438.2007.01165.x Lim S. Kim H. S. Lee K. B. Yoo C. W. Park S. Y. Seo S. S. International Journal of Gynecological Cancer: Official Journal of the International Gynecological Cancer Society Does the use of a uterine manipulator with an intrauterine balloon in total laparoscopic hysterectomy facilitate tumor cell spillage into the peritoneal cavity in patients with endometrial cancer? 3 03 378-382 80 2001 10.1006/gyno.2000.6079 Sonoda Y. Zerbe M. Smith A. Lin O. Barakat R. R. Hoskins W. J. Gynecologic Oncology High incidence of positive peritoneal cytology in low-risk endometrial cancer treated by laparoscopically assisted vaginal hysterectomy 02 28-33 23 2018 10.1016/j.gore.2018.01.003 Albright BB Black JD Passarelli R Gysler S Whicker M Altwerger G et al Gynecologic Oncology Reports Associated characteristics and impact on recurrence and survival of free-floating tumor fragments in the lumen of fallopian tubes in Type I and Type II endometrial cancer 2 03 188-192 32 2013 10.1097/PGP.0b013e31825f7c08 Delair D Soslow RA Gardner GJ Barakat RR Leitao MM International Journal of Gynecological Pathology: Official Journal of the International Society of Gynecological Pathologists Tumoral displacement into fallopian tubes in patients undergoing robotically assisted hysterectomy for newly diagnosed endometrial cancer 2 02 208-219 28 2018 10.1097/IGC.0000000000001181 Machida H Hom MS Adams CL Eckhardt SE Garcia-Sayre J Mikami M Matsuo K International Journal of Gynecological Cancer: Official Journal of the International Gynecological Cancer Society Intrauterine Manipulator Use During Minimally Invasive Hysterectomy and Risk of Lymphovascular Space Invasion in Endometrial Cancer 3 12 496-499 119 2010 10.1016/j.ygyno.2010.08.030 Frimer M Khoury-Collado F Murray MP Barakat RR Abu-Rustum NR Gynecologic Oncology Micrometastasis of endometrial cancer to sentinel lymph nodes: is it an artifact of uterine manipulation? 3 03 355-363 33 2024 10.1089/jwh.2023.0246 Laskov I Michaan N Zeng X Salvador S Lau S Gilbert L Gotlieb WH Kessous R Journal of Women's Health (2002) The Impact of Intrauterine Manipulators on Outcome and Recurrence Patterns of Endometrial Cancer Patients Undergoing Minimally Invasive Surgery 1 01 65.e1-65.e11 224 2021 10.1016/j.ajog.2020.07.025 Padilla-Iserte P Lago V Tauste C Díaz-Feijoo B Gil-Moreno A Oliver R Coronado P et al American Journal of Obstetrics and Gynecology Impact of uterine manipulator on oncological outcome in endometrial cancer surgery 720894 11 2021 10.3389/fonc.2021.720894 Gueli Alletti S Perrone E Fedele C Cianci S Pasciuto T Chiantera V Uccella S et al Frontiers in Oncology A Multicentric Randomized Trial to Evaluate the ROle of Uterine MANipulator on Laparoscopic/Robotic HYsterectomy for the Treatment of Early-Stage Endometrial Cancer: The ROMANHY Trial 10 10 2112-2118 48 2022 10.1016/j.ejso.2022.05.034 Scutiero G. Vizzielli G. Taliento C. Bernardi G. Martinello R. Cianci S. Riemma G. Scambia G. Greco P. European Journal of Surgical Oncology: The Journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology Influence of uterine manipulator on oncological outcome in minimally invasive surgery of endometrial cancer: A systematic review and meta-analysis 2 02 185-198.e4 230 2024 10.1016/j.ajog.2023.09.004 Zorzato PC Uccella S Biancotto G Bosco M Festi A Franchi M Garzon S American Journal of Obstetrics and Gynecology Intrauterine manipulator during hysterectomy for endometrial cancer: a systematic review and meta-analysis of oncologic outcomes