Endometrial Thickness as a Test for Endometrial Cancer in Women With Postmenopausal Vaginal Bleeding

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1 REVIEW Endometrial Thickness as a Test for Endometrial Cancer in Women With Postmenopausal Vaginal Bleeding Ann Tabor, Hilary C. Watt, and Nicholas J. Wald OBJECTIVE: To assess the value of endometrial thickness measurement as a test for endometrial cancer in postmenopausal women with vaginal bleeding (symptomatic women). DATA SOURCES: We conducted a literature search using the MEDLINE database from 1991 to 1997, and the key words vaginal ultrasonography and endometrial thickness measurement. The review was limited to original research reports written in English, concerning symptomatic women having vaginal ultrasonography before a diagnostic test and not receiving tamoxifen. STUDY SELECTION: A total of 48 studies were identified. A questionnaire was sent to the corresponding author of each paper requesting supplementary information. Data were included in our analysis if the corresponding author was able to supply information on the median endometrial thickness in unaffected symptomatic women and the endometrial thickness values in affected women. Nine studies were thus included in our meta-analysis, representing 3483 women without endometrial cancer and 330 women with endometrial cancer. TABULATION, INTEGRATION, AND RESULTS: The median endometrial thickness in women with endometrial cancer was 3.7 times that in unaffected women at the same center, and with the same menopausal status and same hormone replacement therapy use category. The detection rate was 63% (95% confidence interval 58, 69) for a 10% false-positive rate, or 96% (95% confidence interval 94, 98) for a 50% false-positive rate. CONCLUSION: Endometrial thickness measurement in symptomatic women does not reduce the need for invasive diagnostic testing because 4% of the endometrial cancers would still be missed with a false-positive rate as high as From the Department of Obstetrics and Gynaecology, Copenhagen University Hospital, Hvidovre, Denmark; and Department of Environmental and Preventive Medicine, Wolfson Institute of Preventive Medicine, St. Bartholomew s and the Royal London School of Medicine and Dentistry, London, United Kingdom. This study was supported by the Danish Cancer Society, Copenhagen, Denmark. We would like to thank all the authors who kindly supplied us with additional information about their cases. 50%. (Obstet Gynecol 2002;99: by the American College of Obstetricians and Gynecologists.) Measurement of endometrial thickness by vaginal ultrasound is increasingly being used in symptomatic postmenopausal women with vaginal bleeding to determine whether to perform a curettage to detect endometrial cancer. 1,2 It is also being used in premenopausal women who have irregular bleeding for the same reason. The efficacy of this use of endometrial thickness is unknown. We reviewed the literature and performed a metaanalysis to assess its value. DATA SOURCES Publications on endometrial thickness and endometrial cancer among symptomatic women were identified through a MEDLINE search covering the period January 1, 1991 September 30, The review was limited to original research papers written in English using the key words vaginal ultrasonography and endometrial thickness measurement. Studies reporting only Doppler indices or abdominal scans, studies concerning women receiving tamoxifen, and studies where the ultrasound examination was done after the diagnostic test were excluded. STUDY SELECTION A total of 48 1,3 49 studies on symptomatic women were identified. A questionnaire was sent to the corresponding author of each paper requesting supplementary information. The authors were asked to give the mean, standard deviation, median, and 10th and 90th centiles of endometrial thickness (measured in double layer), age, menopausal status, use of hormone replacement therapy (HRT), and recruitment method for all women. For women diagnosed with endometrial cancer, the type and stage of the cancer was sought. To avoid VOL. 99, NO. 4, APRIL /02/$ by The American College of Obstetricians and Gynecologists. Published by Elsevier Science Inc. PII S (01)

2 Figure 1. Unaffected symptomatic women: the median endometrial thickness is shown by a solid square and the 10th to 90th centiles by a line. The scale is logarithmic. Two of the studies 1,31 are multicenter. Tabor. Endometrial Thickness and Cancer. Obstet Gynecol duplication in our analysis, authors were asked to identify data that were published more than once. Data were included for analysis in our paper if the corresponding author was able to provide information on the median endometrial thickness in unaffected symptomatic women and the endometrial thickness values in affected women, and the data were not included more than once. Eighteen studies were excluded because of duplicate publication, 3,20 22,30,39,42,43 or because the raw data were no longer available. 4,6,7,19,33 36 A further study 48 was excluded because it was based on data from fewer than ten unaffected women. Out of the remaining 29 studies, it was possible to obtain additional information from the authors of 12 studies, 1,10,13,15,17,26,31,38,41,44,45,47 which concerned 3667 symptomatic women without endometrial cancer. Three of these studies were excluded in the estimation of detection rates and false-positive rates and in presenting data on women with endometrial cancer on the grounds that they provided results on data from fewer than five cases of endometrial cancer 26,47 or on the grounds that the data in unaffected women were inconsistent with those from other centers. 17 This left data from the nine studies 1,10,13,15,31,38,41,44,45 representing 3483 symptomatic women without endometrial cancer (710 premenopausal, 2407 postmenopausal who were not taking HRT, and 366 taking HRT) and 330 symptomatic women with endometrial cancer (seven premenopausal and 293 postmenopausal not on HRT and 30 on HRT). In all studies, a histologic examination was performed to determine whether or not the women had endometrial cancer at the time of screening. In six studies, 10,13,15,31,38,41 a dilation and curettage (D&C) was done, in two studies 44,46 an endometrial biopsy was 664 Tabor et al Endometrial Thickness and Cancer OBSTETRICS & GYNECOLOGY

3 Figure 2. Symptomatic women with endometrial cancer: endometrial thickness is shown in mm on a logarithmic scale. The median value is shown by a solid circle, and in centers with ten or more cases available, the 10th to 90th centiles are shown by a line. In centers with nine or fewer cases, the range is shown by a line. Two of the studies 1,31 are multicenter. Tabor. Endometrial Thickness and Cancer. Obstet Gynecol taken, and in one multicenter study 1 a D&C or an endometrial biopsy was taken according to the center s choice. We estimated the performance of the measured endometrial thickness as a potential screening test for endometrial cancer. The detection rate was calculated as the proportion of women with endometrial cancer who were screen positive. Screen positive was defined as having an endometrial thickness measurement above the specified centile in unaffected women from the same center, of the same menopausal status and HRT status (women were divided into three groups: premenopausal and not taking HRT, postmenopausal and not taking HRT, and women taking HRT). The false-positive rate was defined as the proportion of women without endometrial cancer who were screen positive. Results were calculated for false-positive rates of 50% and 10% based on the median and 90th centile of endometrial thickness measurements in unaffected women. Exact confidence intervals (CI) were added to estimates of detection rate and false-positive rate, derived from the Binomial distribution. TABULATION, INTEGRATION, AND RESULTS Figure 1 shows the median endometrial thickness and 10th and 90th centiles in symptomatic women without endometrial cancer, according to center, menopausal status, and use of HRT. There were statistically significant between-center differences in median endometrial thickness in postmenopausal women who did not use HRT (from 2 mm to 6.4 mm, P.001) after excluding an outlier of 21 mm, which was reported by Giusa- Chiferi. 17 There were two further differences among median endometrial thickness in symptomatic women without endometrial cancer, according to menopausal status. In the two centers, which reported medians for premenopausal women who did not take HRT, the median endometrial thicknesses were 2 3 mm higher than in postmenopausal women who did not take HRT (P.01 for each). 13,41 Median endometrial thicknesses reported by Karlsson et al 31 were 2 mm higher in women who took HRT compared with postmenopausal women who did not (P.001). This was the only center with VOL. 99, NO. 4, APRIL 2002 Tabor et al Endometrial Thickness and Cancer 665

4 Figure 3. Symptomatic women with endometrial cancer: endometrial thickness in multiples of the unaffected median for women of the same center and menopausal status (divided into premenopausal and not on hormone replacement therapy, postmenopausal and not on hormone replacement therapy, or on hormone replacement therapy). The scale is logarithmic. The median value is shown by a solid circle, and in centers with ten or more cases available, the 10th to 90th centiles are shown by a line. In centers with nine or fewer cases, the range is shown by a line. Two of the studies 1,31 are multicenter. Tabor. Endometrial Thickness and Cancer. Obstet Gynecol substantial numbers of women on HRT, which could be used to make a comparison. The endometrial thickness in symptomatic women with endometrial cancer is shown in Figure 2, whereas Figure 3 shows the endometrial thickness as multiples of the median (MoM) thickness of unaffected women from the same center and the same menopausal and HRT status. This shows that the median MoM thickness in different studies of women with endometrial cancer ranges from 2.1 to 5.9 MoM. The overall median endometrial thickness was 3.7 MoM. Table 1 gives the detection rates of endometrial cancer according to menopausal status and use of HRT that would be obtained with a false-positive rate of 50% or 10%, that is when 50% or 10% of all women were advised to have a D&C. These yield a detection rate of 63% (95% CI 58, 69) for a 10% false-positive rate and a detection rate of 96% (95% CI 94, 98) for a 50% falsepositive rate. Most of these cancers were stage I, and restricting the analysis to these early stage cancers made little difference to the detection rates, as shown in Table 1. Among the studies shown in Figure 2 and Figure 3, the prevalence of endometrial cancer among those screened is 1.1% in premenopausal women, 10.9% in postmenopausal women, and 7.8% in women on HRT. These are obtained by dividing the number of cancers observed among this group (shown in Figure 2) by the total number of unaffected women (from the corresponding studies shown in Figure 1) plus those affected with endometrial cancer (the odds are 1:89, 1:8, and 1:12, respectively). The detection rates shown in Table 1 for all stages of cancer at a 50% false-positive rate therefore translate into an odds of being affected given a positive result of 1:44 (95% CI 1:75, 1:44) in premenopausal women, 1:4.28 (95% CI 1:4.42, 1:4.19) in postmeno- 666 Tabor et al Endometrial Thickness and Cancer OBSTETRICS & GYNECOLOGY

5 Table 1. Detection Rate of Endometrial Cancer According to False-Positive Rate (50% and 10%), Menopausal Status, and Use of HRT From Published Studies* False-positive rate (%) Premenopausal Detection rate (%) (95% CI) Postmenopausal, not on HRT On HRT Total All cancers (n 7) (n 293) (n 30) (n 330) (59, 100) 96 (93, 98) 100 (88, 100) 96 (94, 98) (10, 82) 61 (56, 67) 90 (73, 98) 63 (58, 69) Stage I cancer (n 6) (n 167) (n 21) (n 194) (54, 100) 96 (93, 99) 100 (84, 100) 96 (94, 99) (12, 88) 63 (56, 70) 90 (70, 99) 65 (59, 72) HRT hormone replacement therapy; CI confidence interval. * Reference numbers: 1,10,13,15,31,38,41,44,46. pausal women, and 1:5.93 (95% CI 1:6.74, 1:5.93) in women on HRT. At a 10% false-positive rate, the odds of having endometrial cancer given a positive result are 1:21 (95% CI 1:11, 1:89), 1:1.35 (95% CI 1:1.47, 1:1.23), and 1.32:1 (95% CI 6.23:1, 1.21:1), respectively. In populations of symptomatic women with a higher prevalence of endometrial cancer, these odds will be proportionately higher. A doubling in the prevalence (expressed as odds) will result in a doubling of these odds. Table 2 shows how the detection rates vary according to study. Most of the studies detect all cases at the 50% false-positive rate, though of course the 95% CI is consistent with a lower detection rate than this. The lowest detection rate of any study is 81% (95% CI 63, 93), consistent with the CI of all but one of the other studies. At the 10% false-positive rate, the detection rates are also similar between studies, with the exception of one, namely Karlsson et al. 31 In this study, the detection rate in women on HRT was 100% based on 25 cases. This is substantially higher than the results from most other studies at this false-positive rate. This might be because the performance on HRT is better, though this appears to be inconsistent with the only other study to include women on HRT, 38 which detected only two out of five cases. The small amount of data on HRT makes it hard to determine reliable estimates of screening performance in this subgroup. CONCLUSION Ultrasound is frequently used to measure endometrial thickness in symptomatic women (with vaginal bleeding) to avoid a D&C. The main objective is that cases of cancer should not be missed. A relatively low cutoff level could be used, for example the median, because this would avoid 50% of unaffected symptomatic women having a D&C, if cancers almost never occurred with an Table 2. Detection Rate of Endometrial Cancer According to Published Study, the False-Positive Rate, Menopausal Status, and Use of HRT Center n Detection rate (%) for 10% false-positive rate (95% CI) Detection rate (%) for 50% false-positive rate (95% CI) Premenopausal Conoscenti et al (10, 82) 100 (59, 100) Postmenopausal Tsuda et al (38, 86) 94 (71, 100) Botsis et al (35, 97) 100 (63, 100) Conoscenti et al (30, 67) 81 (63, 93) Dørum et al (44, 97) 100 (69, 100) Karlsson et al (58, 78) 100 (96, 100) Van den Bosch et al (16, 84) 100 (63, 100) Sladkevicius et al (47, 90) 100 (81, 100) Ferrazzi et al (43, 63) 94 (88, 98) Tongsong et al (36, 100) 100 (54, 100) On HRT Karlsson et al (86, 100) 100 (86, 100) Sladkevicius et al (5, 85) 100 (48, 100) Abbreviations as in Table 1. VOL. 99, NO. 4, APRIL 2002 Tabor et al Endometrial Thickness and Cancer 667

6 endometrial thickness less than the median. Our data indicate that 4% of cancers would be missed in this way. In our analysis, we only included those studies from which we were able to get the authors raw data to calculate each center s median endometrial thickness in unaffected symptomatic women. There were statistically significant differences in endometrial thickness between centers (Figure 1), which may reflect differences in the populations studied or in the method of measuring the endometrial thickness. This underlines the importance of determining the median and distribution of endometrial thickness in each center, and not using a fixed cutoff. Another meta-analysis performed by Smith-Bindman et al 50 using a fixed endometrial thickness cutoff of 5 mm arrived at a 96% detection rate for a 39% false-positive rate. Smith-Bindman et al 50 included all published studies in their analysis, whereas we only included those studies where the authors provided supplementary information. The number of studies included in the Smith- Bindman review 50 was therefore larger than in ours, but the results of the two studies are reasonably similar. We disagree, however, on the interpretation of the results. Smith-Bindman et al 50 conclude that an ultrasound endometrial thickness measurement can identify a group of women with vaginal bleeding who do not need a D&C. We conclude that, in a symptomatic woman, a 4% false-negative rate is too high to be acceptable. We recognize that none of the invasive tests used to diagnose endometrial cancer will identify all affected individuals (the false-negative rate for endometrial biopsy is 5 15% 51 and that of D&C is 2 6% 52 ), but this does not affect our conclusion that the use of prior ultrasound will miss additional cases. Therefore, a D&C should be offered to all postmenopausal women with vaginal bleeding. REFERENCES 1. Ferrazzi E, Torri V, Trio D, Zannoni E, Filiberto S, Dordoni D. 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