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ONCOLOGY

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The risk of diagnostic hysteroscopy in women with endometrial cancer


Jennifer E. Soucie, MD, MSc; Pamela A. Chu, MD, MBA; Sue Ross, PhD; Tom Snodgrass, BSc (Hons); Stephen L. Wood, MD, MSc
OBJECTIVE : We sought to evaluate whether hysteroscopy in patients

with endometrial cancer had an effect on disease stage or mortality.


STUDY DESIGN: This was a retrospective cohort analysis of data linked

group (P .38). There was also no difference in death rates, 13.2% vs 15.2% (P .25), or in the proportion of women dying of female genital organ cancer, 46.1% vs 42.1% (P .53), respectively.
CONCLUSION: Hysteroscopy is not associated with a higher rate of

between a registry of women diagnosed with endometrial cancer and physician billing data on hysteroscopy.
RESULTS: A 99.8% match rate was obtained. Eighty-ve percent of

cases had complete data on staging. Of these 1972 cases, 672 (34.1%) had undergone hysteroscopy. There was no difference in stage III disease between the hysteroscopy (7.1%) vs no hysteroscopy (6.5%)

stage III disease or mortality. It allows for accurate diagnosis with direct visualization and biopsy, and should be considered a safe diagnostic tool. Key words: endometrial cancer, hysteroscopy, mortality, stage

Cite this article as: Soucie JE, Chu PA, Ross S, et al. The risk of diagnostic hysteroscopy in women with endometrial cancer. Am J Obstet Gynecol 2012;207:71.e1-5.

ysteroscopy is widely used for the diagnosis of endometrial hyperplasia or carcinoma. The sensitivity has been estimated to be 86.4%.1 In comparison, Pipelle endometrial biopsies have been reported to have a sensitivity of 6783.5%.2,3 It has also been shown that hysteroscopically guided curettage has higher accuracy than dilatation and curettage (D&C) alone.4 However, concern exists that the introduction of high-pressure gas or uid into the uterine cavity, to produce distension, could facilitate the dissemination of malignant cells in

patients with endometrial cancer. It has been found that the distention medium can begin draining transcervically and transtubally when pressures reach approximately 100-150 mm Hg. Thus, in the patient with endometrial cancer, there is the theoretical possibility that malignant cells might be dispersed into the fallopian tubes and the abdominal cavity following hysteroscopy.5 The evidence associating peritoneal dissemination with hysteroscopy and ultimately its possible effect on endometrial cancer mortality outcomes is inconclusive.6-16

This study was undertaken to evaluate whether preoperative hysteroscopy performed in patients with endometrial cancer had an effect on subsequent surgical staging, and ultimately mortality. It is a retrospective cohort analysis of data on women who had been diagnosed with endometrial cancer over a period of 10 years (1997 through 2006).

M ATERIALS AND M ETHODS


Sources of data for this study were the Alberta Cancer Registry and physician billing data from Alberta Health and Wellness. The Alberta Cancer Registry captures data on all patients diagnosed with a cancer that is identied by the International Classication for Diseases for Oncology. Data on women with endometrial cancer were retrieved from the registry from Jan. 1, 1997, through Dec. 31, 2006. This start time was chosen principally because the Alberta Cancer Registry had undergone a number of coding changes prior to this time period. It was not until 1997 that endometrioid adenocarcinoma was differentiated from other more aggressive nonadenocarcinoma histologic types, such as, clear cell and papillary serous. A second benet to this time period was the introduction of new staging criteria for endometrial cancer 71.e1

From the Departments of Obstetrics and Gynecology (Drs Soucie, Chu, Ross, and Wood), Community Health Sciences (Drs Ross and Wood), and Family Medicine (Dr Ross), Faculty of Medicine, University of Calgary, and Cancer Care-Alberta Health Services (Mr Snodgrass), Calgary, Alberta, Canada. Received Jan. 28, 2012; revised March 21, 2012; accepted April 25, 2012. Supported by McClure Memorial Cancer Endowment, University of Calgary (J.E.S.). This study is based in part on data provided by Alberta Health and Wellness. The interpretation and conclusions contained herein are those of the researchers and do not necessarily represent the views of the Government of Alberta. Neither the government nor Alberta Health and Wellness expresses any opinion in relation to this study. The authors report no conict of interest. Presented at the 40th Global Congress of Minimally Invasive Gynecology, American Association of Gynecologic Laparoscopists, Hollywood, FL, Nov. 6-10, 2011, and the 40th annual meeting, Association of Academic Professionals in Obstetrics and Gynecology of Canada, Toronto, Ontario, Canada, Dec. 2-4, 2011. Reprints not available from the authors.
0002-9378/$36.00 2012 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog.2012.04.026

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Oncology
diagnoses would have been made by either ofce endometrial biopsy or D&C. The cases from the cancer registry were then linked to the Alberta Health and Wellness dataset. Information on whether a diagnostic hysteroscopy was performed for each patient was abstracted. Data linkage went back as far as January 1996, to include information on cases that were pulled from the Alberta Cancer Registry for the year of 1997. This would represent hysteroscopy that had been performed within 1 year, isolating that which was used for the diagnosis of endometrial cancer. Data linkage was performed using at least 2 patient-specic variables within each dataset, and all identifying information was removed from the linked dataset before release for analysis. Women with stage IV disease were excluded, since diagnosis with an endometrial sample may not have been required, as disease may have been more clinically apparent at presentation. As the survival in this group is also close to 0, this would have affected our analysis by disproportionably decreasing the survival for women who had not had hysteroscopy. Cases were also excluded if histology indicated a nonadenocarcinoma type of cancer, such as squamous, clear cell, papillary serous, and/or undifferentiated carcinoma. This eliminated advanced disease that was likely due to the inherent disease process of a more aggressive tumor type, rather than the diagnostic technique used. There were 2 primary outcomes in this study: staging and overall survival. Staging IIIa would indicate that the carcinoma had extended out of the uterus. If peritoneal dissemination via the fallopian tubes occurs during hysteroscopy, staging should indicate at least stage III. Therefore, the study hypothesis was that hysteroscopy would be associated with an increased frequency of stage III disease and endometrial cancerrelated deaths. Review of the literature suggested that 10% of those women with endometrial cancer who undergo hysteroscopy for diagnostic purposes and 5% of those who do not undergo hysteroscopy will have stage III disease.12 From this, it was cal-

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culated that a sample size of 387 and 581 women who have and have not undergone hysteroscopy, respectively, would be needed to detect a difference in staging with a power of 80% and an alpha error of 0.05. These numbers were easily attained from the provincial registries. Data were summarized using proportions for categorical variables, and both mean and median for continuous variables. Bivariate analyses were performed to compare the hysteroscopy groups in regard to staging and other possible prognostic risk factors. Comparisons were made using Pearson 2 test for categorical variables. Mantel-Haenszel 2 test was used to identify trends in proportions. A Student t test was used to compare continuous variables if they were normally distributed; otherwise, the Wilcoxon rank sum test was used. P .05 was considered to be statistically signicant. All statistical calculations were performed using the SAS program package (SAS Institute, Cary, NC). Data were managed according to the Alberta Privacy Legislation. Data linkage between Albertas Cancer Registry and the Health and Wellness dataset was performed by Alberta Health and Wellness. This process did not compromise patient condentiality as only anonymous data were received by the research team. Ethical approval was obtained from the Conjoint Health Research Ethics Board at the University of Calgary (Ethics Review Board no: E-20934).

that took place in 1989. Staging after that change included surgical observations.17 Besides diagnosis, the Alberta Cancer Registry provided further information on pathology (histologic cell type and staging) and vital statistics. Loss to follow-up within the Alberta Cancer Registry is minimal, as each month linkage is made to Alberta Vital Statistics to identify those cancer patients who have died and the cause of death. In addition, there is a link made annually with the Canadian National Mortality database. However, patients who die outside Canada could be potentially missed. Cases were selected from the Alberta Cancer Registry based on the diagnosis of endometrial cancer as dened by a positive biopsy. Staging was reported by the treating physician. In Alberta, pelvic washings are considered the standard of care. The majority of cases would have also included pelvic lymph node sampling. For the few cases missing node sampling, the performance of pelvic washings alone would have dictated the classication of stage IIIa disease based on the International Federation of Gynecology and Obstetrics (FIGO) 1989 staging criteria.17 A thorough review of this dataset was then performed to eliminate transcription errors and to clarify staging. When staging information within the dataset was missing or not interpretable, crossreference to other variables (ie, text entered by the physician) in the wider electronic database allowed for clarication in many cases. Finally, any staging based on the American Joint Committees Cancer TNM staging manual (fth and sixth editions) was translated to the FIGO 1989 staging criteria.17 Alberta Health and Wellness administers a universal health care plan that covers all Albertans, and through this, physicians are reimbursed for all procedures performed in the province. The Alberta Health and Wellness dataset provided information on diagnostic hysteroscopy (specically by fee code 80.81) and patient characteristics (age). This code would have captured hysteroscopy performed in both the ofce setting and operating room. When hysteroscopy was not performed, 71.e2

R ESULTS
The initial data request from the Alberta Cancer Board had provided 2331 cases that met both inclusion and exclusion criteria. A 99.8% match rate was obtained when linkage was performed with the Alberta Health and Wellness claims data. Approximately 85% of these cases had complete and appropriate data on staging (350 were missing staging completely, while 5 had staging complicated by coexistent cancer, a different type of cancer, or a benign condition). Of these 1972 cases with complete staging, 672 (34.1%) had undergone hysteroscopy. There was an increase in the utilization of hysteroscopy over the study period,

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and in the number of cases diagnosed. In 1997, 40 hysteroscopies were performed in 154 women who were diagnosed with endometrial cancer (26.0%), whereas, in 2006, 95 hysteroscopies were performed in 232 women (40.9%). The mean age was 62.0 and 60.7 years, respectively, for women who had undergone hysteroscopy and those who had not (Wilcoxon rank sum, P .01). The frequencies of FIGO stages in the 2 groups are shown in Table 1. The rates of stage III disease did not differ statistically between those who had and did not have hysteroscopy (relative risk, 1.16; 95% condence interval [CI], 0.831.62; P .38). There was also no statistically signicant difference found in death rates for those who had a hysteroscopy (13.2%) compared to those who had not (15.2%) (relative risk, 0.87; 95% CI, 0.69 1.10; P .25) (Table 2). The mean years of follow-up for each group were 4.0 (0.039.97) and 4.4 (0.02-10.67), respectively. Survival analysis was not possible because of the relatively fewer numbers of deaths, resulting in high censor rate in the analysis. When evaluating only those women who had died, statistically significant differences were found neither in the proportion of stage III disease (P .10), nor in the proportion of women dying of female genital organ cancer between hysteroscopy groups (P .53) (Table 3).

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TABLE 1

Stage of disease by hysteroscopy


Hysteroscopy Yes n 672 No. (%) 621 (92.9) 51 (7.1) No n 1300 No. (%) 1215 (93.5) 85 (6.5)

Stage Stage III Stage III

Statistical test

.............................................................................................................................................................................................................................................. ..............................................................................................................................................................................................................................................

2 P .38

RR, 1.16; 95% CI, 0.831.62

Details of FIGO stage FIGO 0 FIGO I

..................................................................................................................................................................................................................................... ..................................................................................................................................................................................................................................... a .....................................................................................................................................................................................................................................

1 (0.2)

3 (0.2)

67 (10.0)

112 (8.6)

FIGO Ia FIGO Ic FIGO II

.....................................................................................................................................................................................................................................

133 (19.8) 182 (27.1) 116 (17.3) 2 (0.3) 49 (7.3) 1 (0.2)

265 (20.4) 447 (34.4) 201 (15.5) 19 (1.5) 55 (4.2) 3 (0.2)

FIGO Ib

..................................................................................................................................................................................................................................... ..................................................................................................................................................................................................................................... a .....................................................................................................................................................................................................................................

FIGO IIa FIGO III

.....................................................................................................................................................................................................................................

FIGO IIb

..................................................................................................................................................................................................................................... a .....................................................................................................................................................................................................................................

71 (10.6) 21 (3.1) 3 (0.5) 26 (3.9)

113 (8.7) 54 (4.2) 23 (1.8)

FIGO IIIa FIGO IIIc


a

.....................................................................................................................................................................................................................................

FIGO IIIb

..................................................................................................................................................................................................................................... ..............................................................................................................................................................................................................................................

5 (0.4)

CI, condence interval; FIGO, International Federation of Gynecology and Obstetrics; RR, relative risk. Substaging was not available. Soucie. Risk of hysteroscopy in endometrial cancer. Am J Obstet Gynecol 2012.

C OMMENT
Our results indicate that hysteroscopy in patients with endometrial cancer is not associated with a higher rate of subsequent stage III disease. There was no statistical difference in death rates between hysteroscopy groups. Additionally, among those who had died, there was no statistical difference in stage III disease between hysteroscopy groups. Previous studies have published conicting results about the effect of hysteroscopy on peritoneal dissemination of malignant cells and upstaging of disease in women who have endometrial cancer. The rst of the reports providing evidence against hysteroscopy was by Obermair et al.8 Their group performed a

multicenter, retrospective cohort analysis of 113 consecutive patients with endometrial cancer limited to the inner half of the myometrium, who underwent D&C either with or without prior diagnostic hysteroscopy. They found that the only factor signicantly associated with positive peritoneal cytology was a history of hysteroscopy (12.2% vs 2.5%, P .04). Zerbe et al6 reviewed the charts of 222 patients with endometrial cancer and evaluated the peritoneal dissemination
TABLE 2

of malignant cells during hysteroscopy. They found a difference in positive peritoneal cytology in those who had hysteroscopy vs those who had not (odds ratio, 2.6; 95% CI, 1.02 6.63; P .05). Bradley et al15 reviewed 256 charts of women with endometrial cancer. In all, 204 cases were diagnosed by endometrial biopsy or D&C, whereas 52 were diagnosed with hysteroscopy. A nonsignicant lower proportion of patients (6.9%) had malignant or suspicious cytology in the endometrial biopsy or D&C group, com-

Vital statistics by hysteroscopy


Hysteroscopy Vital statistics Alive Dead Yes n 672 No. (%) 583 (86.8) 89 (13.2) No n 1300 No. (%) 1103 (84.8) 197 (15.2) Statistical test

..............................................................................................................................................................................................................................................

2 P .25

RR, 0.87; 95% CI, 0.691.10

..............................................................................................................................................................................................................................................

CI, condence interval; RR, relative risk. Soucie. Risk of hysteroscopy in endometrial cancer. Am J Obstet Gynecol 2012.

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Research
TABLE 3

Oncology

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de la Cuesta et al12 examined 50 consecutive patients with endometrial cancer. Patients were randomized 3:2 to have or not to have uid hysteroscopy biopsy performed just prior to surgery. There were 3 patients (10%) with positive washings in the hysteroscopic group compared to 1 (5%) among the controls (P .64). This difference was not statistically signicant; however, the small sample size only allowed for a statistical power of 20%. Median follow-up was 34 months, and all patients but 1 (deceased due to unrelated cause) were alive with no evidence of disease. The authors concluded that uid hysteroscopy and directed biopsies may have a small risk of upstaging early endometrial cancer but does not seem to inuence prognosis. Cicinelli et al13 randomized 140 women to undergo or not undergo diagnostic uid minihysteroscopy before surgical staging. There was no difference in peritoneal cytology between those who had hysteroscopy (5.7%) vs those who did not (8.5%). After a mean duration of follow-up of 62 months, overall survival and disease-free survival were not signicantly different for the 2 groups. From the literature, it is evident that there is no rm conclusion as to whether hysteroscopy leads to peritoneal dissemination of malignant cells in women who have endometrial cancer. Prior to this publication, and not including the 2 randomized controlled trials, a metaanalysis indicated that hysteroscopy is associated with a small risk of peritoneal spread, and by direct extension, higher disease upstaging. However, they note that greater numbers are needed to clarify the effect on prognosis.18 The sample sizes of the studies to date have been small to moderate with limited follow-up intervals to adequately evaluate survival differences. Our study provides more information as it included a large sample, with a cohort spanning over 10 years. The results indicate clearly that hysteroscopy is not associated with higher staging of endometrial cancer. From this, it suggests that hysteroscopy does not impose a signicant risk of dissemination. Most importantly, there was no difference in death rates, and more specically, the cause of death from female genital organ

Staging and cause of death by hysteroscopy among women who died


Hysteroscopy Staging Stage III Stage III Yes n 89 No. (%) 70 (78.7) 19 (21.3) No n 197 No. (%) 170 (86.3) 27 (13.7)

2 P value
.10

.............................................................................................................................................................................................................................................. ..............................................................................................................................................................................................................................................

Cause of death

..................................................................................................................................................................................................................................... a

Noncancer death cause Other cancer


a 2

.....................................................................................................................................................................................................................................

25 (28.1) 41 (46.1) 15 (16.9) 8 (9.0)

62 (31.5) 83 (42.1) 37 (18.8)

.53

Female genital organ cancer

..................................................................................................................................................................................................................................... .....................................................................................................................................................................................................................................

Primary unknown death cause not coded

15 (7.6)

..............................................................................................................................................................................................................................................

comparing female genital organ cancer vs all other causes of death.

Soucie. Risk of hysteroscopy in endometrial cancer. Am J Obstet Gynecol 2012.

pared to the hysteroscopy group (13.5%) (P .15). However, after controlling for stage and grade, the odds ratio for positive cytology after hysteroscopy was 3.88 (95% CI, 1.1113.6; P .03). The nal study providing evidence against the use of hysteroscopy was performed by Takac and Zegura.16 In their review of 146 women with endometrial cancer diagnosed with either D&C or ofce hysteroscopy, they found suspicious or positive peritoneal cytology was present in 1.6% (2/122) after D&C and 12.5% (3/24) after hysteroscopy (P .05). Evidence in support of the use of hysteroscopy has also been published. Gu et al9 found that of 23 patients who were diagnosed by D&C with hysteroscopy, 17 had abnormal peritoneal washings (13.0%). Of 177 patients diagnosed by either endometrial biopsy or D&C without hysteroscopy, again 17 had abnormal peritoneal washings (9.6%). The rates were not different statistically. Similarly, Selvaggi et al7 evaluated patients with endometrial cancer and found that 52 had a diagnosis made only by D&C, 56 underwent D&C and then hysteroscopy, and 39 had only hysteroscopy. Peritoneal cytology was positive in 9 patients, and 21 had microscopic intraperitoneal dissemination; neither was signicantly associated with hysteroscopy (P .07). Juhasz-Boss et al14 took a novel approach to evaluating the effects of hysteroscopy. When sentinel lymph node biopsy 71.e4

is performed, a second hysteroscopy is necessary for technetium injection. Juhasz-Boss et al14 took this factor into consideration in their analysis, and examined whether the number of hysteroscopies and the time interval between hysteroscopy and surgery had an effect on cytology. The rate of positive cytology was 18.2% (4/22) in those without hysteroscopy vs 1.9% (2/ 104) and 7.1% (5/70) for those with 1 and 2 hysteroscopies, respectively (P .008). Furthermore, positive cytology was not related to the time interval between preoperative hysteroscopy and denitive surgery. Kudela and Pilka10 prospectively reviewed 134 women diagnosed with hysteroscopy and 61 diagnosed with D&C. Positive or suspect cytology in uid from lavage was present in 30.3% for those with hysteroscopy, compared to 33.9% in those who underwent a D&C. Both groups were comparable for stages of disease. Ben-Arie et al11 reported on a cohort of 392 women diagnosed with endometrial cancer with endometrial biopsy (25.3%), uterine curettage (49.2%), and hysteroscopy (25.5%). In this series, poor histologic types, including serous papillary, clear cell, and small cell cancer were included in the analysis. Peritoneal cytology was positive in only 1 case, thus comparison could not be made. However, no statistic difference in the survival rate was found between diagnostic methods. There have been 2 randomized controlled trials evaluating the effects of hysteroscopy on peritoneal cytology. Sainz

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cancer did not differ signicantly between the groups. There are a few limitations to this study, the main limitation being that positive peritoneal cytology could not be directly evaluated, as the information was not available in either of the electronic databases. To retrieve this information, individual patient charts at each regional health authority would have to have been reviewed, and this was not possible. Instead, disease stage was evaluated, with the hypothesis that any upstaging of disease resulting from hysteroscopy should have been evident in our analysis. It should also be noted that FIGO did replace their staging criteria in 2009, with positive peritoneal cytology not included as it was not considered to have an independent effect on survival.19 Nonetheless, all staging in this cohort was based on the previous criteria, and thus peritoneal cytology would have been captured by this older classication system. This study was also a retrospective cohort study, and therefore by design is subject to several possible biases, namely reporting and selection bias. It would be ideal if all cases of endometrial cancer were reported to the cancer registry; however, this is unlikely and thus, some degree of reporting bias may be evident. It would be impossible to know whether there were differences in reporting for those who had hysteroscopy vs those who had not. However, the Alberta Cancer Registry has an overall calculated capture rate of 95%, and thus a difference in reporting was likely minimal. Finally, 15% of our sample was missing staging data, and this is a common problem with administrative databases. Every effort was made to ascertain missing data from the larger database when available. Our large study covering a period of 10 years of endometrial cancer management offers valuable evidence to guide clinical practice. Our results clearly indicate that hysteroscopy, which allows for direct visualization and directed biopsy, should be considered a safe diagnostic tool in women suspected of having enf dometrial cancer.
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following dilatation and curettage (D & C) versus hysteroscopy and D & C. Cancer 2000;88: 139-43. 9. Gu M, Shi W, Huang J, Barakat RR, Thaler HT, Saigo PE. Association between initial diagnostic procedure and hysteroscopy and abnormal peritoneal washings in patients with endometrial carcinoma. Cancer 2000;90:143-7. 10. Kudela M, Pilka R. Is there a real risk in patients with endometrial carcinoma undergoing diagnostic hysteroscopy (HSC)? Eur J Gynaecol Oncol 2001;22:342-4. 11. Ben-Arie A, Tamir S, Dubnik S, et al. Does hysteroscopy affect prognosis in apparent early-stage endometrial cancer? Int J Gynecol Cancer 2008;18:813-9. 12. Sainz de la Cuesta R, Espinosa JA, Crespo E, Granizo JJ, Rivas F. Does uid hysteroscopy increase the stage or worsen the prognosis in patients with endometrial cancer? A randomized controlled trial. Eur J Obstet Gynecol Reprod Biol 2004;115:211-5. 13. Cicinelli E, Tinelli R, Colaglio G, et al. Risk of long-term pelvic recurrences after uid minihysteroscopy in women with endometrial carcinoma: a controlled randomized study. Menopause 2010;17:511-5. 14. Juhasz-Boss I, Fehm T, Nauth A, et al. Number of hysteroscopies and the time interval between hysteroscopy and surgery: inuence on peritoneal cytology in patients with endometrial cancer. Anticancer Res 2010;30:2425-30. 15. Bradley WH, Boente MP, Brooker D, et al. Hysteroscopy and cytology in endometrial cancer. Obstet Gynecol 2004;104:1030-3. 16. Takac I, Zegura B. Ofce hysteroscopy and the risk of microscopic extrauterine spread in endometrial cancer. Gynecol Oncol 2007;107: 94-8. 17. International Federation of Gynecology and Obstetrics. Corpus cancer staging. Int J Gynaecol Obstet 1989;28:190. 18. Polyzos NP, Mauri D, Tsioras S, Messini CI, Valachis A, Messinis IE. Intraperitoneal dissemination of endometrial cancer cells after hysteroscopy: a systematic review and meta-analysis. Int J Gynecol Cancer 2009;20:261-7. 19. Lewin SN. Revised FIGO staging system for endometrial cancer. Clin Obstet Gynecol 2011; 54:215-8.

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