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Ultrasound Obstet Gynecol2012; 40: 621629Published online in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/uog.12306

Capacity of endometrial thickness measurementto diagnose endometrial carcinoma in asymptomaticpostmenopausal women: a systematic reviewand 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 andGynecology, Albert Schweitzer Hospital, Dordrecht, The Netherlands; Department of Obstetrics and Gynecology, Maxima MedicalCenter, Veldhoven, The Netherlands; Clinical Research Unit, Academic Medical Center, Amsterdam, The Netherlands; Department ofObstetrics 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 isan important tool in the assessment of women with

postmenopausal bleeding, but the role of endometrialthickness measurement by ultrasound in asymptomaticwomen is unclear. The aims of this study wereto determine: (1) the normal endometrial thicknessmeasured by ultrasonography, (2) the prevalence of

serious endometrial pathology and (3) the sensitivityand specificity of endometrial thickness measurementby transvaginal ultrasonography (TVS) for diagnosing

premalignant and malignant endometrial disease inasymptomatic postmenopausal women.

Methods A MEDLINE and EMBASE search (frominception to January 2011) was performed. Articlesreporting on endometrial thickness measurement inthe diagnosis of endometrial carcinoma and atypicalhyperplasia in asymptomatic postmenopausal women notusing hormone replacement therapy (HRT) were selected.Endometrial thickness and the prevalence of endometrial

(pre)malignancies were recorded. If possible, 2 2 tableswere extracted.

Results Thirty-two studies reporting on 11 100 womenwere included. The estimated mean endometrial thicknesswas 2.9 mm (95% CI, 2.63.3 mm). The pooledestimated prevalences of endometrial carcinoma andatypical endometrial hyperplasia were 0.62% (95%CI, 0.420.82%) and 0.59% (95% CI, 0.220.96%),

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: [email protected])

Accepted: 1 September 2012

respectively. Summary estimates for sensitivity andspecificity of TVS endometrial thickness measurementin the prediction of endometrial carcinoma were 0.83(95% CI, 0.191.00) and 0.72 (95% CI, 0.230.95) fora 5-mm cut-off and 0.33 (95% CI, 0.040.85) and 0.94(95% CI, 0.92 0.96) for a 6-mm cut-off.

Conclusions The results from this systematic review donot justify the use of endometrial thickness as a screening

test for endometrial carcinoma and atypical endometrialhyperplasia in asymptomatic postmenopausal women notusing HRT. Copyright 2012 ISUOG. Published by

John Wiley & Sons, Ltd.

INTRODUCTION

Endometrial carcinoma is the most common malignancyof the female genital tract in developed countries andpresents with postmenopausalbleeding in more than 95%of cases1,2. In patients with postmenopausal bleeding,sonographic measurement of endometrial thickness is the

first test to determine whether further investigations areneeded to rule out malignancy3. Guidelines recommenda cut-off value of 4 or 5 mm by transvaginalultrasonography (TVS), below which endometrial canceris unlikely47. When the endometrial thickness is belowthis cut-off, the probability of endometrial carcinoma isbelow 1%3. In contrast to the clear guidelines on themanagement of women with postmenopausal bleeding,clinicians are faced with uncertainty when endometrial

Copyright 2012 ISUOG. Published by John Wiley & Sons, Ltd. SY STEM ATIC RE VI EW

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thickness is measured in asymptomatic postmenopausalwomen. Symptom-free women may undergo TVS forother indications, such as vaginal prolapse or abdominalcomplaints. Inevitably, the endometrium is then visualizedand a thickened endometrium may incidentally beobserved. It is not known how best to manage suchpatients 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 asymptomaticpostmenopausal women with an endometrial thickness of 11 mm an endometrial biopsy should be performed.They argued that women with an endometrial thicknessabove this threshold have a malignancy risk of 6.7%,which is comparable with the risk in patients withpostmenopausal bleeding and an endometrial thicknessof> 5 mm (7.3%), the latter being the widely acceptedthreshold for performing a biopsy in symptomaticpatients.

Apart from the debate on the accuracy of endometrialthickness measurement in asymptomatic postmenopausalwomen, its potential value also depends on the prevalenceof the disease searched for, i.e. endometrial carcinomaand/or its precursors. Since in asymptomatic women theprevalence of endometrial carcinoma is lower than insymptomatic women, the cut-off of endometrial thicknessfor abnormality in these women should be higher.

To address the abovementioned dilemmas, we reviewedthe literature on asymptomatic postmenopausal womennot using hormone replacement therapy (HRT). The aimsof this review were to address in asymptomatic post-menopausal women: (1) normal endometrial thickness as

measured with sonography, (2) the prevalence of seri-ous endometrial pathology and (3) the sensitivity andspecificity of endometrial thickness measurement by TVSfor diagnosing premalignant and malignant endometrialdisease.

METHODS

Identification of studies

We performed an electronic search in January 2011in MEDLINE (from 1948) and EMBASE (from 1980)

to identify articles reporting on endometrial thicknessand/or endometrial carcinoma and hyperplasia in asymp-tomatic postmenopausal women. We used the follow-ing keywords: postmenopausal, asymptomatic, screen-ing, endometrial, thickness, ultrasound, hyperplasia andcarcinoma. The complete search syntax is reported inAppendix S1 online. Language restrictions were notapplied. Abstracts or articles written in languages otherthan English were read by a member of the team withsufficient knowledge of the language; if there was no teammember available, the article was translated by a nativespeaker. References of selected studies were searched forarticles not identified by the electronic searches, and thisprocess was repeated for any further relevant studiesfound. No review protocol was registered.

Selection of studies and data abstraction

Two independent reviewers (M.B., J.P.) screened the elec-tronic search results by reading titles and/or abstracts.Studies that were restricted to patients with post-menopausal bleeding or women using HRT or tamoxifenwere excluded. Titles and abstracts were assessed to

identify eligible studies. Subsequently, these articles wereevaluated in full text for each of the three objectives inde-pendently for the final study selection. Any disagreementswere resolved by consensus. In case of persistent disagree-ment, the judgment of a third reviewer (A.T.) wasdecisive.

If multiple publications reported analyses on the samedataset, only the largest study was included. If a datasetwas split into different subgroups and the subgroupswere reported separately in multiple publications, wecombined the results of these publications. We usedthe quality assessment of diagnostic accuracy studies(QUADAS)9 checklist to assess the methodologicalquality of included studies (Appendix S2 online).

Endometrial thickness

To evaluate normal endometrial thickness in asymp-tomatic postmenopausal women, we searched for studiesthat (1) reported a mean endometrial thickness with ameasure of variance and (2) described a standardizedapproach to measurement of endometrial thickness byTVS. Mean endometrial thickness as well as SD, standarderror or 95% CI were recorded for each included study.A pooled estimate of mean endometrial thickness wasthen calculated using inverse variance weighting in arandom-effects model.

Prevalence of endometrial (pre)malignancies

To assess the prevalence of (pre)malignant lesions ofthe endometrium in asymptomatic postmenopausalwomen, we included studies that reported on any form ofendometrial verification in the total population of asymp-tomatic postmenopausal women not using HRT. Theendometrium could be assessed by histology (hysterec-tomy, dilatation and curettage, hysteroscopy with biopsy,endometrial biopsy) or by cytology. Studies in which therewas partial verification (histological verification only in

a subgroup based on a previous test, e.g. endometrialthickness above a cut-off level or patients positive onprogesterone challenge test) were excluded. The methodof verification, the number of women with atypicalendometrial hyperplasia and the number of women withendometrial carcinoma were recorded for each selectedstudy. The prevalence of endometrial carcinoma andatypical endometrial hyperplasia was then calculated foreach study, and a weighted pooled estimate was derived.

Diagnostic accuracy of endometrial thickness forendometrial (pre)malignancy

Finally, to estimate the diagnostic accuracy of endome-trial thickness for (pre)malignancy of the endometrium,

Copyright 2012 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol2012; 40: 621629.

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Endometrial thickness in asymptomatic postmenopausal women 623

we selected studies that reported on both endometrialthickness measurement and endometrial histologicalverification in asymptomatic postmenopausal women.Information required to construct a 22 table foreach reported endometrial thickness cut-off value wasrecorded for each selected study.Three different outcomeswere considered: benign (including atrophy, endometrial

polypsand endometrial hyperplasia without atypia), atyp-ical endometrial hyperplasia and endometrial carcinoma.

The data from the 22 tables were used to calculatesensitivity and specificity, as well as positive and negativepredictive values for each study. If the study reportedon multiple thresholds, we included 22 tables forall reported thresholds. Subsequently, summary pointestimates for sensitivity and specificity were generated foreach reported endometrial cut-off value using a bivariaterandom effects approach10, for endometrial carcinoma,atypical endometrial hyperplasia and these two diagnosescombined in one group.

RESULTS

Search strategy

Our search resulted in 503 citations; another 31 studieswere identified through reference searches. There were 95studies eligible for inclusion based on title and abstract.After assessment of the full text articles, 63 studies werediscarded (Figure 1). As a result, a set of 32 relevantstudies was available to answer our three questions: 10studies could be used for question 1 (estimating normal

endometrial thickness); 15 studies could be used forquestion 2 (prevalence of endometrial malignancy andpremalignancy) and 20 studies could be used for question

3 (diagnostic accuracy of TVS for these endometrialdiseases).

Assessment of methodological quality

Study quality was considered generally good when eightof the 14 QUADAS items were met, with over 70% of

the included studies fulfilling this criterion (Figure 2).Studies scored poorly on the items regarding blindedinterpretation of the reference test and description ofwithdrawals. In five of the 32 studies, almost the entireQUADAS checklist was scored as not applicable because,for example, no endometrial thickness measurement(index test) or no endometrial verification (reference test)was reported. Absence of the index or reference testautomatically led to problems in completing theQUADASchecklist. For these five studies it was impossible to answersome questions of the QUADAS checklist with yes, noor unclear, and these items were scored not applicable.

Endometrial thickness

We found 10 studies that reported on endometrialthickness measurement with a measure of variance inasymptomatic women not using HRT1120. The 10 stud-ies that were assessed for inclusion had been conductedin nine different countries. One study was published inGerman; the other nine were published in English. Intotal, these 10 studies reported on 3049 women, witha median sample size of 207 (range, 971182). Meanendometrial thickness in the 10 studies varied from 2.1

to 5.7 mm. The pooled estimate of the mean endometrialthickness was 3.2 mm (95% CI, 2.83.6 mm). There wasone outlier, with a mean endometrial thickness of 5.7 mm,

Retrieved from searches:electronic search (n= 503)cross-reference search (n= 31)

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

Retrieved in full (n= 95)

Studies available to answerdifferent 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 variancereported (n= 12)

Multiple publications on the same dataset (n= 4)

Studies included forendometrial thickness(n= 10)

Studies included fordiagnostic accuracy(n= 20)

Studies included forhistological verification(n= 15)

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


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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 reporteda thicker endometrium. Mean body mass index (BMI) inthis study was 29.5 kg/m2. In contrast, mean BMI in theother included studies ranged from 22.4 to 25.6 kg/m2.The purpose of the study by Guven et al. was to correlateBMI to endometrial thickness, which could potentiallyhave 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 pooledestimate of the mean endometrial thickness was 2.9 mm(95% CI,2.6 3.3mm)(Figure 3).Statistical heterogeneitybetween studies (I2) was 28%.

Prevalence of endometrial (pre)malignancy

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

from further analysis, as they had only partial endometrialverification (verification in a subgroup of patients

selected by a previous test, e.g. endometrial thicknessor progesterone challenge test). The 15 remaining studieshad been performed in nine different countries13,14,2133.Thirteen studies were published in English, one inPortuguese and one in Italian. Together, these studies

described a total of 3595 women (Table 2). The mediansample size was 145 (range, 30883). The prevalenceof endometrial carcinoma varied between 0 and 2.1%,

the prevalence of atypical endometrial hyperplasia variedbetween 0 and 3.5% and the prevalence of combined(pre)malignancy varied between 0 and 4.3%. Thepooled estimated prevalence of endometrial carcinomawas 0.62% (95% CI, 0.42 0.82%), of endometrialhyperplasia it was 0.59% (95% CI, 0.220.96%) andof 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 inasymptomatic postmenopausal women without hormone replacement therapy

Endometrial thickness (mm)

Reference Year Country n Mean SD Range

Andolf11 1993 Sweden 300 2.30 1.8 010Gull12 1996 Sweden 361 3.00 0.1* 128

Kasraeian14 2011 Iran 259 3.83 2.95 125

Malinova15 1996 Bulgaria 130 3.86 2.35 NR

Minagawa16 2005 Japan 146 2.80 2.2 0.214.1Neele17 2000 The Netherlands 148 3.40 1.7 0.912.8

Osmers18 1989 Germany 155 3.40 7.9 163

Pirhonen19 1993 Finland 271 2.20 0.77 NR

Warming20

2002 Denmark 1182 2.10 1.4 NR

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


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Andolf11

First author

Gull12

Kasraeian14

Malinova15

Minagawa16

Neele17

Osmers18

Warming20

Pirhonen19

Summary

2.0 2.5 3.0 3.5

Endometrial thickness (mm)

4.0 4.5

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

Diagnostic accuracy of endometrial thickness forendometrial (pre)malignancy

There were 20 studies that reported on the endome-trial thickness cut-off value and histological or cytologi-cal endometrial verification1116,23,26,29,31,32,3442. These

studies were performed in 13 different countries. Sixteen

studies were published in English, one in Italian, one inSpanish, one in Portuguese and one in German. In total,

these 20 studies described 6974 women, with a median

sample size of 209 (range, 471926) (Table 3). In 13 stud-iespartial verification wasperformed, whereas in theotherseven studies endometrial verification was performed inall women. In 5198 out of 6974 women an endometrialsample was obtained. Endometrial carcinoma was foundin 32 and atypical endometrial hyperplasia in 21 women.

Diagnosis of endometrial carcinoma

Eight different endometrial thickness cut-off values werereported in the 20 studies. Sensitivity, specificity, negativepredictive value andpositive predictive value for thedetec-tion of endometrial carcinoma for each reported endome-trial thickness cut-off value are reported in Table S1online. Positive predictive valuesvaried between 0 and 0.2and negative predictive value, if it was possible to ascer-tain, was 1. For the reported endometrial thickness cut-offs of 4, 5 and 6 mmwewere able to calculate a summarysensitivity and specificity for the detection of endometrial

carcinoma. The remaining five cut-offs were reported byone single study, so for these cut-offs we were unable tocalculate summary sensitivity and specificity. The sum-mary estimate of the sensitivity for the different cut-offsvaried between 0.00 and 0.83. The summary estimateof the specificity for the different cut-offs varied between0.72 and 0.94 (Table4). For the summary estimates of sen-sitivity andspecificity as well as for the reported sensitivityand specificity, the 95% CIs were very wide, indicatingthe high uncertainty surrounding these estimates.

Diagnosis of atypical endometrial hyperplasia

Six different endometrial thickness cut-off values werereported in 13 studies. The other seven studies did

Table 2 Characteristics of studies included in meta-analysis for assessment of prevalence of endometrial (pre)malignancies in asymptomaticpostmenopausal women not using hormone replacement therapy

Endometrial carcinoma AEH

Reference Year Country nVerificationmethod n

Prevalence(%) n

Prevalence(%)

Prevalence of(pre)malignancy (%)

Bortoletto21 1997 Brazil 150 EBNS 0 0 1 0.67 0.67

Buccoliero22 2003 Italy 107 hysterectomy,EBN, EES

0 0 0 0 0

Cohen23 1999 USA 60 EBP 0 0 0 0 0Elewa24 2001 Egypt 30 Hyst + biopsy 0 0 0 0 0Gol25 2001 Turkey 556 D&C 3 0.54 3 0.54 1.1

Gouveia26 2007 Brazil 47 EBP 1 2.1 1 2.1 4.3

Guven13 2004 Turkey 97 D&C 0 0 0 0 0Kasraeian14 2011 Iran 259 Hyst + biopsy 1 0.39 9 3.5 3.9

Langer27 1997 USA 145 EBNS 1 0.69 0 0 0.69

Macia28 1993 Spain 130 EBS 0 0 1 0.77 0.77

Marello29 2000 Italy 328 Hyst + biopsy 1 0.30 NR NR NRMartinez-Rubio30 2003 Spain 369 EBP 3 0.81 0 0 0.81

Paraskevaidis31 2002 Greece 59 EBK 1 1.7 1 1.7 3.4

Tsuda32 1997 Japan 375 EES, EBNS 1 0.27 NR NR NRTsuda33 2005 Japan 883 SC 8 0.91 1 0.11 1.0

Only first 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 specified; 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 specificity of endometrial thickness as measured by transvaginalultrasound with regard to premalignant or malignant endometrium in asymptomatic postmenopausal women without hormone replacementtherapy

Patients < cut off: Patients > cut off:

Reference Year Country nVerificationmethod

Patientsverified (n) Cut-off*

Total(n)

WithEC (n)

WithAEH (n)

Total(n)

WithEC (n)

WithAEH (n)

Andolf11

1993 Sweden 300 D&C 11 5 mm 289 NR NR 11 0 0Cohen23 1999 USA 60 EBP 60 5 mm 38 0 0 22 0 0

Exacoustos34 1996 Italy 910 Hyst + biopsy 83 8 mm 827 NR NR 83 3 NRParra35 2008 Spain 209 Hyst + biopsy 209 5 mm NR NR NR 209 5 NR

Fleischer36 2001 USA 1926 EBNS 1792 6 mm 1833 1 4 93 1 0

Gouveia26 2007 Brazil 47 EBP 47 5 mm 28 0 NR 19 1 NRGull12 1996 Sweden 361 Hyst + D&C 18 8 mm 343 NR NR 18 0 0

Guven13 2004 Turkey 97 D&C 97 5 mm 75 0 0 22 0 0

Kasraeian14 2011 Iran 259 Hyst + biopsy 259 5 mm 218 0 5 41 1 4Malinova15 1996 Bulgaria 130 D&C 30 6 mm 95 NR NR 35 0 NR

Marello29 2000 Italy 328 Hyst + biopsy 328 4 mm 199 1 NR 129 0 NR

Minagawa16 2005 Japan 146 SC 5 5 mm 141 NR NR 5 1 0

Paraskevaidis31 2002 Greece 59 EBK 59 9 mm 39 0 0 20 1 1Pardo37 1998 Israel 85 Hyst + biopsy 85 7 mm NR NR NR 85 3 0

Psillaki38 2010 Greece 850 Hyst + D&C 149 5 mm 701 NR NR 149 0 1

Ribeiro39 2007 Brazil 399 Hyst + biopsy 399 4 mm NR NR NR 399 1 1Schmidt40 1999 Germany 209 Hyst + D&C 209 6 mm NR NR NR 209 8 4

Tsuda32 1997 Japan 375 EES + EBNS 375 3 mm 264 0 NR 111 1 NR

4 mm 312 1 NR 63 0 NR

6 mm 345 1 NR 30 0 NR8 mm 352 1 NR 23 0 NR

10 mm 362 1 NR 13 0 NR

Valadares41 2005 Portugal 150 Hyst + biopsy 150 4 mm NR NR NR 150 2 NRZacchi42 1993 Italy 74 Hyst + biopsy 6 8 mm 68 NR NR 6 0 0

Only first author of each study is given. *Reported number is included in cut-off, i.e. cut-off of 5mm means endometrial thickness 5mm.Single layer measurement; values reported in article are multiplied by two. AEH, atypical endometrial hyperplasia; D&C, dilatation andcurettage; EBK, endometrial biopsy, Karman; EBNS, endometrial biopsy not specified; EBP, endometrial biopsy, Pipelle; EC, endometrialcarcinoma; EES, endocyte endometrial sampler; Hyst, hysteroscopy; NR, not reported; SC, softcyto.

Table 4 Summary estimates of sensitivity and specificity withregard to endometrial carcinoma for different transvaginalultrasound-derived endometrial thickness cut-off values*

Threshold(mm)

Studies(n)

Women(n)

Sensitivity(95% CI)

Specificity(95% CI)

3 1 375 1.00 (0.03 1.00) 0.71 (0.66 0.75)

4 2 703 0.00 (0.00 1.00) 0.73 (0.55 0.86)5 2 306 0.83 (0.19 1.00) 0.72 (0.23 0.95)

6 2 2301 0.33 (0.04 0.85) 0.94 (0.92 0.96)

7 0 0 NE NE

8 1 375 0.00 (0.00 0.97) 0.94 (0.91 0.96)9 1 59 1.00 (0.03 1.00) 0.67 (0.54 0.79)

10 1 375 0.00 (0.00 0.97) 0.96 (0.94 0.98)

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

not report on an endometrial thickness cut-off foratypical endometrial hyperplasia. Sensitivity, specificity,negative predictive value and positive predictive valuefor the detection of atypical endometrial hyperplasiafor each reported endometrial thickness cut-off valueare reported in Table S2 online. There were no cut-offvalues for which multiple studies reported sufficient datato calculate both sensitivity and specificity. Therefore,we were unable to calculate summary estimates ofsensitivity andspecificity forthedifferentcut-off values for

atypical endometrial hyperplasia. With regard to atypicalendometrial hyperplasia, the range of sensitivity was0.001.00 and the range of specificity was 0.630.95.

Diagnosis of combined (pre)malignancy

For this combined analysis, studies were included ifthey reported on both endometrial carcinoma and atyp-ical endometrial hyperplasia. All 20 studies reported onendometrial carcinoma and 13 studies reported on atypi-

cal endometrial hyperplasia as well. Six different endome-trial cut-off values were reported. Sensitivity, specificity,negative predictive value and positive predictive valuefor the detection of endometrial (pre)malignancy foreach reported endometrial thickness cut-off value arereported in Table S3 online. As for atypical endometrialhyperplasia, there were no cut-off values for whichmultiple studies reported sufficient data to calculateboth sensitivity and specificity. Therefore, we wereunable to calculate summary estimates of sensitivity

andspecificity for the different cut-off values for thecombined outcome of (pre)malignancy. With regard tothe combined diagnosis of premalignant and malignantendometrium, the range of sensitivity was 0.171.0 andthe range of specificity was 0.630.95.


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DISCUSSION

Ourreview shows that in a population of postmenopausalwomen without postmenopausal bleeding and not usingHRT, the mean endometrial thickness is 2.9 mm andthe prevalences of endometrial carcinoma and atypicalendometrial hyperplasia are 0.62and 0.59%, respectively.Positive predictive values for the three outcomes(endometrial carcinoma, atypical endometrial hyperplasiaandboth combined) forall reported endometrial thicknesscut-offs were between 0 and 0.2. The negative predictivevalue of TVS was between 0.98 and 1.0 at all endometrialthickness cut-offs and for all three disease outcomes.However, the utility of a negative test in an asymptomaticpostmenopausal population is limited because theabsolute risk of disease is already low, as demonstratedin this review (prevalence of endometrial carcinoma0.62% and atypical endometrial hyperplasia 0.59%).Thiscontrastswithsymptomatic postmenopausalwomen,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 womenwith vaginal bleeding because a clinically substantialreduction in the estimated probability of disease maybe achieved by the observation of a normal endometrialthickness on TVS. This reduction is typically fromaround 10% to below 1% for endometrial carcinoma3,a probability threshold where firstly, the majority ofclinicians recommend reassurance and no need for furtherevaluation of the endometrium, and secondly, post-TVSprobability is demonstrated to be equivalent to theprevalence in the asymptomatic postmenopausal femalepopulation47.

The strength of our analysis is the complete overviewof data combining endometrial thickness, endometrialcarcinomaand atypical endometrial hyperplasia in asymp-tomatic postmenopausal women not using HRT. Wedescribe mean endometrial thickness and the preva-lence of endometrial (pre)malignancies in these women.Furthermore, we assessed the diagnostic accuracy ofendometrial thickness measurements in this population.Efforts were made to identify all available publica-tions on this subject and we used the most appropriatetechnique to summarize the sensitivity and speci-ficity, to come to better estimates than the formerly

applied summary receiveroperating characteristics curve(sROC) technique for meta-regression in diagnostic meta-analysis10,4547. To our knowledge, there is no previouslypublished review or meta-analysis on this subject.

A limitation of our study is that despite the thousandsof women included in our analysis, the estimates ofsensitivity and specificity are very imprecise, especiallythose of sensitivity. Another limitation could be a biasbecause of the quality of the included studies. We triedto minimize this bias by performing quality assessmentand applying strict criteria for inclusion of studies in themeta-analysis.

In a decision analysis performed by Smith-Bindmanet al.8, an endometrial thickness cut-off of 11 mm for anincidentally measured increased endometrial thickness in

an asymptomatic woman was proposed. In this decisionanalysis the risk of malignancy in a woman below thethreshold is extremely low and the risk of malignancyabove the threshold varies between 2.2 and 9.3%. Incontrast to this analysis, which was a decision analysisin a theoretical cohort, we analyzed observational data.Unfortunately, wehadinsufficient data from thepublished

studies to calculate an optimal threshold for endometrialthickness based on the sensitivity and specificity reportedin the different studies. Because of the low prevalenceof the disease, the 95% CI for the summary estimatesof sensitivity are very wide, indicating a high degree ofinaccuracy.

The use of TVS is not limited to women withpostmenopausal bleeding. The portability and improvedresolution of TVS have contributed to the ubiquity of thetest in routine gynecological practice. Postmenopausalwomen undergo TVS for a variety of gynecologicalindications (e.g. pelvic pain, suspicion of a pelvic

mass, uterine prolapse). During TVS for such non-bleeding indications, images of the endometrium arefrequently obtained and a thickened endometrium maybe observed. This situation of an apparently incidentalfinding of an abnormal endometrium will be familiar toall practicing sonologists. Faced with such a TVS finding,it is difficult for the physician to decide on the rightmanagement and this usually results in a decision toundertake further, more invasive testing with endometrialsampling and/or hysteroscopy, in keeping with currentguidelines for postmenopausal bleeding. Therefore, thefindings of this review, describing normative valuesfor endometrial thickness, determining serious disease

prevalence and estimating diagnostic accuracy at variousTVS thresholds, in this non-bleeding postmenopausalpopulation areclinically important. Ourreviewhasshownthat the average TVS-derived endometrial thickness is2.9 mm. However, the significance of an endometrialthickness beyond 4 mm is not the same as for asymptomatic postmenopausal bleeding population, andextrapolating protocols from postmenopausal bleeding toan asymptomatic population is not justifiable in view ofthe low overall disease prevalence and poor performanceof TVS in detecting serious endometrial disease at allcut-offs.

Because the prevalence of the target disease in anunselected postmenopausal population without bleedingsymptoms and not using HRT is very low, andendometrial thickness measurement in this populationcannot achieve a sufficiently high sensitivity to provideadditional reassurance to women with a negative testor achieve a sufficiently high specificity to justify furtherinvasive testing in women with a positive test, endometrialthickness measurement has no value in this population.Furthermore, there is no evidence that patients in whomendometrial cancer was discovered while asymptomatichave a prognostic advantage over postmenopausalendometrial cancer patients who visited their gynecologistimmediately after bleeding had occurred48. Thus, theresults from this systematic review do not justify the use of


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endometrial thickness as a screening test for endometrialcarcinoma and atypical endometrial hyperplasia in anyasymptomatic postmenopausal woman not using HRT.Hence, the need for further diagnostic evaluation ofthe endometrium should be made by the clinician onan individual patient basis taking into account clinicalsigns (e.g. abnormal findings at physical examination,

pelvic pain, distension, urinary and bowel complaints),risk factors for endometrial disease (e.g. abnormalBMI, medical comorbidities, family history) and patientpreference4954.

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S U P P O R T I N G I N F O R M A T I O N O N T H E I N T E R N E T

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 S1 S3 Sensitivity, specificity and positive and negative predictive values of endometrial thickness asmeasured by transvaginal ultrasound, in detection of endometrial carcinoma (Table S1), atypical endometrialhyperplasia (Table S2) and endometrial malignancy/premalignancy (Table S3). Studies are grouped byreported cut-off value.


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