Concerns remain that the introduction of a device into the endometrial cavity may cause disruption of endometrial cancer cells and affect patient’s outcome. Available data is limited and indicates that this type of disruption does not seem to have clinically observable adverse effects [12–15]. Data regarding the possible effect of the use of intrauterine manipulators on the long-term outcome of patients with endometrial cancer is scarce. As a result, debates still take place in the gynecologic oncology community raising concern about the use of these devices. Two previous studies have tried to analyse survival after laparoscopic surgery for endometrial cancer using a uterine manipulator. However, those were largely underpowered to investigate long-term outcomes (< 70 patients included in each group) [16, 17]. In a multicenter study by the Italian society of gynecological endoscopy, authors reviewed data from 951 consecutive patients who underwent laparoscopic surgery for endometrial cancer with or without intrauterine manipulator. In this study, data regarding the effect of the manipulator on the rate of positive cytology and LVSI was not reported but results showed a non-significant difference in the recurrence rate (13.5% vs. 11.6%) between the manipulator and no manipulator groups . Results of our study raise some safety concerns regarding the use of uterine manipulators during MIS for endometrial cancer. For the entire cohort, total recurrence rate was similar between the two comparison groups but with higher rates of local vaginal recurrence for patients in whom a uterine manipulator was used during surgery. After excluding patients who received adjuvant treatment, the rate of vaginal vault recurrence and total recurrence was significantly higher with a worse DFS in the intra-uterine manipulator group compared to the no manipulator group. However, the use of a uterine manipulator was not found to be a predictor of worse outcome on multivariate analysis that was performed for the entire cohort but was close to statistical significance when performed for the subgroup of patients who did not receive adjuvant treatment.
A recent multicenter study by the Spanish society of gynecology and obstetrics, followed over 2000 women with uterus confined endometrial cancer who underwent minimally invasive surgery and found, in concordance with the results presented here, that patients that were operated using a uterine manipulator had worse oncological outcome .
A possible explanation might be that local recurrence may be salvageable by either surgery or radiotherapy, with good long term outcomes . Following recurrence, most patients in our cohort were either operated or received radiotherapy with or without chemotherapy. This is also in accordance to the previously reported LAP2 study that found a potential increased risk of uterine cancer recurrence with manipulator assisted laparoscopic hysterectomies compared to hysterectomies via laparotomy but this risk was quantified and found to be small . We can speculate that the effect of higher recurrence rates on long term outcome of patients in the manipulator group, was eventually diluted by additional treatment modalities and that the presence of a uterine manipulator during surgery did not negatively affect the outcome of endometrial cancer patients on multivariate analysis.
Our results show that the use of an intra-uterine manipulator in MIS for endometrial cancer was not associated with an increase in rates of LVSI, however, we found higher incidence of positive cytology in patients for whom a uterine manipulator was used during surgery. Previously published studies regarding LVSI and positive peritoneal cytology are conflicting, with some suggesting that the use of manipulators does not affect positive peritoneal cytology and/or LVSI [20–24], while other studies show an association between uterine manipulator use and positive peritoneal cytology and/or LVSI [25, 26]. LVSI was previously shown to be an independent adverse prognostic factor for extra-uterine disease, particularly pelvic lymph node metastasis [27, 28], isolated para-aortic lymph node Metastasis [29, 30], and distant hematogenous recurrences . LVSI in the presence of a uterine manipulator may reflect true invasion, pseudo-invasion, or an artifact of manipulator use that resulted in cell displacement into the vessels via a closed pressure system . In the current study, LVSI was found in 27% of patients, which is in agreement previously published data. According to our results, the use of intrauterine manipulator was not associated with a significant difference in the rate of LVSI.
With regard to positive cytology, we found that the rate of positive cytology was significantly higher in the group of patients who had an intra-uterine manipulator. Positive cytology was an independent prognostic factor for both DFS and OS on univariate and multivariate analysis. Other reports showed similar results that peritoneal washings were significantly more likely to be positive in women in whom a uterine manipulator had been used [25, 26, 33]. To elucidate whether the use of intra-uterine manipulator increases the risk of positive cytology, its necessary to obtain cytology twice in the same individual, before and after the insertion of the intra-uterine manipulator and compare them.
The current study offers several strengths; data was collected from a large cohort of patients who underwent surgery by a team of surgeons who share a joint surgical protocol and unified approach. This enhances the impact of the use of intrauterine manipulators and allows the current comparison. Moreover, in our study we were also able to perform a subgroup analysis that excludes the effect of adjuvant radiation treatment on the outcome measures. In addition, the follow up time in our study is relatively long and was previously shown to include over 90% of recurrences from initial treatment . However, this study is not without limitations including the inherent limitations that results from its retrospective nature. In addition, we did not perform coagulation of the tubes at the beginning of the procedure and this might have an effect with regard to positive cytology.
Finally, in the current study we deal with the long-term outcome of uterine manipulators in endometrial cancer, but can we extrapolate these results to cervical cancer? Could the data presented here provide some hints to explain the poorer results for cervical cancer patients undergoing minimal invasive surgery with a uterine manipulator. Several theories have been proposed to explain the unexpected results of the LACC trial that compared minimally invasive radical hysterectomy to open abdominal radical hysterectomy among women with early-stage cervical cancer. One theory suggests that the use of a uterine manipulator is a possible cause of the poorer oncological outcome after minimal invasive radical hysterectomy for cervical cancer . The results presented here show higher recurrence rates, mainly at the vaginal vault and decreased disease-free survival in a subgroup of patients who were operated using an intra-uterine manipulator and did not receive adjuvant treatment. In contrast to cervical cancer, the rise in disease recurrence did not significantly affect OS. We can speculate that this could either be related to differences in the biology of squamous cell carcinomas of the cervix and endometrial cancers, and/or be due to the salvage potential of the treatment modalities for recurrent localized endometrial cancer. A recent international European observational study comparing minimally invasive surgery versus open abdominal radical hysterectomy in patients with stage IB1 cervical cancer found that patients that underwent minimally invasive surgery using a uterine manipulator had a 2.76-times higher hazard of relapse and those without the use of a uterine manipulator had similar disease-free-survival to the open surgery group .
In conclusion, results of the current study show that the use of an intra uterine manipulator is associated with a minimal impact on the oncological outcomes of patient who undergo MIS and adjuvant treatment for endometrial cancer, but may have implications on outcome for low risk patients who do not receive adjuvant treatment.