Number of Hysteroscopies and the Time Interval between Hysteroscopy and Surgery: Influence on Peritoneal Cytology in Patients with Endometrial Cancer

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1 Number of Hysteroscopies and the Time Interval between Hysteroscopy and Surgery: Influence on Peritoneal Cytology in Patients with Endometrial Cancer INGOLF JUHASZ-BÖSS 1,2, TANJA FEHM 1, ALEXANDER NAUTH 1, SVEN BECKER 1, RALF ROTHMUND 1, KONSTANTINOS GARDANIS 1, BERNHARD KRÄMER 1, DIETHELM WALLWIENER 1 and ERICH SOLOMAYER 1,2 1 Department of Obstetrics and Gynecology, University of Tübingen, Tübingen, Germany; 2 Department of Obstetrics and Gynecology, University of Saarland, Homburg/Saar, Germany Abstract. Aim: Hysteroscopy is a routine procedure for the diagnosis of endometrial cancer (EC). Moreover, with implementation of sentinel lymph node technique, a second hysteroscopy is necessary for technetium injection before perfoming lymphadenectomy. As yet, no data are available showing whether the time interval between hysteroscopy and definitive surgery, or the number of preoprative hysteroscopies, have an influence on the intraperitoneal cytology results. Patients and Methods: Data from patients with EC undergoing surgery in the years at the Department of Obstetrics and Gynecology, University of Tübingen, were analyzed retrospectively. Cytological results were correlated with the number of preoperative hysteroscopies and with the time interval between hysteroscopy and surgery. Results: In , a total of 196 patients with EC and known cytological results underwent surgery. Positive cytological results (C+) were obtained in 11 patients (5.6%). The rate of C+ in patients without hysteroscopy was 18.2% (n=4) and in patients after one and two hysteroscopies, 1.9% (n=2) and 7.1% (n=5), respectively (p=0.008). The rate of C+ in patients with early EC (FIGO I and II) increased after two hysteroscopies (3.1% vs. 1% after one hysteroscopy and 0% without hysteroscopy) but the difference did not reach statistical significance (p=0.513). The mean time interval between hysteroscopy and definitive surgery with cytological examination was 11.1±15.2 days (range 0-97 days, median=1). C+ in the group of patients with a time gap between hysteroscopy and Correspondence to: Ingolf Juhasz-Böss, MD, Department of Obstetrics and Gynecology, University of Saarland, Kirrbergerstr. 100, Homburg/Saar, Germany. Tel: , Fax: , ingolf.juhasz-boess@uks.eu Key Words: Endometrial cancer, hysteroscopy, peritoneal cytology, tumor cell dissemination, sentinel node. surgery of 1days was found in 6 cases (8.1%), while in the group with a time gap >1day there was in 1 case (p=0.161). Conclusion: The finding of positive cytology results is independent from the time interval between preoperative hysteroscopy and definitive surgery. Furthermore, multiple hysteroscopies do not appear to significantly increase peritoneal tumor cell dissemination. Hysteroscopy is safe and indispensable in patients with EC. Endometrial carcinoma (EC) is the most frequent type of cancer encountered in the female genital system. In the Western world, the age-standardized incidence of the disease is between 9.9 and 15.0 per 100,000 women. With increasing age, the likelihood of developing the disease increases and peaks between 75 and 80 years. In the countries with the highest prevalence, the mean five-year survival rate ranges between 72-84% (1). The main symptom is uterine bleeding of postmenopausal women, and menstrual bleeding anomalies of perimenopausal women. Hysteroscopy. As part of the clarification process of these symptoms, most patients undergo a diagnostic hysteroscopy with cervical dilatation and curettage (D&C) (Figure 1). Hysteroscopy is a routine procedure in patients with uterine bleeding disorders or conspicuous sonographic findings in the endometrium. It is unclear if any intra-abdominal dissemination of tumor cells possibly occurs during hysteroscopy. To date, only a few, predominantely retrospective, studies exist in this regard, with small case numbers and partly conflicting results (2-4). Moreover, no data have been presented regarding in what respect the time interval between hysteroscopy and stage-ajusted surgery is of relevance for a possible cytological evidence of tumor cells. The time interval between diagnostic hysteroscopy and stage-adjusted surgery is often several days to weeks (2, 5). Some studies point to a higher prevalence of positive cytological results especially after hysteroscopy dating back /2010 $

2 undergo extensive pelvic and paraaortal lymphadenectomy. In what respect this imminently preoperatively performed hysteroscopy favors an intra-peritoneal dissemination of tumor cells has been insufficiently resolved but is of paramount importance, especially since a majority of patients undergo a preceding diagnostic hysteroscopy. The aim of our work was to investigate the safety of hysteroscopy in terms of intra-abdominal dissemination of tumor cells. Thereby specifically addressing the safety of hysteroscopy regarding the interdependence between the time interval of hysteroscopy and stage-ajusted surgery, including possible tumor cell detection during cytological examination. Furthermore, this study should also clarify if more than one preoperative hysteroscopy increases the rate of positive cytological results. Patients and Methods Figure 1. Hysteroscopic view of endometrial tumor. a longer time (4, 6). Nonetheless, Hefler et al. showed that the time interval between hysteroscopy and stage-ajusted surgery has no influence on the disease-free and overallsurvival rate in patients with EC (5). Role of cytological examination. The results of cytological examination serve as a prognostic factor in patients with EC stages FIGO II and III; as a prognostic factor in FIGO stage I, there are contradictory results (7-10). Positive cytological results mainly correlate with tumor affection of the adnexa/fallopian tubes and the cervix, and peritoneal tumor metastasis, as well as with a higher grading (11). With positive cytological outcomes, some studies ascertain a higher recurrence rate (8, 12), allthough these findings have also been partly refuted (2, 13, 14). Therapy of endometrial cancer. In the treatment of EC, surgery is the primary approach which in principle should be carried out. The therapeutic decision is taken in light of the general condition of the patient, tumor stage and risk factors. According to the FIGO classification, after histological reconfirmation of the diagnosis, a surgical staging is necessary, requiring an exploration of the abdomen with hysterectomy and bilateral adnexectomy, and in stages I and II, pelvic and para-aortic lymphadenectomy, and including peritoneal cytological analysis (1). Regarding surgical treatment of EC, sentinel node biopsy is increasingly gaining importance. This requires a preoperative marking of the EC with technetium and/or blue solution under hysteroscopic guidance (15). This minimally invasive diagnostic procedure can spare patients who may have increased perisurgical risks from having to Retrospective evaluation was carried out of all patients with a primary EC who had undergone surgery at the Department of Obstetrics and Gynecology, University of Tübingen, in the years Excluded from the study were patients who, in addition to EC, had an ovarian carcinoma, or those with other uterine malignancies, e.g. Müllerian mixed tumors. The following patient characteristics were evaluated: age at the time of the initial diagnosis of EC, number of preoperatively performed hysteroscopies and the time interval between the last hysteroscopy and stage-ajusted surgery. In addition, the following tumor characteristics were evaluated for all patients: initial FIGO stage, myometrial infiltration, tumor grading, nodal involvement, remote metastasis and date of recurrence, and time of death. The intraoperatively obtained cytological results, which normally are stored immediately after inspection of the abdomen at the beginning of surgery, were similarly evaluated. Follow-up data of all patients were taken into account up to and including April The diagnosis of EC was determined by diagnostic hysteroscopy and D&C. All patients received stage-adjusted surgery with hysterectomy, bilateral salpingo-oophorectomy and pelvic and paraaortal lymphadenectomy, and sentinel node lymphadenectomy. Therefore, some patients received preoperative sentinel node marking with technetium under hysteroscopy. The sentinel node lymphadenectomy technique has been practised in our clinic since late 2006 in patients with EC stages FIGO I and II. Postsurgically, all patients cases were discussed in an interdisciplinary tumor conference. The supporting therapy recommendation of this tumor conference was chosen in light of the stage of the tumor and the general condition of the patients, and included a brachy- and/or teletherapy or chemotherapy. All patients received regular tumor aftercare in our hospital, from supporting gynecologists. Statistical analysis was carried out with SPSS 15.0 for Windows (SPSS Inc., Chicago, IL, USA). P<0.05 was considered to be statistically significant. Results Patient population. From 2005 to 2008, a total of 196 patients having a primary EC with known cytological 2426

3 Juhasz-Böss et al: Hysteroscopy and Surgery: Influence an Peritoneal Cytology in Endometrial Cancer Table I. Patient characteristics. Discrete data are given as numbers, continuous as the mean ± standard deviation. Parameter Value Total number of patients 196 Age at first diagnosis (years) 62.4±11.6 Time interval from hysteroscopy 1 to surgery (median) (days) Number of hysteroscopies 0 22 (11.2%) (53.1%) 2 70 (35.7%) Tumor stage I 168 II 8 III 17 IV 3 Myometrial infiltration None 28 <50% 114 >50% 46 Serosa involvement 8 Tumor grade Cytology Negative 185 (94%) Positive 11 (5.6%) Histotype Endometrioid 159 (81.1%) Nonendometrioid 37 (18.9%) Time of follow-up (month) 20.3±14.4 (range 0-50) Outcome Alive 168 Recurrent disease 8 Dead 20 outcomes received stage-ajusted surgery at the Department of Obstetrics and Gynecology, University of Tübingen. Data of the patients including tumor characteristics are summarized in Table I. A total of 11 patients (5.6%) had tumor cells in the cytological analysis and thus positive cytological results. The data of these 11 patients, including their cytological tumor findings, are summarized in Table II. Hysteroscopy. A total of 173 patients (88.3%) underwent hysteroscopy as part of the diagnostic procedure, where 104 underwent only one and 70 two hysteroscopies. None underwent more than two. Twenty-two patients did not undergo preoperative hysteroscopy; in these patients, the EC was detected either intraoperatively by frozen section or by coincidence after a hysterectomy in clinically asymptomatic patients, or was the result of a primary, exploratory laparotomy regarding the clinical assumption of advanced genital carcinoma. Figure 2. Rate of positive cytological findings in relation to the number of preoperative hysteroscopies. All endometrial carcinomas were taken into account (n=196). The three groups differ significantly from each other (p=0.008) with regard to rate. The patient populations of each group are further described in Table III. Looking at the number of positive cytological results in relation to the number of hysteroscopies undertaken, 4 patients out of the 22 (18.2%) patients without preoperative hysteroscopy, 2 patients out of the 104 (1.9%) with one preoperative hysteroscopy, and 5 patients out of the 70 (7.1%) with two preoperative hysteroscopies had positive cytological outcomes. These three groups differ significantly from each other (p=0.008) in the rate of positive cytology results (Figure 2). Table III shows the tumor characteristics of the patients in terms of the number of hysteroscopies undergone. Looking only at the early stage FIGO I and II EC (n=176 patients), none of the patients in the group without hysteroscopy (n=16) had positive cytological results, one patient (1%) in the group with 1 hysteroscopy (n=97) and two patients (3.1%) in the group with 2 hysteroscopies (n=63) had positive cytological outcomes. Although an increase in the rate of positive cytological results was recorded after one and two hysteroscopies, the three groups do not differ significantly from each other (p=0.513) (Figure 3). Time interval. The average time interval between the last performed hysteroscopy and stage-ajusted surgery including cytological examination was 11.1±15.2 (range 0-97, median=1) days. The patients who received preoperative hysteroscopy were divided into two groups: group A patients (n=74) whose last hysteroscopy was 1 day prior (equalling the median), and group B (n=66) with their last hysteroscopy 2427

4 Figure 3. Rate of positive cytological findings in relation to the number of preoperative hysteroscopies in patients with EC, stages FIGO I and II (n=176). Although an increase in the rate of positive cytological findings was recorded after one as well as two hysteroscopies, the three groups did not differ significantly from each other (p=0.513) in this respect. >1 day prior. Patients who had not undergone hysteroscopy (n=22) or those where the time of the last hysteroscopy was no longer traceable were not taken into account (n=34). In group A, 6 patients (8.1%) had positive cytological results and in group B only 1 (1.5%). Although more positive findings were recorded in group A patients, statistically, the two groups did not differ significantly from each other (p=0.161). Discussion To date, different studies on the safety of hysteroscopy have presented conflicting results regarding intra-abdominal tumor cell dissemination. While some studies report increased rates of positive cytological results (4, 6, 10, 11, 16, 17), others did not confirm this (2, 18-21). These were mostly retrospective studies, however, with relatively small numbers of cases. In Germany, patients with uterine bleeding disorders and/or sonographically conspicuous findings usually undergo hysteroscopy and D&C. Therefore, nearly all of our patients with EC have undergone this examination preoperatively. With 173 patients having undergone hysteroscopy with D&C, we thus describe one of the largest patient populations with hysteroscopy and D&C regarding endometrial cancer. We did not record an increased rate of positive cytological results after hysteroscopy. Only a few prospective studies exist regarding this topic, mostly ones with small case numbers (17-19); these also mainly confirm the safety of hysteroscopy regarding intra-abdominal dissemination of tumor cells. The safety of hysteroscopy was also confirmed by the authors of two systematic reviews (22, 23). To our knowledge, this is the first time that the rate of positive cytological results after more than only one preoperative hysteroscopy has been investigated. Even after two presurgically performed hysteroscopies, the rate of positive cytological results was not significantly elevated. On contrary, in our study, the fact that patients without hysteroscopy in particular have the highest rate of positive cytological results is remarkable. This led us to examine the patient groups regarding hysteroscopies further in light of their different composition (Table III). In the group of patients without hysteroscopy, more patients had a higher tumor stage, higher grading, more extensive tumor infiltration (partly attaining the serosa), remarkably more often lymph node involvement and more frequently a nonendometroid EC. The three groups, however, only differ significantly regarding the tumor stage. A correlation of positive cytological results with prognostically unfavorable tumor characteristics such as a higher grading, more extensive myometrial infiltration and lymph node metastasis is known in the literature (24). Moreover, there are also indications of an association between positive cytological results and cervical tumor invasion, lymphovascular space invasion and extrauterine tumor spread (9, 11). This could explain the significantly increased rate of positive cytological results, especially in patients without hysteroscopy. Even after the evaluation of only those patients with an early stage EC (FIGO I and II), no significant increase of positive cytological results after two hysteroscopies was recorded here. In the literature, several cofactors are discussed which, in the context of hysteroscopy, could have an influence on intraabdominal tumor cell dissemination. Apart from the distention medium (3) and distention pressure (2, 15) used, these also include the time interval between hysteroscopy and the cytological exploration. In most studies, the time interval between hysteroscopy and stage-ajusted surgery amounts to several days to weeks (2, 5, 6, 21). This also applies to our study; however, we explicitly investigated the time effect by subdividing our patient population into two groups. In one group, the time span between hysteroscopy and stage-ajusted surgery was 1 day (median) and in the other group >1 day. The difference between both groups was not statistically significant. This separate investigation regarding hysteroscopies dating back a few days or longer is important, since some studies reported more frequent positive cytological results after hysteroscopies dating back further (4, 6). In hospitals, however, more and more patients undergo the hysteroscopy some hours up to a few days before surgery, since increasingly more receive a hysteroscopic sentinel node marking of the EC. Therefore, it was important for us to examine this time effect more 2428

5 Juhasz-Böss et al: Hysteroscopy and Surgery: Influence an Poritoneal Cytology in Endometrial Cancer Table II. Details of patients with endometrial cancer showing positive cytology. Patient Age Histotype FIGO Grading Myometrial Nodal Number of Time interval Follow-up Outcome (years) invasion involvement hysteroscopies between (months) hysteroscopy and surgery (d) 1 64 Endometroid I 2 <50% Alive 2 62 Endometroid III 3 <50% Alive 3 57 Endometroid II 2 >50% Recurrent disease 4 62 Endometroid III 3 <50% Alive 5 69 Endometroid III 3 >50% Dead 6 78 Nonendometroid III 3 none Dead 7 77 Endometroid III 3 >50% Alive 8 74 Nonendometroid III 3 <50% Recurrent disease 9 68 Nonendometroid III 3 >50% Alive Endometroid IV 3 Serosa involvement Dead Endometroid I 2 <50% Alive closely. Even if we change our group composition and compare patients with a preoperative hysteroscopy interval of 2 days with those of >2 days, the result does not change (data not shown). Concering imminently pre- or intraoperatively performed hysteroscopies, conflicting statements regarding subsequent peritoneal tumor cell dissemination also exist (11, 15). After intraoperative clamping of the fallopian tubes, Lo et al. recorded reduced intraperitoneal tumor cell dissemination during the subsequently conducted hysteroscopy (11). Solima et al. were also unable to determine an increased rate of tumor cell dissemination during imminently preoperatively performed hysteroscopy (15). The time interval between hysteroscopy with D&C and surgery also has no influence on the deseasefree and overall-survial rate of patients with EC (5). In one of the largest patient populations ever, we have investigated and confirmed the safety of hysteroscopy in the context of preoperative diagnostics of EC regarding possible intra-abdominal tumor cell dissemination. We were able to show that the detection of intra-abdominal tumor cells is independent of the time interval between surgery and the preceding hysteroscopy. Moreover, we were able to show for the first time that the number of preceding hysteroscopies also does not increase the rate of positive cytological results. This finding is of relevance since, in the future, patients will probably increasingly more frequently undergo hysteroscopic sentinel node marking in addition to a diagnostic hysteroscopy. Hence, from an oncological perspective, hysteroscopy seems to be a safe and indispensable medical examination in patients with endometrial carcinoma. Conflict of interest The Authors indicated no potential conflicts of interest. Table III. Patient characteristics in relation to number of preoperative hysteroscopies. Parameter Number of hysteroscopies p-value Number of patients 22 (11.2%) 104 (53.1%) 70 (35.7%) Age at first diagnosis (years) 64.3± ± ± Time interval from hysteroscopy to surgery (days) ± ±0.3 Tumor stage I 15 (68.2%) 92 (88.5%) 61 (87.1%) II 1 (4.5%) 5 (4.8%) 2 (2.9%) III 5 (22.7%) 6 (5.8%) 6 (8.6%) IV 1 (4.5%) 1 (0.9%) 1 (1.4) Myometrial infiltration None 4 (18.2%) 16 (15.4%) 8 (11.4%) <50% 9 (40.9%) 56 (53.8) 49 (70%) >50% 6 (27.3%) 29 (27.9%) 11 (15.7%) Serosa involvement 3 (13.6%) 3 (2.9%) 2 (2.9%) Tumor grade (27.3%) 13 (12.5%) 18 (25.7%) 2 11 (50%) 74 (71.2%) 40 (57.1%) 3 5 (22.7%) 17 (16.3%) 12 (17.1%) Nodal involvement Negative 16 (72.7%) 96 (92.3%) 66 (94.3%) Positive 5 (22.7%) 6 (5.8%) 4 (5.7%) Unknown 1 (4.5%) 2 (1.9%) - Cytology Negative 18 (81.8%) 102 (98.1%) 65 (92.9%) Positive 4 (18.2%) 2 (1.9%) 5 (7.1%) Histotype Endometrioid 16 (72.7%) 86 (82.7%) 58 (82.9%) Nonendometrioid 6 (27.3%) 18 (17.3%) 12 (17.1%) 2429

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