Ultrasound Obstet Gynecol 2012; 40: 621629 Published online in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/uog.

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Capacity of endometrial thickness measurement to diagnose endometrial carcinoma in asymptomatic postmenopausal women: a systematic review and meta-analysis
M. C. BREIJER*, J. A. H. PEETERS, B. C. OPMEER, T. J. CLARK, R. H. M. VERHEIJEN**, B. W. J. MOL* and A. TIMMERMANS*
*Department of Obstetrics and Gynecology, Academic Medical Center, Amsterdam, The Netherlands; Department of Obstetrics and Gynecology, Albert Schweitzer Hospital, Dordrecht, The Netherlands; Department of Obstetrics and Gynecology, Maxima Medical Center, Veldhoven, The Netherlands; Clinical Research Unit, Academic Medical Center, Amsterdam, The Netherlands; Department of Obstetrics and Gynecology, Birmingham Womens Hospital, Edgbaston, Birmingham, UK; **Department of Gynecological Oncology, University Medical Center, Utrecht, The Netherlands

K E Y W O R D S: asymptomatic postmenopausal women; atypical hyperplasia; endometrial carcinoma; endometrial thickness; meta-analysis

ABSTRACT
Objectives Measurement of endometrial thickness is an important tool in the assessment of women with postmenopausal bleeding, but the role of endometrial thickness measurement by ultrasound in asymptomatic women is unclear. The aims of this study were to determine: (1) the normal endometrial thickness measured by ultrasonography, (2) the prevalence of serious endometrial pathology and (3) the sensitivity and specicity of endometrial thickness measurement by transvaginal ultrasonography (TVS) for diagnosing premalignant and malignant endometrial disease in asymptomatic postmenopausal women. Methods A MEDLINE and EMBASE search (from inception to January 2011) was performed. Articles reporting on endometrial thickness measurement in the diagnosis of endometrial carcinoma and atypical hyperplasia in asymptomatic postmenopausal women not using hormone replacement therapy (HRT) were selected. Endometrial thickness and the prevalence of endometrial (pre)malignancies were recorded. If possible, 2 2 tables were extracted. Results Thirty-two studies reporting on 11 100 women were included. The estimated mean endometrial thickness was 2.9 mm (95% CI, 2.63.3 mm). The pooled estimated prevalences of endometrial carcinoma and atypical endometrial hyperplasia were 0.62% (95% CI, 0.420.82%) and 0.59% (95% CI, 0.220.96%),

respectively. Summary estimates for sensitivity and specicity of TVS endometrial thickness measurement in the prediction of endometrial carcinoma were 0.83 (95% CI, 0.191.00) and 0.72 (95% CI, 0.230.95) for a 5-mm cut-off and 0.33 (95% CI, 0.040.85) and 0.94 (95% CI, 0.920.96) for a 6-mm cut-off. Conclusions The results from this systematic review do not justify the use of endometrial thickness as a screening test for endometrial carcinoma and atypical endometrial hyperplasia in asymptomatic postmenopausal women not using HRT. Copyright 2012 ISUOG. Published by John Wiley & Sons, Ltd.

INTRODUCTION
Endometrial carcinoma is the most common malignancy of the female genital tract in developed countries and presents with postmenopausal bleeding in more than 95% of cases1,2 . In patients with postmenopausal bleeding, sonographic measurement of endometrial thickness is the rst test to determine whether further investigations are needed to rule out malignancy3 . Guidelines recommend a cut-off value of 4 or 5 mm by transvaginal ultrasonography (TVS), below which endometrial cancer is unlikely4 7 . When the endometrial thickness is below this cut-off, the probability of endometrial carcinoma is below 1%3 . In contrast to the clear guidelines on the management of women with postmenopausal bleeding, clinicians are faced with uncertainty when endometrial

Correspondence to: Dr M. C. Breijer, Department of Obstetrics and Gynecology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands (e-mail: m.c.breijer@amc.uva.nl) Accepted: 1 September 2012

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thickness is measured in asymptomatic postmenopausal women. Symptom-free women may undergo TVS for other indications, such as vaginal prolapse or abdominal complaints. Inevitably, the endometrium is then visualized and a thickened endometrium may incidentally be observed. It is not known how best to manage such patients in whom a thick endometrium is observed incidentally. Based on a decision analysis in a theoretical cohort, Smith-Bindman et al.8 concluded that in asymptomatic postmenopausal women with an endometrial thickness of 11 mm an endometrial biopsy should be performed. They argued that women with an endometrial thickness above this threshold have a malignancy risk of 6.7%, which is comparable with the risk in patients with postmenopausal bleeding and an endometrial thickness of > 5 mm (7.3%), the latter being the widely accepted threshold for performing a biopsy in symptomatic patients. Apart from the debate on the accuracy of endometrial thickness measurement in asymptomatic postmenopausal women, its potential value also depends on the prevalence of the disease searched for, i.e. endometrial carcinoma and/or its precursors. Since in asymptomatic women the prevalence of endometrial carcinoma is lower than in symptomatic women, the cut-off of endometrial thickness for abnormality in these women should be higher. To address the abovementioned dilemmas, we reviewed the literature on asymptomatic postmenopausal women not using hormone replacement therapy (HRT). The aims of this review were to address in asymptomatic postmenopausal women: (1) normal endometrial thickness as measured with sonography, (2) the prevalence of serious endometrial pathology and (3) the sensitivity and specicity of endometrial thickness measurement by TVS for diagnosing premalignant and malignant endometrial disease.

Selection of studies and data abstraction

Two independent reviewers (M.B., J.P.) screened the electronic search results by reading titles and/or abstracts. Studies that were restricted to patients with postmenopausal bleeding or women using HRT or tamoxifen were excluded. Titles and abstracts were assessed to identify eligible studies. Subsequently, these articles were evaluated in full text for each of the three objectives independently for the nal study selection. Any disagreements were resolved by consensus. In case of persistent disagreement, the judgment of a third reviewer (A.T.) was decisive. If multiple publications reported analyses on the same dataset, only the largest study was included. If a dataset was split into different subgroups and the subgroups were reported separately in multiple publications, we combined the results of these publications. We used the quality assessment of diagnostic accuracy studies (QUADAS)9 checklist to assess the methodological quality of included studies (Appendix S2 online). Endometrial thickness To evaluate normal endometrial thickness in asymptomatic postmenopausal women, we searched for studies that (1) reported a mean endometrial thickness with a measure of variance and (2) described a standardized approach to measurement of endometrial thickness by TVS. Mean endometrial thickness as well as SD, standard error or 95% CI were recorded for each included study. A pooled estimate of mean endometrial thickness was then calculated using inverse variance weighting in a random-effects model. Prevalence of endometrial (pre)malignancies To assess the prevalence of (pre)malignant lesions of the endometrium in asymptomatic postmenopausal women, we included studies that reported on any form of endometrial verication in the total population of asymptomatic postmenopausal women not using HRT. The endometrium could be assessed by histology (hysterectomy, dilatation and curettage, hysteroscopy with biopsy, endometrial biopsy) or by cytology. Studies in which there was partial verication (histological verication only in a subgroup based on a previous test, e.g. endometrial thickness above a cut-off level or patients positive on progesterone challenge test) were excluded. The method of verication, the number of women with atypical endometrial hyperplasia and the number of women with endometrial carcinoma were recorded for each selected study. The prevalence of endometrial carcinoma and atypical endometrial hyperplasia was then calculated for each study, and a weighted pooled estimate was derived. Diagnostic accuracy of endometrial thickness for endometrial (pre)malignancy Finally, to estimate the diagnostic accuracy of endometrial thickness for (pre)malignancy of the endometrium,

METHODS Identication of studies

We performed an electronic search in January 2011 in MEDLINE (from 1948) and EMBASE (from 1980) to identify articles reporting on endometrial thickness and/or endometrial carcinoma and hyperplasia in asymptomatic postmenopausal women. We used the following keywords: postmenopausal, asymptomatic, screening, endometrial, thickness, ultrasound, hyperplasia and carcinoma. The complete search syntax is reported in Appendix S1 online. Language restrictions were not applied. Abstracts or articles written in languages other than English were read by a member of the team with sufcient knowledge of the language; if there was no team member available, the article was translated by a native speaker. References of selected studies were searched for articles not identied by the electronic searches, and this process was repeated for any further relevant studies found. No review protocol was registered.

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Endometrial thickness in asymptomatic postmenopausal women we selected studies that reported on both endometrial thickness measurement and endometrial histological verication in asymptomatic postmenopausal women. Information required to construct a 2 2 table for each reported endometrial thickness cut-off value was recorded for each selected study. Three different outcomes were considered: benign (including atrophy, endometrial polyps and endometrial hyperplasia without atypia), atypical endometrial hyperplasia and endometrial carcinoma. The data from the 2 2 tables were used to calculate sensitivity and specicity, as well as positive and negative predictive values for each study. If the study reported on multiple thresholds, we included 2 2 tables for all reported thresholds. Subsequently, summary point estimates for sensitivity and specicity were generated for each reported endometrial cut-off value using a bivariate random effects approach10 , for endometrial carcinoma, atypical endometrial hyperplasia and these two diagnoses combined in one group.

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3 (diagnostic accuracy of TVS for these endometrial diseases).

Assessment of methodological quality

Study quality was considered generally good when eight of the 14 QUADAS items were met, with over 70% of the included studies fullling this criterion (Figure 2). Studies scored poorly on the items regarding blinded interpretation of the reference test and description of withdrawals. In ve of the 32 studies, almost the entire QUADAS checklist was scored as not applicable because, for example, no endometrial thickness measurement (index test) or no endometrial verication (reference test) was reported. Absence of the index or reference test automatically led to problems in completing the QUADAS checklist. For these ve studies it was impossible to answer some questions of the QUADAS checklist with yes, no or unclear, and these items were scored not applicable.

RESULTS Search strategy

Our search resulted in 503 citations; another 31 studies were identied through reference searches. There were 95 studies eligible for inclusion based on title and abstract. After assessment of the full text articles, 63 studies were discarded (Figure 1). As a result, a set of 32 relevant studies was available to answer our three questions: 10 studies could be used for question 1 (estimating normal endometrial thickness); 15 studies could be used for question 2 (prevalence of endometrial malignancy and premalignancy) and 20 studies could be used for question
Retrieved from searches: electronic search (n = 503) cross-reference search (n = 31)

Endometrial thickness
We found 10 studies that reported on endometrial thickness measurement with a measure of variance in asymptomatic women not using HRT11 20 . The 10 studies that were assessed for inclusion had been conducted in nine different countries. One study was published in German; the other nine were published in English. In total, these 10 studies reported on 3049 women, with a median sample size of 207 (range, 971182). Mean endometrial thickness in the 10 studies varied from 2.1 to 5.7 mm. The pooled estimate of the mean endometrial thickness was 3.2 mm (95% CI, 2.83.6 mm). There was one outlier, with a mean endometrial thickness of 5.7 mm,

Excluded after reading: titles (n = 289) abstracts (n = 150)

Retrieved in full (n = 95)

Studies available to answer different questions (n = 32)

Excluded after reading article: No separate data for: Asymptomatic women (n = 7) Women not using HRT (n = 17) Postmenopausal women (n = 3) No information regarding HRT use (n = 12) Review / editorial (n = 4) Endometrial thickness reported for subgroups only (n = 4) No mean endometrial thickness or measure for variance reported (n = 12) Multiple publications on the same dataset (n = 4)

Studies included for endometrial thickness (n = 10)

Studies included for histological verification (n = 15)

Studies included for diagnostic accuracy (n = 20)

Figure 1 Flowchart of studies included in the meta-analysis. HRT, hormone replacement therapy.

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100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0%
sp ec Se tr le um ct io R n ef cr er ite en ria ce st an da Ti rd m Pa e in rt t ia D er lv iff va er er l en ifi ca tia tio lv n er ifi ca In t io co n rp In o R d r a ef ex tio er te n en xt ce de st ta an ils da R rd ev de ie w ta R ils bi ev a ie s w (in bi de as x) (r ef er en U C ni ce lin nt ) ic er al pr da et ab ta le re su W lts ith dr aw al s

Breijer et al.

Figure 2 Summary of evaluation of the 32 studies analyzed using the quality assessment of diagnostic accuracy studies (QUADAS) checklist. See Appendix S2 for the 14 questions summarized as labels on the x-axis. , Yes; , No; , Unclear; , Not applicable.

compared with the other studies; Guven et al.13 reported a thicker endometrium. Mean body mass index (BMI) in this study was 29.5 kg/m2 . In contrast, mean BMI in the other included studies ranged from 22.4 to 25.6 kg/m2 . The purpose of the study by Guven et al. was to correlate BMI to endometrial thickness, which could potentially have led to inclusion bias. We therefore excluded this study from the meta-analysis for endometrial thickness. The remaining nine studies reported on 2952 women, with a median sample size of 259 (Table 1). The pooled estimate of the mean endometrial thickness was 2.9 mm (95% CI, 2.63.3 mm) (Figure 3). Statistical heterogeneity between studies (I2 ) was 28%.

Pa tie nt

Prevalence of endometrial (pre)malignancy

In 28 studies a histological diagnosis of the endometrium (endometrial verication) was obtained. We excluded 13

from further analysis, as they had only partial endometrial verication (verication in a subgroup of patients selected by a previous test, e.g. endometrial thickness or progesterone challenge test). The 15 remaining studies had been performed in nine different countries13,14,21 33 . Thirteen studies were published in English, one in Portuguese and one in Italian. Together, these studies described a total of 3595 women (Table 2). The median sample size was 145 (range, 30883). The prevalence of endometrial carcinoma varied between 0 and 2.1%, the prevalence of atypical endometrial hyperplasia varied between 0 and 3.5% and the prevalence of combined (pre)malignancy varied between 0 and 4.3%. The pooled estimated prevalence of endometrial carcinoma was 0.62% (95% CI, 0.420.82%), of endometrial hyperplasia it was 0.59% (95% CI, 0.220.96%) and of combined (pre)malignancies it was 1.21% (95% CI, 0.631.79%).

Table 1 Characteristics of studies included in meta-analysis for mean endometrial thickness measured by transvaginal ultrasound in asymptomatic postmenopausal women without hormone replacement therapy Endometrial thickness (mm) Reference Andolf11 Gull12 Kasraeian14 Malinova15 Minagawa16 Neele17 Osmers18 Pirhonen19 Warming20 Year 1993 1996 2011 1996 2005 2000 1989 1993 2002 Country Sweden Sweden Iran Bulgaria Japan The Netherlands Germany Finland Denmark n 300 361 259 130 146 148 155 271 1182 Mean 2.30 3.00 3.83 3.86 2.80 3.40 3.40 2.20 2.10 SD 1.8 0.1* 2.95 2.35 2.2 1.7 7.9 0.77 1.4 Range 010 128 125 NR 0.214.1 0.912.8 163 NR NR

Only rst author of each study is given. *Standard error. NR, not reported.

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First author Andolf11 Gull12 Kasraeian14 Malinova15 Minagawa16 Neele17 Osmers18 Warming20 Pirhonen19

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sample size of 209 (range, 471926) (Table 3). In 13 studies partial verication was performed, whereas in the other seven studies endometrial verication was performed in all women. In 5198 out of 6974 women an endometrial sample was obtained. Endometrial carcinoma was found in 32 and atypical endometrial hyperplasia in 21 women. Diagnosis of endometrial carcinoma Eight different endometrial thickness cut-off values were reported in the 20 studies. Sensitivity, specicity, negative predictive value and positive predictive value for the detection of endometrial carcinoma for each reported endometrial thickness cut-off value are reported in Table S1 online. Positive predictive values varied between 0 and 0.2 and negative predictive value, if it was possible to ascertain, was 1. For the reported endometrial thickness cutoffs of 4, 5 and 6 mm we were able to calculate a summary sensitivity and specicity for the detection of endometrial carcinoma. The remaining ve cut-offs were reported by one single study, so for these cut-offs we were unable to calculate summary sensitivity and specicity. The summary estimate of the sensitivity for the different cut-offs varied between 0.00 and 0.83. The summary estimate of the specicity for the different cut-offs varied between 0.72 and 0.94 (Table 4). For the summary estimates of sensitivity and specicity as well as for the reported sensitivity and specicity, the 95% CIs were very wide, indicating the high uncertainty surrounding these estimates. Diagnosis of atypical endometrial hyperplasia Six different endometrial thickness cut-off values were reported in 13 studies. The other seven studies did

Summary

2.0

2.5 3.0 3.5 4.0 Endometrial thickness (mm)

4.5

Figure 3 Forest plot of the meta-analysis for mean endometrial thickness.

Diagnostic accuracy of endometrial thickness for endometrial (pre)malignancy

There were 20 studies that reported on the endometrial thickness cut-off value and histological or cytological endometrial verication11 16,23,26,29,31,32,34 42 . These studies were performed in 13 different countries. Sixteen studies were published in English, one in Italian, one in Spanish, one in Portuguese and one in German. In total, these 20 studies described 6974 women, with a median

Table 2 Characteristics of studies included in meta-analysis for assessment of prevalence of endometrial (pre)malignancies in asymptomatic postmenopausal women not using hormone replacement therapy Endometrial carcinoma Reference Bortoletto21 Buccoliero22 Cohen23 Elewa24 Gol25 Gouveia26 13 Guven Kasraeian14 Langer27 Macia28 Marello29 Martinez-Rubio30 Paraskevaidis31 Tsuda32 Tsuda33 Year 1997 2003 1999 2001 2001 2007 2004 2011 1997 1993 2000 2003 2002 1997 2005 Country Brazil Italy USA Egypt Turkey Brazil Turkey Iran USA Spain Italy Spain Greece Japan Japan n 150 107 60 30 556 47 97 259 145 130 328 369 59 375 883 Verication method EBNS hysterectomy, EBN, EES EBP Hyst + biopsy D&C EBP D&C Hyst + biopsy EBNS EBS Hyst + biopsy EBP EBK EES, EBNS SC n 0 0 0 0 3 1 0 1 1 0 1 3 1 1 8 Prevalence (%) 0 0 0 0 0.54 2.1 0 0.39 0.69 0 0.30 0.81 1.7 0.27 0.91 n 1 0 0 0 3 1 0 9 0 1 NR 0 1 NR 1 AEH Prevalence (%) 0.67 0 0 0 0.54 2.1 0 3.5 0 0.77 NR 0 1.7 NR 0.11 Prevalence of (pre)malignancy (%) 0.67 0 0 0 1.1 4.3 0 3.9 0.69 0.77 NR 0.81 3.4 NR 1.0

Only rst author of each study is given. AEH, atypical endometrial hyperplasia; D&C, dilatation and curettage; EBK, endometrial biopsy, Karman; EBN, endometrial biopsy, Novak curette; EBNS, endometrial biopsy not specied; EBP, endometrial biopsy, Pipelle; EBS, endometrial biopsy, Semms cannula; EES, endocyte endometrial sampler; Hyst, hysteroscopy; NR, not reported; SC, softcyto.

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Table 3 Characteristics of studies included for estimation of sensitivity and specicity of endometrial thickness as measured by transvaginal ultrasound with regard to premalignant or malignant endometrium in asymptomatic postmenopausal women without hormone replacement therapy Patients < cut off: Reference Andolf11 Cohen23 Exacoustos34 Parra35 Fleischer36 Gouveia26 Gull12 13 Guven Kasraeian14 Malinova15 Marello29 Minagawa16 Paraskevaidis31 Pardo37 Psillaki38 Ribeiro39 Schmidt40 Tsuda32 Year 1993 1999 1996 2008 2001 2007 1996 2004 2011 1996 2000 2005 2002 1998 2010 2007 1999 1997 Country Sweden USA Italy Spain USA Brazil Sweden Turkey Iran Bulgaria Italy Japan Greece Israel Greece Brazil Germany Japan n 300 60 910 209 1926 47 361 97 259 130 328 146 59 85 850 399 209 375 Verication method D&C EBP Hyst + biopsy Hyst + biopsy EBNS EBP Hyst + D&C D&C Hyst + biopsy D&C Hyst + biopsy SC EBK Hyst + biopsy Hyst + D&C Hyst + biopsy Hyst + D&C EES + EBNS Patients veried ( n) 11 60 83 209 1792 47 18 97 259 30 328 5 59 85 149 399 209 375 Total Cut-off* ( n) 5 mm 5 mm 8 mm 5 mm 6 mm 5 mm 8 mm 5 mm 5 mm 6 mm 4 mm 5 mm 9 mm 7 mm 5 mm 4 mm 6 mm 3 mm 4 mm 6 mm 8 mm 10 mm 4 mm 8 mm 289 38 827 NR 1833 28 343 75 218 95 199 141 39 NR 701 NR NR 264 312 345 352 362 NR 68 With EC ( n) NR 0 NR NR 1 0 NR 0 0 NR 1 NR 0 NR NR NR NR 0 1 1 1 1 NR NR Patients > cut off: With EC ( n) 0 0 3 5 1 1 0 0 1 0 0 1 1 3 0 1 8 1 0 0 0 0 2 0 With AEH ( n) 0 0 NR NR 0 NR 0 0 4 NR NR 0 1 0 1 1 4 NR NR NR NR NR NR 0

With Total AEH ( n) ( n) NR 0 NR NR 4 NR NR 0 5 NR NR NR 0 NR NR NR NR NR NR NR NR NR NR NR 11 22 83 209 93 19 18 22 41 35 129 5 20 85 149 399 209 111 63 30 23 13 150 6

Valadares41 Zacchi42

2005 1993

Portugal Italy

150 74

Hyst + biopsy Hyst + biopsy

150 6

Only rst author of each study is given. *Reported number is included in cut-off, i.e. cut-off of 5 mm means endometrial thickness 5mm. Single layer measurement; values reported in article are multiplied by two. AEH, atypical endometrial hyperplasia; D&C, dilatation and curettage; EBK, endometrial biopsy, Karman; EBNS, endometrial biopsy not specied; EBP, endometrial biopsy, Pipelle; EC, endometrial carcinoma; EES, endocyte endometrial sampler; Hyst, hysteroscopy; NR, not reported; SC, softcyto. Table 4 Summary estimates of sensitivity and specicity with regard to endometrial carcinoma for different transvaginal ultrasound-derived endometrial thickness cut-off values* Threshold Studies Women (mm) ( n) ( n) 3 4 5 6 7 8 9 10 1 2 2 2 0 1 1 1 375 703 306 2301 0 375 59 375 Sensitivity (95% CI) 1.00 (0.031.00) 0.00 (0.001.00) 0.83 (0.191.00) 0.33 (0.040.85) NE 0.00 (0.000.97) 1.00 (0.031.00) 0.00 (0.000.97) Specicity (95% CI) 0.71 (0.660.75) 0.73 (0.550.86) 0.72 (0.230.95) 0.94 (0.920.96) NE 0.94 (0.910.96) 0.67 (0.540.79) 0.96 (0.940.98)

atypical endometrial hyperplasia. With regard to atypical endometrial hyperplasia, the range of sensitivity was 0.001.00 and the range of specicity was 0.630.95.

Diagnosis of combined (pre)malignancy For this combined analysis, studies were included if they reported on both endometrial carcinoma and atypical endometrial hyperplasia. All 20 studies reported on endometrial carcinoma and 13 studies reported on atypical endometrial hyperplasia as well. Six different endometrial cut-off values were reported. Sensitivity, specicity, negative predictive value and positive predictive value for the detection of endometrial (pre)malignancy for each reported endometrial thickness cut-off value are reported in Table S3 online. As for atypical endometrial hyperplasia, there were no cut-off values for which multiple studies reported sufcient data to calculate both sensitivity and specicity. Therefore, we were unable to calculate summary estimates of sensitivity and specicity for the different cut-off values for the combined outcome of (pre)malignancy. With regard to the combined diagnosis of premalignant and malignant endometrium, the range of sensitivity was 0.171.0 and the range of specicity was 0.630.95.

*Reported number is included in cut-off, i.e. cut-off of 5 mm means endometrial thickness 5 mm. NE, not possible to estimate.

not report on an endometrial thickness cut-off for atypical endometrial hyperplasia. Sensitivity, specicity, negative predictive value and positive predictive value for the detection of atypical endometrial hyperplasia for each reported endometrial thickness cut-off value are reported in Table S2 online. There were no cut-off values for which multiple studies reported sufcient data to calculate both sensitivity and specicity. Therefore, we were unable to calculate summary estimates of sensitivity and specicity for the different cut-off values for

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DISCUSSION
Our review shows that in a population of postmenopausal women without postmenopausal bleeding and not using HRT, the mean endometrial thickness is 2.9 mm and the prevalences of endometrial carcinoma and atypical endometrial hyperplasia are 0.62 and 0.59%, respectively. Positive predictive values for the three outcomes (endometrial carcinoma, atypical endometrial hyperplasia and both combined) for all reported endometrial thickness cut-offs were between 0 and 0.2. The negative predictive value of TVS was between 0.98 and 1.0 at all endometrial thickness cut-offs and for all three disease outcomes. However, the utility of a negative test in an asymptomatic postmenopausal population is limited because the absolute risk of disease is already low, as demonstrated in this review (prevalence of endometrial carcinoma 0.62% and atypical endometrial hyperplasia 0.59%). This contrasts with symptomatic postmenopausal women, in whom the pre-testing risk of endometrial cancer or atypical hyperplasia varies between 5 and 20%43,44 . Thus, TVS is only of value in postmenopausal women with vaginal bleeding because a clinically substantial reduction in the estimated probability of disease may be achieved by the observation of a normal endometrial thickness on TVS. This reduction is typically from around 10% to below 1% for endometrial carcinoma3 , a probability threshold where rstly, the majority of clinicians recommend reassurance and no need for further evaluation of the endometrium, and secondly, post-TVS probability is demonstrated to be equivalent to the prevalence in the asymptomatic postmenopausal female population4 7 . The strength of our analysis is the complete overview of data combining endometrial thickness, endometrial carcinoma and atypical endometrial hyperplasia in asymptomatic postmenopausal women not using HRT. We describe mean endometrial thickness and the prevalence of endometrial (pre)malignancies in these women. Furthermore, we assessed the diagnostic accuracy of endometrial thickness measurements in this population. Efforts were made to identify all available publications on this subject and we used the most appropriate technique to summarize the sensitivity and specicity, to come to better estimates than the formerly applied summary receiveroperating characteristics curve (sROC) technique for meta-regression in diagnostic metaanalysis10,45 47 . To our knowledge, there is no previously published review or meta-analysis on this subject. A limitation of our study is that despite the thousands of women included in our analysis, the estimates of sensitivity and specicity are very imprecise, especially those of sensitivity. Another limitation could be a bias because of the quality of the included studies. We tried to minimize this bias by performing quality assessment and applying strict criteria for inclusion of studies in the meta-analysis. In a decision analysis performed by Smith-Bindman et al.8 , an endometrial thickness cut-off of 11 mm for an incidentally measured increased endometrial thickness in

an asymptomatic woman was proposed. In this decision analysis the risk of malignancy in a woman below the threshold is extremely low and the risk of malignancy above the threshold varies between 2.2 and 9.3%. In contrast to this analysis, which was a decision analysis in a theoretical cohort, we analyzed observational data. Unfortunately, we had insufcient data from the published studies to calculate an optimal threshold for endometrial thickness based on the sensitivity and specicity reported in the different studies. Because of the low prevalence of the disease, the 95% CI for the summary estimates of sensitivity are very wide, indicating a high degree of inaccuracy. The use of TVS is not limited to women with postmenopausal bleeding. The portability and improved resolution of TVS have contributed to the ubiquity of the test in routine gynecological practice. Postmenopausal women undergo TVS for a variety of gynecological indications (e.g. pelvic pain, suspicion of a pelvic mass, uterine prolapse). During TVS for such nonbleeding indications, images of the endometrium are frequently obtained and a thickened endometrium may be observed. This situation of an apparently incidental nding of an abnormal endometrium will be familiar to all practicing sonologists. Faced with such a TVS nding, it is difcult for the physician to decide on the right management and this usually results in a decision to undertake further, more invasive testing with endometrial sampling and/or hysteroscopy, in keeping with current guidelines for postmenopausal bleeding. Therefore, the ndings of this review, describing normative values for endometrial thickness, determining serious disease prevalence and estimating diagnostic accuracy at various TVS thresholds, in this non-bleeding postmenopausal population are clinically important. Our review has shown that the average TVS-derived endometrial thickness is 2.9 mm. However, the signicance of an endometrial thickness beyond 4 mm is not the same as for a symptomatic postmenopausal bleeding population, and extrapolating protocols from postmenopausal bleeding to an asymptomatic population is not justiable in view of the low overall disease prevalence and poor performance of TVS in detecting serious endometrial disease at all cut-offs. Because the prevalence of the target disease in an unselected postmenopausal population without bleeding symptoms and not using HRT is very low, and endometrial thickness measurement in this population cannot achieve a sufciently high sensitivity to provide additional reassurance to women with a negative test or achieve a sufciently high specicity to justify further invasive testing in women with a positive test, endometrial thickness measurement has no value in this population. Furthermore, there is no evidence that patients in whom endometrial cancer was discovered while asymptomatic have a prognostic advantage over postmenopausal endometrial cancer patients who visited their gynecologist immediately after bleeding had occurred48 . Thus, the results from this systematic review do not justify the use of

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15. Malinova M, Pehlivanov B. Transvaginal sonography and progesterone challenge for identifying endometrial pathology in postmenopausal women. Int J Gynaecol Obstet 1996; 52: 4953. 16. Minagawa Y, Sato S, Ito M, Onohara Y, Nakamoto S, Kigawa J. Transvaginal ultrasonography and endometrial cytology as a diagnostic schema for endometrial cancer. Gynecol Obstet Invest 2005; 59: 149154. 17. Neele SJ, Marchien van Baal W, van der Mooren MJ, Kessel H, Netelenbos JC, Kenemans P. Ultrasound assessment of the endometrium in healthy, asymptomatic early post-menopausal women: saline infusion sonohysterography versus transvaginal ultrasound. Ultrasound Obstet Gynecol 2000; 16: 254259. 18. Osmers R, Volksen M, Rath W, Teichmann A, Kuhn W. [Vaginosonographic measurement of the postmenopausal endometrium in the early detection of endometrial cancer]. Geburtshilfe Frauenheilkd 1989; 49: 262265. 19. Pirhonen JP, Vuento MH, Makinen JI, Salmi TA. Long-term effects of hormone replacement therapy on the uterus and on uterine circulation. Am J Obstet Gynecol 1993; 168: 620630. 20. Warming L, Ravn P, Skouby S, Christiansen C. Measurement precision and normal range of endometrial thickness in a postmenopausal population by transvaginal ultrasound. Ultrasound Obstet Gynecol 2002; 20: 492495. 21. Bortoletto CC, Baracat EC, Goncalves WJ, Lima GR, Stavale JN. Transvaginal ultrasonography and the progestogen challenge test in postmenopausal endometrial evaluation. Int J Gynaecol Obstet 1997; 58: 293298. 22. Buccoliero AM, Caldarella A, Noci I, Borri P, Giachi M, Borrani E, Taddei GL. [Thin-layer cytology in endometrial diagnosis]. Pathologica 2003; 95: 179184. 23. Cohen MA, Sauer MV, Keltz M, Lindheim SR. Utilizing routine sonohysterography to detect intrauterine pathology before initiating hormone replacement therapy. Menopause 1999; 6: 6870. 24. Elewa AM, Abd El Karim MA, Saad SA, Ramadan MA, Abd El Hai MA. Correlation of vaginal ultrasound and hysteroscopy with endometrial histopathology in postmenopausal women. Middle East Fertility Soc J 2001; 6: 2633. 25. Gol K, Saracoglu F, Ekici A, Sahin I. Endometrial patterns and endocrinologic characteristics of asymptomatic menopausal women. Gynecol Endocrinol 2001; 15: 6367. 26. Gouveia DA, Bahamondes L, Aldrighi JM, Tamanaha S, Ribeiro AL, Aoki T. [Prevalence of endometrial injury in asymptomatic obese women]. Rev Assoc Med Bras 2007; 53: 344348. 27. Langer RD, Pierce JJ, OHanlan KA, Johnson SR, Espeland MA, Trabal JF, Barnabei VM, Merino MJ, Scully RE. Transvaginal ultrasonography compared with endometrial biopsy for the detection of endometrial disease. Postmenopausal Estrogen/Progestin Interventions Trial. N Engl J Med 1997; 337: 17921798. 28. Macia M, Novo A, Ces J, Gonzalez M, Quintana S, Codesido J. Progesterone challenge test for the assessment of endometrial pathology in asymptomatic menopausal women. Int J Gynaecol Obstet 1993; 40: 145149. 29. Marello F, Bettocchi S, Greco P, Ceci O, Vimercati A, Di Venere R, Loverro G. Hysteroscopic evaluation of menopausal patients with sonographically atrophic endometrium. J Am Assoc Gynecol Laparosc 2000; 7: 197200. 30. Martinez-Rubio MP, Alcazar JL. Ultrasonographic and pathological endometrial ndings in asymptomatic postmenopausal women taking antihypertensive drugs. Maturitas 2003; 46: 2732. 31. Paraskevaidis E, Papadimitriou D, Kalantaridou SN, Pappa L, Malamou-Mitsi V, Zikopoulos K, Kazantzis E, Lolis ED, Agnantis NJ. Screening transvaginal uterine ultrasonography for identifying endometrial pathology in postmenopausal women. Anticancer Res 2002; 22: 25172520. 32. Tsuda H, Kawabata M, Yamamoto K, Inoue T, Umesaki N. Prospective study to compare endometrial cytology and

endometrial thickness as a screening test for endometrial carcinoma and atypical endometrial hyperplasia in any asymptomatic postmenopausal woman not using HRT. Hence, the need for further diagnostic evaluation of the endometrium should be made by the clinician on an individual patient basis taking into account clinical signs (e.g. abnormal ndings at physical examination, pelvic pain, distension, urinary and bowel complaints), risk factors for endometrial disease (e.g. abnormal BMI, medical comorbidities, family history) and patient preference49 54 .

REFERENCES
1. Brenner PF. Differential diagnosis of abnormal uterine bleeding. Am J Obstet Gynecol 1996; 175: 766769. 2. Parkin DM, Bray F, Ferlay J, Pisani P. Estimating the world cancer burden: Globocan 2000. Int J Cancer 2001; 94: 153156. 3. Smith-Bindman R, Kerlikowske K, Feldstein VA, Subak L, Scheidler J, Segal M, Brand R, Grady D. Endovaginal ultrasound to exclude endometrial cancer and other endometrial abnormalities. JAMA 1998; 280: 15101517. 4. Epstein E. Management of postmenopausal bleeding in Sweden: a need for increased use of hydrosonography and hysteroscopy. Acta Obstet Gynecol Scand 2004; 83: 8995. 5. Goldstein RB, Bree RL, Benson CB, Benacerraf BR, Bloss JD, Carlos R, Fleischer AC, Goldstein SR, Hunt RB, Kurman RJ, Kurtz AB, Laing FC, Parsons AK, Smith-Bindman R, Walker J. Evaluation of the woman with postmenopausal bleeding: Society of Radiologists in Ultrasound-Sponsored Consensus Conference statement. J Ultrasound Med 2001; 20: 10251036. 6. Dutch Society of Obstetrics and Gynaecology (NVOG). NVOG-richtlijn Abnormaal vaginaal bloedverlies in de menopauze [In Dutch]. NVOG Guideline: Abnormal vaginal bleeding during menopause. NVOG, 2003. 7. Scottish Intercollegiate Guidelines Network. Investigation of postmenopausal bleeding. Scottish Intercollegiate Guidelines Network, Royal College of Physicians. 2002. 8. Smith-Bindman R, Weiss E, Feldstein V. How thick is too thick? When endometrial thickness should prompt biopsy in postmenopausal women without vaginal bleeding. Ultrasound Obstet Gynecol 2004; 24: 558565. 9. Whiting P, Rutjes AW, Reitsma JB, Bossuyt PM, Kleijnen J. The development of QUADAS: a tool for the quality assessment of studies of diagnostic accuracy included in systematic reviews. BMC Med Res Methodol 2003; 3: 25. 10. Reitsma JB, Glas AS, Rutjes AW, Scholten RJ, Bossuyt PM, Zwinderman AH. Bivariate analysis of sensitivity and specicity produces informative summary measures in diagnostic reviews. J Clin Epidemiol 2005; 58: 982990. 11. Andolf E, Dahlander K, Aspenberg P. Ultrasonic thickness of the endometrium correlated to body weight in asymptomatic postmenopausal women. Obstet Gynecol 1993; 82: 936940. 12. Gull B, Karlsson B, Milsom I, Wikland M, Granberg S. Transvaginal sonography of the endometrium in a representative sample of postmenopausal women. Ultrasound Obstet Gynecol 1996; 7: 322327. 13. Guven MA, Pata O, Bakaris S, Kafkasli A, Mgoyi L. Postmenopausal endometrial cancer screening: is there a correlation between transvaginal sonographic measurement of endometrial thickness and body mass index? Eur J Gynaecol Oncol 2004; 25: 373375. 14. Kasraeian M, Asadi N, Ghaffarpasand F, Karimi AA. Value of transvaginal ultrasonography in endometrial evaluation of non-bleeding postmenopausal women. Climacteric 2011; 14: 126131.

Copyright 2012 ISUOG. Published by John Wiley & Sons, Ltd.

Ultrasound Obstet Gynecol 2012; 40: 621629.

Endometrial thickness in asymptomatic postmenopausal women

transvaginal ultrasonography for identication of endometrial malignancies. Gynecol Oncol 1997; 65: 383386. Tsuda H, Nakamura H, Inoue T, Kawamura N, Adachi K, Bandera CA. Transvaginal ultrasonography of the endometrium in postmenopausal Japanese women. Gynecol Obstet Invest 2005; 60: 218223. Exacoustos C, Chiaretti M, Minghetti MC, Bianchi L, Arduini D, Romanini C. Endometrial evaluation in asymptomatic postmenopausal women by transvaginal sonography and color ow Doppler. J Am Assoc Gynecol Laparosc 1996; 3 (Suppl): S12. Parra JF, Paredes AG, Oliver AJR, Ventoso FM. Endometrial alterations on ultrasonography in asymptomatic postmenopausal women. Progresos de Obstetricia y Ginecolog a 2008; 51: 398403. Fleischer AC, Wheeler JE, Lindsay I, Hendrix SL, Grabill S, Kravitz B, MacDonald B. An assessment of the value of ultrasonographic screening for endometrial disease in postmenopausal women without symptoms. Am J Obstet Gynecol 2001; 184: 7075. Pardo J, Aschkenazi S, Kaplan B, Orvieto R, Nitke S, Ben-Refael Z. Abnormal sonographic endometrial ndings in asymptomatic postmenopausal women: possible role of antihypertensive drugs. Menopause 1998; 5: 223225. Psillaki AN, I. Transvaginal sonographic prognostic value to detect endometrial pathology in postmenopausal asymptomatic women without hormone replacement therapy. Abstracts of the 58th Congress of the German Society of Gynecology and Obstetrics. October 58, 2010. Munich, Germany. Arch Gynecol Obstet 2010; 282 (Suppl): S112. MF, Rosa-E-Silva Ribeiro CT, Rosa-E-Silva JC, Silva-de-Sa AC, Poli Neto OB, Candido Dos Reis FJ, Nogueira AA. Hysteroscopy as a standard procedure for assessing endometrial lesions among postmenopausal women. Sao Paulo Med J 2007; 125: 338342. Schmidt TR. The role of hysteroscopy in the management of asymptomatic postmenopausal patients with suspicious ultrasound ndings of the uterine endometrium Correlation with sonographic and histologic ndings. Geburtshilfe Frauenheilkd 1999; 59: 163166. N. Ambulatory hysValadares S, Coutinho S, Assunc ao teroscopy results post-menopause: Comparative study between patients with and without metrorrhagia. Gynecol Surg 2005; 2: 259263. Zacchi V, Zini R, Canino A. [Transvaginal sonography as a screening method for the identication of patients at risk of postmenopausal endometrial pathology]. Minerva Ginecol 1993; 45: 339342.

629

33.

34.

35.

36.

37.

38.

39.

40.

41.

42.

43. Dijkhuizen FP, Brolmann HA, Potters AE, Bongers MY, Heinz AP. The accuracy of transvaginal ultrasonography in the diagnosis of endometrial abnormalities. Obstet Gynecol 1996; 87: 345349. 44. Emanuel MH, Verdel MJC, Stas H, Wamsteker K, Lammes FB. An audit of true prevalence of intra-uterine pathology: The hysteroscopical ndings controlled for patient selection in 1202 patients with abnormal uterine bleeding. Gynaecol Endosc 1995; 4: 237241. 45. Deeks JJ. Systematic reviews in health care: Systematic reviews of evaluations of diagnostic and screening tests. BMJ 2001; 323: 157162. 46. Leeang MM, Deeks JJ, Gatsonis C, Bossuyt PM. Systematic reviews of diagnostic test accuracy. Ann Intern Med 2008; 149: 889897. 47. Shapiro DE. Issues in combining independent estimates of the sensitivity and specicity of a diagnostic test. Acad Radiol 1995; 2 (Suppl 1): S37S47. 48. Gerber B, Krause A, Muller H, Reimer T, Kulz T, Kundt G, Friese K. Ultrasonographic detection of asymptomatic endometrial cancer in postmenopausal patients offers no prognostic advantage over symptomatic disease discovered by uterine bleeding. Eur J Cancer 2001; 37: 6471. 49. Anderson KE, Anderson E, Mink PJ, Hong CP, Kushi LH, Sellers TA, Lazovich D, Folsom AR. Diabetes and endometrial cancer in the Iowa womens health study. Cancer Epidemiol Biomarkers Prev 2001; 10: 611616. 50. McPherson CP, Sellers TA, Potter JD, Bostick RM, Folsom AR. Reproductive factors and risk of endometrial cancer. The Iowa Womens Health Study. Am J Epidemiol 1996; 143: 11951202. 51. Timmermans A, Opmeer BC, Veersema S, Mol BW. Patients preferences in the evaluation of postmenopausal bleeding. BJOG 2007; 114: 11461149. 52. van Doorn LC, Dijkhuizen FP, Kruitwagen RF, Heintz AP, Kooi GS, Mol BW; DUPOMEB (Dutch Study in Postmenopausal Bleeding). Accuracy of transvaginal ultrasonography in diabetic or obese women with postmenopausal bleeding. Obstet Gynecol 2004; 104: 571578. 53. Weiderpass E, Persson I, Adami HO, Magnusson C, Lindgren A, Baron JA. Body size in different periods of life, diabetes mellitus, hypertension, and risk of postmenopausal endometrial cancer (Sweden). Cancer Causes Control 2000; 11: 185192. 54. Xu WH, Xiang YB, Ruan ZX, Zheng W, Cheng JR, Dai Q, Gao YT, Shu XO. Menstrual and reproductive factors and endometrial cancer risk: Results from a population-based casecontrol study in urban Shanghai. Int J Cancer 2004; 108: 613619.

SUPPORTING INFORMATION ON THE INTERNET

The following supporting information may be found in the online version of this article: Appendix S1 Search strategy for MEDLINE and EMBASE Appendix S2 Quality assessment of diagnostic accuracy studies (QUADAS) checklist Tables S1S3 Sensitivity, specicity and positive and negative predictive values of endometrial thickness as measured by transvaginal ultrasound, in detection of endometrial carcinoma (Table S1), atypical endometrial hyperplasia (Table S2) and endometrial malignancy/premalignancy (Table S3). Studies are grouped by reported cut-off value.

Copyright 2012 ISUOG. Published by John Wiley & Sons, Ltd.

Ultrasound Obstet Gynecol 2012; 40: 621629.