Abstract
Study Objective
Considering the hypothetical concern of retrograde tumor spread to the peritoneal cavity by insertion of an intrauterine manipulator, we examined the correlation between the timing of manipulator insertion and the results of pelvic cytology during total laparoscopic hysterectomy (TLH) in endometrial cancer.
Design
Case-control study (Canadian Task Force classification II-2).
Setting
University-based hospitals.
Patients
Stage I to IV endometrial cancer patients who underwent TLH in which an intrauterine manipulator was used. Medical records were reviewed for patient demographics, surgical details, and tumor characteristics.
Interventions
Archived medical record review.
Measurements and Main Results
A total of 333 patients was identified. Cases were divided into those with intrauterine manipulator insertion after pelvic cytology sampling (Group 1, n = 103) and those with intrauterine manipulator insertion before pelvic cytology sampling (Group 2, n = 230). Types of intrauterine manipulator were similar across the 2 groups (p = .77). There was no statistical difference in the results of pelvic cytology between the 2 groups: Group 1 versus 2, atypical cells 2.9% versus 4.8% and malignant cells 5.8% versus 9.6% (p = .36). Uterine perforation related to intrauterine manipulator insertion was seen in 1.0% and .4% of each group (p = .52). In a multivariate analysis controlling for demographics and tumor characteristics, advanced-stage disease remained an independent risk factor associated with increased risk of atypical and malignant cells (adjusted odds ratio, 10.3; 95% confidence interval, 4.44–23.8; p < .001).
Conclusion
Our study suggested that the timing of intrauterine manipulator insertion during TLH for endometrial cancer is not associated with the results of pelvic cytology.
Keywords: Cytology, Endometrial cancer, Minimal invasive surgery, Uterine manipulator
Endometrial cancer is the most prevalent gynecologic malignancy in the United States, with an estimated 54 870 new cases and 10 170 deaths identified in 2014 [1]. Some 67.5% of patients are diagnosed with localized endometrial cancer and are surgically staged with hysterectomy, bilateral salpingo-oophorectomy, and possible lymphadenectomy [2]. The treatment of endometrial cancer has seen a paradigm shift toward minimally invasive surgery, which serves as an alternative to standard laparotomy for surgical management [3]. Randomized control trials comparing laparoscopy with laparotomy in the surgical management of early-stage endometrial cancer have shown that the laparoscopic approach had similar rates of overall and disease-free survival and similar rates of severe postoperative morbidity. The laparoscopic approach has also been shown to be associated with reduced operative morbidity and length of hospital stay [4–7]. Consequently, the use of this approach is increasing. According to a Nationwide Inpatient Sample database 38% of endometrial cancer patients underwent minimally invasive surgery in 2010 [8].
Most gynecologic surgeons recognize the advantage of uterine manipulators during hysterectomy. Nevertheless, some surgeons avoid their use with endometrial cancer for fear of iatrogenic spillage, uterine perforation, and the potential risk of pushing cancer cells into the peritoneal cavity or lymphatic spaces. However, the clinical significance of positive pelvic cytology with endometrial cancer confined to the uterus is controversial [9–11]. A recent study suggested that minimally invasive hysterectomy-based surgical staging for endometrial cancer with the use of an intrauterine manipulator is associated with increased risk of atypical cells in pelvic cytology compared with conventional abdominal hysterectomy [12]. However, a weakness of this study was that the timing of intrauterine manipulator insertion was not clearly defined for each candidate.
Concerns remain regarding whether the use of an intrauterine manipulator is associated with an increased risk of disease spread. The aim of our study was to evaluate the influence of the timing of intrauterine manipulator placement on the histopathologic outcomes in women undergoing minimally invasive surgery for the management of endometrial cancer.
Methods
Study Design and Eligibility
After Institutional Review Board approval was obtained at the University of Southern California, an institutional surgical pathology database was used to identify cases. Eligibility criteria for the study included patients with a diagnosis of endometrial cancer and those who were treated via conventional laparoscopic hysterectomy, laparoscopic radical hysterectomy, or robot-assisted hysterectomy at Los Angeles County Medical Center and Keck Medical Center of University of Southern California between January 1, 2000 and August 31, 2015. Cases were excluded if the following criteria were met: (1) the patient did not undergo minimally invasive surgery, (2) use of intrauterine manipulator was absent, (3) inadequate information about intrauterine manipulator insertion was provided, and (4) timing of pelvic cytology or performance of cytology was not defined.
Eligible cases were divided into 2 groups: patients having undergone pelvic cytology followed by intrauterine manipulator during surgery (Group 1) and control groups in which insertion of the intrauterine manipulator was followed by cytology (Group 2). The decision as to the timing of intrauterine manipulator insertion was at the discretion of the surgeon. All cases were performed or supervised by a faculty member of the division of gynecologic oncology at the University of Southern California. The Strengthening the Reporting of Observational studies in Epidemiology guidelines were consulted for reporting in a case-control study [13]. Some of the patients in this study were within the context of our previous studies [14].
Clinical Information
Among eligible cases, medical records were examined to abstract patient demographics at the time of surgery, surgical outcomes, and histopathology results for hysterectomy and pelvic cytology during the surgery. Patient demographics included age, ethnicity, body mass index (BMI), presence of medical comorbidities (hypertension, diabetes mellitus, and hypercholesterolemia), and past history of fallopian tubal ligation. Diagnostic procedures were based on endometrial biopsy within 3 months of surgical staging, whereas other cases were diagnosed by other procedures: hysteroscopy, uterine curettage, and vacuum curettage by Vabra (Sterylab, Milan, Italy). Surgical demographics included estimated blood loss (EBL, in mL), details regarding surgical staging (type of hysterectomy, salpingo-oophorectomy, and lymphadenectomy), use of intraoperative fallopian tube coagulation, intraoperative complications (laparotomic conversion, uterine perforation), and institution at which the surgical procedure was performed. Histopathology results included uterine weight (g), histologic subtype, grade, stage, depth of myometrial tumor invasion, presence of lymphovascular space invasion (LVSI), cervical involvement, and classification of pelvic cytology during surgery.
Definition
Cancer stage was evaluated based on the 2009 International Federation of Gynecology and Obstetrics system. In our study, histologic subtypes were grouped as endometrioid, serous, clear cell, or other adenocarcinoma. Tumor grade was grouped into low-grade versus high-grade. Grade 1 and 2 endometrioid tumors were categorized as low grade. Grade 3 endometrioid, serous, and clear cell tumors were categorized as high grade. Deep myometrial tumor invasion was defined as the presence of tumor in the outer half of the myometrial layer (≥50%). Cervical involvement was defined as the tumor existing within the cervical glands or stroma. Intrauterine manipulator was defined as a uterine manipulator device (VCare [Conmed, Utica, NY], RUMI/Koh [Cooper Surgical, Inc, Trumbull, CT], and HUMI [Medline Industries, Inc, Mundelein, IL]) inserted into the uterine cavity.
Pelvic cytology was performed by infusion of saline into the pelvis and followed by aspiration of the peritoneal washing. Pelvic cytology was classified as negative, atypical or malignant. Cytology was considered “atypical” when pathologists could not provide a definitive diagnosis for malignancy [15]. Laparotomy conversion was defined as conversion from laparoscopic to abdominal hysterectomy caused by complication or mini-laparotomy to deliver the specimen. The co-investigators performed the data entry into the identified database, and the principal investigator of the study examined the database for accuracy, consistency, and quality.
Statistical Analysis
The primary interest of analysis was to identify independent predictors for the presence of positive pelvic cytology in laparoscopic surgery for endometrial cancer and to evaluate the risk of using intrauterine manipulators. Continuous variables were examined for normality by the Kolmogorov-Smirnov test and expressed with mean (± standard deviation) or median (range) as appropriate. Statistical significance of continuous variables was assessed with Student t test or Mann-Whitney U test as appropriate. For continuous variables, clinically relevant age (<60 vs ≥60), median values for BMI (<30 vs ≥30 kg/m2), median values for EBL (<100 vs ≥100 mL), and uterine weight (<250 vs ≥250 g) were used for cutoff values. Categorical or ordinal variables were expressed with number (%), and statistical significance was examined by χ2 test or the Fisher’s exact test as appropriate.
Logistic regression was used to determine independent risk factors for pelvic cytology results in malignancy and atypical values and also used to determine effect of the timing of intrauterine manipulator insertion. All variables with significance of p < .05 in univariate analysis were considered as candidates in the final model. These included BMI (<30 vs ≥30 kg/m2), pelvic lymphadenectomy (yes vs no), histology (endometrioid vs nonendometrioid), stage (I-II vs III-IV), tumor grade (low grade vs high grade), LVSI (yes vs no), deep myometrial invasion (yes vs no), cervical involvement (yes vs no), and timing of manipulator insertion (Group 1 vs Group 2). A conditional backward method was then used to determine the independently significant covariates in the final model, expressed with odds ratio (OR) and 95% confident interval (CI). All statistical tests were 2-tailed, and p < .05 was considered to be statistically significant. SPSS, version 22.0 (IBM SPSS Inc., Chicago, IL) was used for the analysis.
Results
A selection criterion for each group is shown in Fig. 1. During the study period 1074 cases with endometrial cancer who underwent surgical staging were identified. Of those, 660 cases who had abdominal or vaginal surgery were excluded. The records of the remaining 414 cases were reviewed. Of note, the oldest case for minimally invasive surgical staging for endometrial cancer in our institution was recorded in 2007. Of these, adequate information regarding the timing of the uterine manipulator insertion was not available in 57 patients and were subsequently excluded. Intrauterine manipulator insertion was confirmed in 357 patients. The timing of cytology was not defined in 24 patients who were also excluded. The remaining 333 cases, including 103 cases of cytology followed by intrauterine manipulator insertion, met the inclusion criteria representing the case group. For the control group 230 cases in which intrauterine manipulator insertion was followed by cytology were included.
Fig. 1.
Study schema. EMCA = endometrial cancer; TLH = total laparoscopic hysterectomy.
Clinical demographics are shown in Tables 1 and 2. Most patients in Group 1 were postmenopausal (median age, 57.6 years), Hispanic (48.5%), and obese (BMI ≥30 kg/m2; 63.1%), and these rates were similar between the 2 groups (all p > .05). Medical comorbidities (diabetes mellitus, hypertension, and hypercholesteremia), past history of tubal ligation, and diagnostic procedures were not significantly different, when comparing Group 1 and Group 2 (all p > .05). There were 18.9 % of patients who had a history of tubal ligations. Three-fourths of the patients (71.2%) were diagnosed by endometrial biopsy, and the remaining 96 cases (28.8%) were diagnosed by other procedures with hysteroscopic biopsy, dilation and curettage, and Vabra. Diagnostic procedures were not associated with cytology results (all p > .05).
Table 1.
Patient demographics
| Group 1 (n = 103) | Group 2 (n = 230) | p | |
|---|---|---|---|
| Median age, yr (range) | 57.6 (30.4–86.8) | 56.8 (24.7–84.3) | .10 |
| <60 | 41 (51.9%) | 129 (64.5%) | |
| ≥60 | 38 (48.1%) | 71 (35.5%) | |
| Ethnicity | .34 | ||
| White | 34 (33.0%) | 57 (24.8%) | |
| African | 2 (1.9%) | 7 (3.0%) | |
| Hispanic | 50 (48.5%) | 135 (58.7%) | |
| Asian | 13 (13.6%) | 28 (12.2%) | |
| Others | 3 (2.9%) | 3 (1.3%) | |
| Median BMI, kg/m2 (range) | 31.8 (18.3–56.2) | 33.3 (17.5–74.4) | .13 |
| <30 | 38 (36.9%) | 80 (34.8%) | |
| ≥30 | 65 (63.1%) | 150 (65.2%) | |
| Diabetes mellitus | 1.0 | ||
| No | 70 (68.0%) | 156 (67.8%) | |
| Yes | 33 (32.0%) | 74 (32.2%) | |
| Hypertension | .81 | ||
| No | 50 (48.5%) | 108 (47.0%) | |
| Yes | 53 (51.5%) | 122 (53.0%) | |
| Hypercholesteremia | .90 | ||
| No | 74 (71.8%) | 167 (72.6%) | |
| Yes | 29 (28.2%) | 63 (27.4%) | |
| History of tubal ligation | .17 | ||
| No | 88 (85.4%) | 182 (79.1) | |
| Yes | 15 (14.6%) | 48 (20.9) | |
| Hysteroscopy | .18* | ||
| No | 102 (99.0%) | 221 (96.1%) | |
| Yes | 1 (1.0%) | 9 (3.9%) | |
| Dilation and curettage | .33 | ||
| No | 90 (87.4%) | 209 (90.9%) | |
| Yes | 13 (12.6%) | 21 (9.1%) | |
| Vacuum curettage | 1.0 | ||
| No | 86 (83.5%) | 191 (83.0%) | |
| Yes | 17 (16.5%) | 39 (17.0%) |
BMI = body mass index.
Mann-Whitney U test, χ2 and Fisher’s exact test for p values.
Table 2.
Surgical outcome
| Group 1 (n = 103) | Group 2 (n = 230) | p | |
|---|---|---|---|
| Median EBL, mL (range) | 100 (10–1200) | 100 (10–2200) | .35 |
| <100 | 39 (37.9%) | 85 (37.3%) | |
| ≥100 | 64 (62.1%) | 143 (62.7%) | |
| Hysterectomy | <.001 | ||
| Laparoscopic | 69 (67.0%) | 198 (86.1%) | |
| Robotic | 34 (33.0%) | 32 (13.9%) | |
| BSO | 1.0* | ||
| No | 4 (3.9%) | 11 (4.8%) | |
| Yes | 99 (96.1%) | 219 (95.2%) | |
| Pelvic lymphadenectomy | .63 | ||
| No | 73 (70.9%) | 157 (68.3%) | |
| Yes | 30 (29.1%) | 73 (31.7%) | |
| Aortic lymphadenectomy | .14* | ||
| No | 98 (95.1%) | 206 (89.6%) | |
| Yes | 5 (4.9%) | 24 (10.4%) | |
| Laparotomic conversion | .45* | ||
| No | 99 (96.1%) | 215 (93.5%) | |
| Yes | 4 (3.9%) | 15 (6.5%) | |
| Uterine perforation | .52* | ||
| No | 102 (99.0%) | 229 (99.6%) | |
| Yes | 1 (1.0%) | 1 (.4%) | |
| Institution | <.001 | ||
| LAC | 60 (58.3%) | 185 (80.4%) | |
| KMC | 43 (41.7%) | 45 (19.6%) | |
| Type of uterine manipulator | .77 | ||
| V Care | 95 (92.2%) | 207 (90.0%) | |
| RUMI/Koh | 7 (6.8%) | 19 (8.3%) | |
| HUMI | 1 (1.0%) | 4 (1.7%) |
BSO = bilateral salpingo-oophorectomy; EBL = estimated blood loss; KMC = Keck Medical Center of University of Southern California; LAC = Los Angeles County Medical Center.
There are 2 missing data for EBL.
p Values in bold indicate significance.
Mann-Whitney U test, χ2.
Fisher’s exact test for p values.
The most common use for hysterectomy was laparoscopic (67.0% vs 86.1%, p < .01). Types of intrauterine manipulator were similar across the 2 groups (p = .77). The rates of bilateral salpingo-oophorectomy (96.1% vs 95.2%) and pelvic (29.1% vs 31.7%) or aortic lymph node dissection (4.9% vs 10.4%) were similar between the 2 groups (p > .05). The distribution of institution in which each group underwent surgery was significantly different (p < .01). The median EBL was 100 mL (range, 10–2200), with no significant difference between the 2 groups (p = .35). Nineteen patients (5.7%) converted to laparotomy during surgery. Among them, 16 cases underwent laparotomy because of a complication, whereas the remaining 3 cases had mini-laparotomies performed to deliver the specimens. Uterine perforation caused by insertion of intrauterine manipulator occurred in 1 case in each group, and both cases were stage I and had less than 50% myometrial invasion.
Pathologic variables were compared between the 2 groups and are shown in Table 3. The presence of atypical cells in pelvic cytology of Group 1, when compared with Group 2, was not statistically different (2.9% vs 4.8%, p = .56). Moreover, the difference in presence of malignant cells was also not statistically significant between the 2 groups (5.8% vs 9.6%, p = .29). Most Group 1 cases had stage I disease (88.3%), endometrioid histology (90.3%), and were low grade (82.5%). Additionally, most Group 1 cases did not have cervical involvement (93.2%), LVSI (82.5%), or deep myometrial invasion (85.4%). Disease stage, histologic subtype, tumor grade, cervical status, presence of LVSI, and deep myometrial invasion were not significantly different, when comparing Group 1 and Group 2 (all p > .05). Uterine weight was also similar between the 2 groups (p = .61).
Table 3.
Tumor characteristics
| Group 1 (n = 103) | Group 2 (n = 230) | p | |
|---|---|---|---|
| Median uterine weight, g (range) | 137 (39–534) | 145 (30–740) | .61 |
| <250 g | 80 (82.5%) | 195 (88.2%) | |
| ≥250 g | 17 (17.5%) | 26 (11.8%) | |
| Stage | .53 | ||
| I | 91 (88.3%) | 203 (88.2%) | |
| II | 4 (3.9%) | 5 (2.2%) | |
| III | 6 (5.8%) | 20 (8.7%) | |
| IV | 2 (1.9%) | 2 (.9%) | |
| Histology | .51 | ||
| Endometrioid | 93 (90.3%) | 194 (84.3%) | |
| Serous | 7 (6.8%) | 22 (9.6%) | |
| Clear cell | 2 (1.9%) | 10 (4.3%) | |
| Other | 1 (1.0%) | 4 (1.7%) | |
| Grade | .57 | ||
| 1 | 74 (71.8%) | 153 (66.5%) | |
| 2 | 11 (10.7%) | 33 (14.3%) | |
| 3 | 18 (17.5%) | 44 (19.1%) | |
| Cervical involvement | .71 | ||
| No | 96 (93.2%) | 219 (95.2%) | |
| Mucosa | 2 (1.9%) | 4 (1.7%) | |
| Stroma | 5 (4.9%) | 7 (3.0%) | |
| LVSI | .41 | ||
| No | 85 (82.5%) | 198 (86.1%) | |
| Yes | 18 (17.5%) | 32 (13.9%) | |
| Deep invasion | .88 | ||
| No | 88 (85.4%) | 195 (84.8%) | |
| Yes | 15 (14.6%) | 35 (15.2%) | |
| Cytology | .36 | ||
| Negative | 94 (91.3%) | 197 (85.7%) | |
| Atypical | 3 (2.9%) | 11 (4.8%) | |
| Malignant | 6 (5.8%) | 22 (9.6%) |
LVSI = lymphovascular space invasion.
Mann-Whitney U test, χ2 for p values.
There were 15 missing data for uterine weight.
To examine the risk factors for the presence of malignant or atypical cells in the pelvic cytology sample, univariate analysis was performed (Table 4). The timing of intrauterine manipulator insertion was not associated with presence of malignant and atypical cytology (OR, 1.75; 95% CI, .80–3.81; p = .16). However, the presence of malignant or atypical cytology was significantly associated with BMI, past history of tubal ligation, pelvic lymph node dissection, histology, stage, tumor grade, LVSI, deep myometrial invasion, and cervical involvement (all p < .05). In multivariate analysis controlling for the significant variables found in univariate analysis, BMI (adjusted OR, .40; 95% CI, .20–.80; p = .01) and advanced stage (adjusted OR, 10.3; 95% CI, 4.44–23.8; p < .001) remained independent risk factors associated with positive cytology.
Table 4.
Risk factor for malignant/atypical cytology
| Univariate |
Multivariate |
|||||
|---|---|---|---|---|---|---|
| No. | Pos* | OR (95% CI) | p | OR (95% CI) | p | |
| BMI, kg/m2 | <.01 | |||||
| <30 | 118 | 19.5% | 1 | 1 | .01 | |
| ≥30 | 215 | 8.8% | .40 (.20–.80) | |||
| Tubal ligation | .048 | |||||
| No | 270 | 14.4% | 1 | |||
| Yes | 63 | 4.8% | .30 (.09–.99) | |||
| Pelvic lymphadenectomy | <.001 | |||||
| No | 230 | 7.4% | 1 | |||
| Yes | 103 | 24.3% | 4.02 (2.06–7.84) | |||
| Histology | .02 | |||||
| Endometrioid | 287 | 10.8% | 1 | |||
| Nonendometrioid | 46 | 23.9% | 2.60 (1.20–5.62) | |||
| Stage | <.001 | <.001 | ||||
| I–II | 303 | 8.9% | 1 | 1 | ||
| III–IV | 30 | 50.0% | 10.2 (4.51–23.2) | 10.3 (4.44–23.8) | ||
| Tumor grade | <.01 | |||||
| Low grade | 271 | 10.0% | 1 | |||
| High grade | 62 | 24.2% | 2.88 (4.13–5.83) | |||
| LVSI | <.001 | |||||
| No | 283 | 9.5% | 1 | |||
| Yes | 50 | 30.0% | 40.6 (1.97–8.38) | |||
| Deep myometrial invasion | .01 | |||||
| No | 283 | 10.6% | 1 | |||
| Yes | 50 | 24.0% | 2.67 (1.26–5.65) | |||
| Cervical stroma involvement | .01 | |||||
| No | 315 | 11.4% | 1 | |||
| Yes | 18 | 33.3% | 3.88 (1.37–11.0) | |||
| Timing of manipulator insertion | .16 | |||||
| Group 1 | 103 | 8.7% | 1 | |||
| Group 2 | 230 | 14.3% | 1.75 (.80–3.81) | |||
BMI = body mass index; LVSI = lymphovascular space invasion.
Binary logistic regression model for multivariate analysis entered all listed variables.
p Values in bold are significant.
Pos, malignant/atypical cytology results.
Discussion
The key finding of the present study is that the timing of intrauterine manipulator insertion during minimally invasive surgical staging is not associated with atypical or malignant cells in the pelvic cytology specimen in women with early-stage endometrial cancer. The number of minimally invasive surgeries for endometrial cancer has been increasing dramatically, after the feasibility, surgical safety, and effectiveness were verified by several large prospective trials comparing these procedures to standard laparotomy [4–7]. These studies provided evidence that an initial laparoscopic approach for early-stage endometrial cancer did not increase recurrence and mortality rates [4,5,7]. Uterine manipulators are a useful adjunct for total laparoscopic hysterectomy (TLH) because they can improve the maneuverability of the uterus during surgery [16]. Uterine manipulators also assist with anatomic definition by facilitating the detection of the anatomic landmark for colpotomy. However, some surgeons fear the potential of tumor spillage caused by intrauterine manipulator use. There are opinions on the pros and cons of using an intrauterine manipulator for TLH in women with endometrial cancer [12,17–22].
Our study found that the number of cases with malignant cytology was not significantly different between the 2 groups, which were divided according to the timing of intrauterine manipulator insertion (5.8% vs 9.6%). Previous studies demonstrated that the incidence of malignant cytology ranged from 0 to 14.3% in women undergoing TLH with intrauterine manipulator use for early-stage endometrial cancer (Supplemental Table 1) [17–22]. For women with low-risk endometrial cancer undergoing conventional laparotomy, 5.0% to 21% were found to have malignant cytology [23–25]. It remains unclear whether hysterectomy modality influences the likelihood of positive cytology. Previous retrospective studies on the performance of TLH with intrauterine manipulator use did not document in detail the timing of intrauterine manipulator insertion during surgery [18–20]. These retrospective studies assessed the relationship between malignant cytology results and minimally invasive surgery or laparotomy surgery, but the results are conflicting. A recent retrospective study with a relatively large patient population demonstrated that minimally invasive hysterectomy-based surgical staging for endometrial cancer was not associated with an increased risk of malignant cells in pelvic cytology samples compared with conventional abdominal hysterectomy [12]. Various prospective studies in minimally invasive surgery did describe the timing of intrauterine manipulator insertion and collection of pelvic cytology in detail [17,21,22]. According to these studies, the incidence of malignant cytology was not significantly different as compared with laparotomy surgery. Also, as shown in Supplemental Table 1, there is no association between timing of intrauterine manipulator and pelvic cytology results. These studies featured relatively small sample sizes (median, 46 cases), making the results difficult to adopt and interpret for proper analysis.
Our study showed a 4.2% prevalence of atypical cytology in 333 cases of TLH with intrauterine manipulator use for early-stage endometrial cancer, and the incidence of atypical cytology did not significantly differ between the 2 groups (2.9% vs 4.8%, p = .56). A previous study that compared TLH in women with endometrial cancer with conventional abdominal hysterectomy found an increased risk of atypical cells in pelvic cytology in women undergoing TLH and also reported a rate of atypical cytology to be 8% [12]. The difference in the rate of positive cytology results may depend on the patient demographics, for example, a history previous radiation, chemotherapy, or hormonal therapy. The method and timing of collection of pelvic cytology may lead to bias in the results [26,27]. Our study demonstrated that the risk for malignant or atypical pelvic cytology was influenced by advanced stage (adjusted OR, 10.3; p < .001) and higher BMI (adjusted OR, .40; p = .01). Particularly, higher BMI was associated with lower risk of malignant or atypical cytology results. This is likely that obese women with endometrial cancer tend to have a type I disease characterized by low-grade tumor and early stage.
It remains controversial whether or not use of an intrauterine manipulator increases risks of retrograde tumor spread during surgical staging for endometrial cancer. The optimal study to examine this association would be to collect the pelvic cytology before and after the insertion of the intrauterine manipulator (Supplemental Table 1), but our study did not have that information. In addition, there was no case of fallopian tube coagulation at the time of surgical staging in our study, and hysteroscopy, uterine curettage, and Vabra before hysterectomy were not associated with pelvic cytology results. However, our study found that history of tubal ligation was associated with decreased risk of malignant/atypical pelvic cytology (4.8% vs 14.4%, p = .048), although it did not remain an independent risk factor in multivariate analysis. This finding supports a recent large-scale study examining 4489 endometrial cancer cases [28] that concluded that tubal ligation was associated with lower stage and cancer-related mortality in high-grade tumors, proposing an important hypothesis of endometrial cancer spread via a retrograded fashion through the fallopian tube. Although our study and others (Supplemental Table 1) did not point toward this findings of retrograde tumor spread via the fallopian tube by intrauterine manipulator use, there may a possibility that this is a Type II error due to a lack of adequate sample size. Further study with a larger sample size is warranted.
Strengths of this study are the relatively large sample size among published data in the literature with detailed information regarding the timing of uterine manipulator insertion and pelvic cytology. Possible limitations of this study are that most of our results are based on women with early-stage and low-grade disease. In addition, because this was a retrospective study, bias regarding the timing of intrauterine insertion may also have existed, and the exact reason and indication for the timing of intrauterine manipulator were not collected in the study. We also do not know the exact reason for the difference in the patterns for the timing of intrauterine manipulator insertion between the 2 institutions. Because minimally invasive surgical staging for endometrial cancer is a relatively new treatment modality in our institution and our study includes the relatively new cases (the oldest case in 2007 and study end period in 2015), follow-up time was not adequate enough to do survival analysis to examine the association between intrauterine manipulator use and risk of recurrence. Future follow-up study is warranted.
In summary, the timing of intrauterine manipulator insertion during minimally invasive surgical staging was not associated with an increased risk of positive pelvic cytology. Intrauterine manipulator use seems to be safe in the treatment of women with early-stage endometrial cancer.
Supplementary Material
Acknowledgments
Supported by Ensign Endowment for Gynecologic Cancer Research (to K.M. and L.D.R.). There are no conflicts of interest to report.
Footnotes
Supplementary Data
Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.jmig.2015.10.002.
Contributor Information
Hiroko Machida, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, California.
Jacob P. Casey, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, California.
Jocelyn Garcia-Sayre, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, California.
Carrie E. Jung, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, California.
Jennifer K. Casabar, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, California.
Aida Moeini, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, California.
Kazuyoshi Kato, Department of Gynecology, Cancer Institute Hospital, Tokyo, Japan.
Lynda D. Roman, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, California; Norris Comprehensive Cancer Center, Los Angeles, California.
Koji Matsuo, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, California; Norris Comprehensive Cancer Center, Los Angeles, California.
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