uva-dare (digital academic repository) management of ... · biopsy should be performed.8 they...

UvA-DARE is a service provided by the library of the University of Amsterdam (http://dare.uva.nl)

UvA-DARE (Digital Academic Repository)

Management of endometrial abnormalities in postmenopausal women, an individualizedapproach

Breijer, M.C.

Link to publication

Citation for published version (APA):Breijer, M. C. (2013). Management of endometrial abnormalities in postmenopausal women, an individualizedapproach.

General rightsIt is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s),other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons).

Disclaimer/Complaints regulationsIf you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, statingyour reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Askthe Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam,The Netherlands. You will be contacted as soon as possible.

Download date: 03 Jun 2020

https://dare.uva.nl/personal/pure/en/publications/management-of-endometrial-abnormalities-in-postmenopausal-women-an-individualized-approach(967320f0-bde3-4e3e-8b28-dacbcd2f79f7).html

8|The capacity of endometrial thickness measurement to diagnose endometrial carcinoma in asymptomatic postmenopausal women: a systematic review and meta analysis

M.C. BreijerJ.A.H. PeetersB.C. OpmeerT.J. Justin ClarkR.H.M. VerheijenB.W.J. MolA. Timmermans

Ultrasound Obstet Gynecol. 2012 ; 40: 621-629.

Chapter 8

96

AbSTRACT

Objectives: Measurement of endometrial thickness is an important tool in the assessment of women with postmenopausal bleeding. The place of endometrial thickness measurement by ultrasound in asymptomatic women is unclear. The aims of this study were to address: (I) the normal endometrial thickness measured with ultrasonography, (II) the prevalence of serious endometrial pathology and (III) the sensitivity and specificity 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 without HRT were selected. Endometrial thickness and the prevalence of endometrial (pre-)malignancies were recorded. If possible, 2x2 tables were extracted.

Results: We included 32 studies reporting on 11,100 women to answer our three objectives: (I) The estimated mean endometrial thickness was 2.9 mm (95% CI 2.6-3.3). (II) The pooled estimated prevalence of endometrial carcinoma and atypical endometrial hyperplasia were 0.62% (95% CI 0.42-0.82), and 0.59% (95% CI 0.22-0.96), respectively. (III) Summary estimates for sensitivity and specificity of TVS endometrial thickness measurement were 0.83 (95% CI 0.19-1.00) and 0.72 (95% CI 0.32-0.93) for 5 mm cut-off and 0.33 (95% CI 0.04 -0.85) and 0.94 (95% CI 0.92-0.96) for 6 mm cut-off.

Conclusions: The results from this review do not justify the use of endometrial thickness as a screening test for endometrial carcinoma and atypical hyperplasia in asymptomatic postmenopausal women not using HRT.

Endometrial thickness measurement in asymptomati c postmenopausal women

97

8

InTRODuCTIOn

Endometrial carcinoma is the most common malignancy of the female genital tract in the developed countries and presents itself with postmenopausal bleeding in more than 95% of cases.1, 2 In pati ents with postmenopausal bleeding, sonographic measurement of endometrial thickness (ET) is, the fi rst test to determine whether further investi gati ons are needed to rule out malignancy.3 Guidelines recommend a cut-off value of 4 or 5 mm by transvaginal ultrasonography (TVS), below which endometrial cancer is unlikely.4-7 When the endometrial thickness is below this cut-off , the probability of endometrial carcinoma is below 1%.3 In contrast with the clear guidelines on the management of women with postmenopausal bleeding, clinicians are faced with uncertainty when endometrial thickness is measured in asymptomati c postmenopausal women. Symptom free women may undergo TVS for other indicati ons, such as vaginal prolapse or abdominal complaints. Inevitably, the endometrium is then visualized and incidentally a thickened endometrium may be observed. It is unknown how to manage such an incidentally observed thick endometrium.Based on a decision analysis in a theoreti cal cohort, Smith-Bindman et al concluded that in asymptomati c postmenopausal women with an ET of 11 mm or thicker an endometrial biopsy should be performed.8 They argued that women with an endometrial thickness above this threshold have a malignancy risk of 6.7% which is comparable to the risk in pati ents with postmenopausal bleeding and an ET larger than 5 mm (7.3%), the latt er being the widely accepted threshold to perform a biopsy in symptomati c pati ents. Apart from this debate on the accuracy of endometrial thickness measurement in asymptomati c postmenopausal women, its potenti al value also depends on the prevalence of the disease searched for, i.e. endometrial thickness and or its precursors. Since in asymptomati c women the prevalence of endometrial carcinoma is lower than in symptomati c women, the cut-off of endometrial thickness for abnormality in these women should be higher. To address the above menti oned dilemmas, we reviewed the literature on asymptomati c postmenopausal women not using hormone replacement therapy (HRT). The aims of this review were: to address in asymptomati c postmenopausal women: (1) normal endometrial thickness measured with ultrasonography, (2) the prevalence of serious endometrial pathology and (3) the sensiti vity and specifi city of endometrial thickness measurement by TVS for diagnosing premalignant and malignant endometrial disease.

METHODS

Identi fi cati on of studies

We performed an electronic search in January 2011 in MEDLINE (from 1948) and EMBASE (from 1980) to identi fy arti cles reporti ng on endometrial thickness and/or endometrial

Chapter 8

98

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 1. Language restrictions were not applied. Abstracts or articles written in languages other than English were read by a member of the team with sufficient knowledge of the language, if there was no team member available, the article was translated by a native speaker. References and cross references of selected studies were searched for articles not identified by the electronic searches. No review protocol was registered.

Selection of studies and data abstraction

Two independent reviewers (MB, JP) 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 final study selection. Any disagreements were resolved by consensus. In case of persistent disagreement, the judgment of a third reviewer (AT) 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 2).

Endometrial thicknessTo evaluate normal endometrial thickness in asymptomatic postmenopausal, 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 standard deviation, standard error or 95% confidence intervals 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 verification on the total population of asymptomatic postmenopausal women without HRT. The endometrium could be assessed with histology (hysterectomy, dilatation and curettage (D&C), hysteroscopy with biopsy, endometrial biopsy) or with cytology. Studies that performed partial verification (histological verification only in a subgroup based on a


99

8

previous test e.g. ET above a cut-off level or progesterone challenge test positi ve pati ents) were excluded. The method of verifi cati on, the number of women with atypical endometrial hyperplasia and the number of women with endometrial carcinoma was recorded for each selected study. The prevalence of endometrial carcinoma and atypical endometrial hyperplasia was then calculated for each study, and a weighted pooled esti mate was derived.

Diagnosti c accuracy of endometrial thickness for endometrial (pre-) malignancyFinally, to esti mate the diagnosti c accuracy of endometrial thickness for (pre)malignancy of the endometrium, we selected studies that reported on both endometrial thickness measurement and endometrial histological verifi cati on in asymptomati c postmenopausal women. Informati on required to construct a two-by-two table for each reported endometrial thickness cut-off value was recorded for each selected study. Three diff erent outcomes were considered: benign (including atrophy, endometrial polyps, and endometrial hyperplasia without atypia), atypical endometrial hyperplasia, and endometrial carcinoma.The data from the two-by-two tables were used to calculate sensiti vity and specifi city, as well as positi ve and negati ve predicti ve values for each study. If the study reported on multi ple thresholds, we included two-by-two tables for all reported thresholds. Subsequently, summary point esti mates for sensiti vity and specifi city were generated for each reported endometrial cut-off value using a bivariate random eff ects approach10, for endometrial carcinoma, atypical endometrial hyperplasia, and these two diagnoses combined in one group.

RESulTS

Search strategy

Our search resulted in 503 citati ons; another 31 studies were identi fi ed through reference search. There were 95 studies eligible for inclusion based on ti tle and abstract. Aft er assessment of the full text arti cles, 63 studies were discarded as there were no separate data for asymptomati c pati ents (N = 7), non HRT using pati ents or no clear informati on on HRT use (N = 29), postmenopausal pati ents (N = 3), being a review or editorial (N = 4), endometrial thickness reported in subgroups only (N = 4), no mean endometrial thickness or measure for variance reported (N = 12), or having multi ple publicati ons on the same dataset (N = 4) (Figure 1). As a result, a set of 32 relevant studies was available to answer our three questi ons: 10 studies could be used for questi on 1 (esti mati ng normal endometrial thickness); 15 studies could be used for questi on 2 (prevalence of endometrial malignancy and pre-malignancy) and 20 studies could be used for questi on 3 (diagnosti c accuracy of TVS for these endometrial diseases).

Chapter 8

100

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 variance

reported (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. Flow chart of studies included in the meta-analysis. HRT, hormone replacement therapy.

Assessment of methodological qualityStudy quality was considered generally good when eight of the 14 QUADAS items were met by over 70% of the included studies (Figure 2).

0%

Patientspectrum

Selectioncriteria

Referencestandard

Timeinterval

Partialverification

Differentialverification

Incorporation

Indextextdetails

Referencestandarddetails

Reviewbias(index)

Reviewbias(reference)

Clinicaldata

Uninterpretableresults

Withdrawals

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

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.


101

8

Studies scored poor on the items regarding blinded interpretati on of the reference test and descripti on of withdrawals. In 5 of the 32 studies, almost the enti re QUADAS checklist was scored as not applicable because e.g. no endometrial thickness measurement (index test) was reported or no endometrial verifi cati on (reference test) was reported. Absence of the index or reference test, automati cally led to problems in completi ng the QUADAS checklist. For these fi ve studies it was impossible to answer some questi ons of the QUADAS checklist with ‘yes’, ‘no’ or ‘unclear’ and these items were scored ‘not applicable’.

Endometrial thicknessWe found ten studies that reported on endometrial thickness measurement with a measure of variance in asymptomati c women without HRT.11-20 The 10 studies that were assessed for inclusion had been conducted in nine diff erent countries. One study was published in German; the other nine were published in English. In total, these 10 studies reported on 3,049 women, with a median sample size of 207 (range 97 to 1182). Mean endometrial thickness in the 10 studies varied from 2.1 mm to 5.7 mm. The pooled esti mate of the mean endometrial thickness was 3.2 mm (95% CI 2.8-3.6). There was one outlier, with a mean endometrial thickness of 5.7 mm, compared to the other studies; Güven et al reported a thicker endometrium.13 Mean BMI in this study was 29.5 kg/m2. In contrast, mean BMI in the other included studies ranged between 22.4 and 25.6 kg/m2. The purpose of the study by Güven et al was to correlate BMI to endometrial thickness, this potenti ally could have lead 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 esti mate of the mean endometrial thickness was 2.9 mm (95% CI 2.6 -3.3) (Figure 3). Stati sti cal heterogeneity between studies (I2) was 28%.

Table 1. Characteristi cs of studies included in meta-analysis for mean endometrial thickness measured by transvaginal ultrasound in asymptomati c postmenopausal women without hormone replacement therapy.

Endometrial thickness (mm)

Reference Year Country n Mean SD Range

Andolf11 1993 Sweden 300 2.30 1.8 0-10

Gull12 1996 Sweden 361 3.00 0.1† 1-28

Kasraeian14 2011 Iran 259 3.83 2.95 1-25

Malinova15 1996 Bulgaria 130 3.86 2.35 NR

Minagawa16 2005 Japan 146 2.80 2.2 0.2-14.1

Neele17 2000 The Netherlands 148 3.40 1.7 0.9-12.8

Osmers18 1989 Germany 155 3.40 7.9 1-63

Pirhonen19 1992 Finland 271 2.20 0.77 NR

Warming20 2002 Denmark 1182 2.10 1.4 NR†standard error. NR, not reported

Chapter 8

102

Andolf 11

Firstauthor

Gull 12

Kasraeian 14

Malinova 15

Minagawa 16

Neele17

Osmers 18

Warming 20

Pirhonen 19

Summary

2.0 2.5 3.0 3.5

Endometrialthickness(mm)

4.0 4.5

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

Prevalence of endometrial (pre-) malignancies

In 28 studies, a histological diagnosis of the endometrium (endometrial verification) was obtained. We excluded 13 studies from further analysis, as they had only partial endometrial verification (verification in a subgroup of patients selected by a previous test e.g. endometrial thickness or progesterone challenge test). The 15 remaining studies were performed in nine different countries.13, 14, 21-33 Thirteen studies were published in English, one in Portuguese and one in Italian. Together, these studies described a total of 3,595 women. Characteristics of these studies are reported in Table 2. The median sample size was 145 (range 30 to 883). 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 0.42-0.82) of endometrial hyperplasia was 0.59% (95% CI 0.22-0.96) and of combined (pre-) malignancies 1.21% (95% CI 0.63-1.79).

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 verification.11-16, 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.


103

8

Table 2. Characteristi cs of studies included in meta analysis for assessment of prevalence of endometrial (pre)malignancies in asymptomati c postmenopausal women not using hormone replacement therapy.

Endometrial carcinoma

AEH

Author Year Country nVerifi cati on method

nPrevalence

(%)n

Prevalence (%)

Prevalence of (pre-) malignancy (%)

Bortolett o21 1997 Brazil 150 EBNS 0 0 1 0.67 0.67

Buccoliero22 2003 Italy 107Hysterectomy, EBN, EES

0 0 0 0 0

Cohen23 1999 USA 60 EBP 0 0 0 0 0

Elewa24 2001 Egypt 30 Hyst + biopsy 0 0 0 0 0

Gol25 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

Güven13 2003 Turkey 97 D&C 0 0 0 0 0

Kasraeian14 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 NR

Marti nez-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 0.21 NR NR NR

Tsuda33 2005 Japan 883 SC 8 0.91 1 0.11 1.0

EC, endometrial carcinoma; AEH, atypical endometrial hyperplasia; NA, not applicable; NR, not reported.Endometrial verifi cati on methods: EB NS, endometrial biopsy not specifi ed; EB N, endometrial biopsy, Novak curett e; EES, endocyte endometrial sampler; EB P, endometrial biopsy, Pipelle; Hyst, hysteroscopy; D&C, dilatati on and curett age; EB S, endometrial biopsy, Semm’s canula; EB K, endometrial biopsy, Karman; SC, soft cyto.

In total, these 20 studies described 6,974 women with a median sample size of 209 (range 47 to 1,926). Study characteristi cs are reported in Table 3. In 13 studies parti al verifi cati on occurred, whereas in the other seven studies endometrial verifi cati on was performed in all women. In 5,198 out of 6,974 women an endometrial sample was obtained. Endometrial carcinoma was found in 32 and atypical endometrial hyperplasia in 21 women.

Diagnosis of endometrial carcinomaEight diff erent endometrial thickness cut-off values were reported in the 20 studies. Sensiti vity, specifi city, negati ve predicti ve value and positi ve predicti ve value for the detecti on of endometrial carcinoma for each reported endometrial thickness cut-off value are reported in Table 4. Positi ve predicti ve values varied between 0 and 0.2 and negati ve predicti ve value, if esti mable, was 1. For the reported endometrial thickness cut-off s 4, 5 and 6 mm we were able to calculate a summary sensiti vity and specifi city for the detecti on of endometrial carcinoma, the remaining fi ve cut-off s were reported by one single study, for these cut-off s we were therefore unable to calculate summary sensiti vity and specifi city.

Chapter 8

104

Tabl

e 3.

Cha

ract

eris

tics

of s

tudi

es in

clud

ed fo

r es

timati

on o

f sen

sitiv

ity a

nd s

peci

ficity

of e

ndom

etri

al t

hick

ness

as

mea

sure

d by

tra

nsva

gina

l ultr

a-so

und

with

rega

rd to

pre

mal

igna

nt o

r mal

igna

nt e

ndom

etri

um in

asy

mpt

omati

c po

stm

enop

ausa

l wom

en n

ot u

sing

hor

mon

e re

plac

emen

t the

rapy

.

Pati

ents

< c

ut o

ffPa

tien

ts >

cut

off

Aut

hor

Year

Coun

try

nVe

rific

ation

m

etho

dPa

tien

ts

veri

fied

(n)

Cut-

off†

Tota

l (n)

Wit

h EC

(n)

Wit

h A

EH (n

)To

tal (

n)W

ith

EC (n

)W

ith

AEH

(n)

And

olf11

1993

Swed

en30

0D

&C

115

mm

289

NR

NR

110

0

Cohe

n2319

99U

SA60

EBP

605

mm

380

022

00

Exac

oust

os34

1996

Ital

y91

0H

yst +

bio

psy

838

mm

827

NR

NR

833

NR

Fern

ande

z3520

08Sp

ain

209

Hys

t + b

iops

y20

95

mm

NR

NR

NR

209

5N

R

Flei

sche

r3620

01U

SA19

26EB

NS

1792

6 m

m18

331

493

10

Gou

veia

2620

07Br

azil

47EB

P47

5 m

m28

0N

R19

1N

R

Gul

l1219

96Sw

eden

361

Hys

t + D

&C

188

mm

343

NR

NR

180

0

Güv

en13

2003

Turk

ey97

D&

C97

5 m

m75

00

220

0

Kasr

aeia

n1420

11Ir

an25

9H

yst +

bio

psy

259

5 m

m21

80

541

14

Mal

inov

a1519

96Bu

lgar

ia13

0D

&C

306

mm

95N

RN

R35

0N

R

Mar

ello

2920

00It

aly

328

Hys

t + b

iops

y32

84

mm

199

1N

R12

90

NR

Min

agaw

a1620

05Ja

pan

146

SC5

5 m

m14

1N

RN

R5

10

Para

skev

aidi

s3120

02G

reec

e59

EBK

599

mm

390

020

11

Pard

o3719

98Is

rael

85H

yst +

bio

psy

857

mm

NR

NR

NR

853

0

Psyl

laki

3820

10G

reec

e85

0H

yst +

D&

C14

95

mm

701

NR

NR

149

01

Ribe

iro39

2007

Braz

il39

9H

yst +

bio

psy

399

4 m

mN

RN

RN

R39

91

1

Schm

idt40

1999

Ger

man

y20

9H

yst +

D&

C20

96

mm

NR

NR

NR

209

84

Tsud

a3219

97Ja

pan

375

EES

+ EB

NS

375

3 m

m26

40

NR

111

1N

R

4 m

m31

21

NR

630

NR

6 m

m34

51

NR

300

NR

8 m

m35

21

NR

230

NR

10 m

m36

21

NR

130

NR

Vala

dare

s4120

05Po

rtug

al15

0H

yst +

bio

psy

150

4 m

mN

RN

RN

R15

02

NR

Zacc

hi42

*19

93It

aly

74H

yst +

bio

psy

68

mm

68N

RN

R6

00

*Sin

gle

laye

r mea

sure

men

t, v

alue

s rep

orte

d in

arti

cle

are

mul

tiplie

d by

two.

† The

repo

rted

num

ber i

s inc

lude

d in

the

cut-

off, i

.e. c

ut o

ff 5

mm

mea

ns E

T ≥

5mm

. EC,

end

omet

rial

car

cino

ma;

AEH

, at

ypic

al e

ndom

etri

al h

yper

plas

ia;T

VS, t

rans

vagi

nal u

ltras

onog

raph

y; E

T, e

ndom

etri

al t

hick

ness

; NR,

not

rep

orte

d; N

A, n

ot a

pplic

able

End

omet

rial

ver

ifica

tion

met

hods

: D&

C, d

ilata

tion

and

cure

ttag

e; E

B P,

end

omet

rial

bio

psy,

Pip

elle

; Hys

t, h

yste

rosc

opy;

EB

NS,

end

omet

rial

bio

psy

not s

peci

fied;

SC,

soft

cyto

; EB

K, e

ndom

etri

al b

iops

y, K

arm

an; E

ES, e

ndoc

yte

endo

met

rial

sam

pler

.


105

8

Table 4. Sensiti vity, specifi city, positi ve and negati ve predicti ve value of endometrial thickness as measured by transvaginal ultrasound with regard to endometrial carcinoma. Studies are grouped by reported cut-off value.

Study Year TP FP Fn Tn Sensiti vity Specifi city PPv nPv

Endometrial thickness cut-off 3 mm

Tsuda32 1997 1 110 0 264 1.00 (0.03-1.00) 0.71 (0.66-0.75) 0.009 1


Marello29 2000 0 129 1 198 0.00 (0.00-0.97) 0.61 (0.55-0.66) 0 1

Ribeiro39 2007 1 398 NR NR NE NE 0.003 NE

Tsuda32 1997 0 63 1 311 0.00 (0.00-0.97) 0.83 (0.79-0.87) 0 1

Valadares41 2005 2 148 NR NR NE NE 0.01 NE


Andolf11 1993 0 11 NR NR NE NE 0 NE

Cohen23 1999 0 22 0 38 NE 0.63 (0.50-0.75) 0 1

Fernandez35 2008 5 204 NR NR NE NE 0.02 NE

Gouveia26 2007 1 18 0 28 1.00 (0.03-1.00) 0.61 (0.45-0.75) 0.05 1

Guven13 2003 0 22 0 75 NE 0.77 (0.68-0.85) 0 1

Kasraeian14 2011 1 40 0 218 1.00 (0.03-1.00) 0.84 (0.79-0.89) 0.02 1

Minagawa16 2005 1 4 NR NR NE NE 0.2 NE

Psyllaki38 2010 0 149 NR NR NE NE 0 NE


Fleischer36 2001 1 92 1 1832 0.50 (0.01-0.99) 0.95 (0.94-0.96) 0.01 1

Malinova15 1996 0 35 NR NR NE NE 0 NE

Schmidt40 1999 8 201 NR NR NE NE 0.04 NE

Tsuda32 1997 0 30 1 344 0.00 (0.00-0.97) 0.92 (0.98-0.95) 0 1


Pardo37 1998 3 82 NR NR NE NE 0.04 NE


Exacoustos34 1996 3 80 NR NR NE NE 0.04 NE

Gull12 1996 0 18 NR NR NE NE 0 NE

Tsuda32 1997 0 23 1 351 0.00 (0.00-0.97) 0.94 (0.91-0.96) 0 1

Zacchi42 1993 0 6 NR NR NE NE 0 NE


Paraskevaidis31 2002 1 19 0 39 1.00 (0.03-1.00) 0.67 (0.54-0.79) 0.05 1


Tsuda32 1997 0 13 1 361 0.00 (0.00-0.97) 0.97 (0.94-0.98) 0 1

TP, true positi ve; FP, false positi ve; FN, false negati ve; TN, true negati ve; PPV, positi ve predicti ve value; NPV, negati ve predicti ve value; NR, not reported; NE, not esti mable.

Chapter 8

106

The summary estimate of the sensitivity for the different cut-offs varied between 0.00 and 0.83. The summary estimate of the specificity for the different cut-offs varied between 0.72 and 0.93 (Table 5). For the summary estimates of sensitivity and specificity as well as for the reported sensitivity and specificity, the 95% confidence intervals were very wide, indicating the high uncertainty surrounding these estimates.

Table 5. Summary estimates of sensitivity and specificity with regard to endometrial carcinoma for different transvaginal ultrasound derived endometrial thickness cutoff values.

Threshold mm No of studies No of women sens (95% CI) spec (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)

95% CI, 95% confidence interval; NE, not possible to estimate

Diagnosis of atypical endometrial hyperplasiaSix different endometrial thickness cut-off values were reported by 13 studies. The other seven studies did not report on an endometrial thickness cut-off for atypical endometrial hyperplasia. Sensitivity, specificity, 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 6. There were no cut-off values for which multiple studies reported sufficient data to calculate both sensitivity and specificity. Therefore, we were unable to calculate summary estimates of sensitivity and specificity for the different cut-off values for atypical endometrial hyperplasia. With regard to atypical endometrial hyperplasia, the range of sensitivity was 0.00–1.00 and the range of specificity was 0.63–0.95.

Diagnosis of combined (pre-) malignancyFor 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, specificity, 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 7. As for atypical endometrial hyperplasia, there were no cut-off values for which multiple studies reported


107

8

suffi cient data to calculate both sensiti vity and specifi city. Therefore, we were unable to calculate summary esti mates of sensiti vity and specifi city for the diff erent cut-off values for the combined outcome of (pre-) malignancy. With regard to the combined diagnosis of premalignant and malignant endometrium, the range of sensiti vity was 0.17–1.0 and the range of specifi city was 0.63–0.95.

Table 6. Sensiti vity, specifi city, positi ve and negati ve predicti ve value of endometrial thickness as measured by transvaginal ultrasound with regard to atypical endometrial hyperplasia. Studies are grouped by reported cut-off value.

Study Year TP FP Fn Tn Sensiti vity Specifi city PPv nPv





Cohen23 1999 0 22 0 38 NE 0.63 (0.50-0.75) 0 1

Guven13 2003 0 22 0 75 NE 0.77 (0.68-0.85) 0 1

Kasraeian14 2011 4 37 5 213 0.44 (0.14-0.79) 0.85 (0.80-0.89) 0.098 0.98

Minagawa16 2005 0 5 NR NR NE NE 0 NE

Psyllaki38 2010 1 148 NR NR NE NE 0.007 NE


Fleischer36 2001 0 93 4 1829 0.00 (0.00-0.60) 0.95 (0.94-0.96) 0 1



Pardo37 1998 0 85 NR NR NE NE 0 NE





Paraskevaidis31 2002 1 19 0 39 1.00 (0.03-1.00) 0.67 (0.54-0.79) 0.05 1

TP, true positi ve; FP, false positi ve; FN, false negati ve; TN, true negati ve; PPV, positi ve predicti ve value; NPV, negati ve predicti ve value; NR, not reported; NE, not esti mable.

Chapter 8

108

Table 7. Sensitivity, specificity, positive and negative predictive value of endometrial thickness as measured by transvaginal ultrasound with regard to endometrial malignancy /premalignancy. Studies are grouped by reported cut-off value.

Study Year TP FP Fn Tn Sensitivity Specificity PPv nPv





Cohen23 1999 0 22 0 38 NE 0.63 (0.50-0.75) 0 1

Guven13 2003 0 22 0 75 NE 0.77 (0.68-0.85) 0 1

Kasraeian14 2011 5 36 5 213 0.50 (0.19-0.81) 0.86 (0.81-0.90) 0.12 0.98

Minagawa16 2005 1 4 NR NR NE NE 0.2 NE

Psyllaki38 2010 1 148 NR NR NE NE 0.007 NE


Fleischer36 2001 1 92 5 1828 0.17 (0.00-0.64) 0.95 (0.94-0.96) 0.01 1



Pardo37 1998 3 82 NR NR NE NE 0.04 NE





Paraskevaidis31 2002 2 18 0 39 1.00 (0.16-1.00) 0.68 (0.55-0.80) 0.1 1

TP, true positive; FP, false positive; FN, false negative; TN, true negative; PPV, positive predictive value; NPV, negative predictive value; NR, not reported; NE, not estimable.

DISCuSSIOn

Our review shows that in a population of postmenopausal women without PMB and not using HRT, the mean endometrial thickness is 2.9 mm and the prevalence of endometrial carcinoma and atypical endometrial hyperplasia is 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 NPV 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 to symptomatic postmenopausal women where 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


109

8

(PMB) because a clinically substanti al reducti on in disease probability may be achieved by the use of TVS. This reducti on is typically from around 10% to below 1% for endometrial carcinoma,3 a probability threshold where fi rstly, the majority of clinicians recommend reassurance and no need for further evaluati on of the endometrium, and secondly, a post-TVS probability is demonstrated to be equivalent to the prevalence in asymptomati c postmenopausal female populati on.4-7 The strength of our analysis is the complete overview of data combining endometrial thickness, endometrial carcinoma and atypical endometrial hyperplasia in asymptomati c postmenopausal women without HRT. We describe mean endometrial thickness and the prevalence of endometrial (pre-) malignancies in these women. Furthermore, we assessed the diagnosti c accuracy of endometrial thickness measurements in this populati on. Eff orts were made to identi fy all available publicati ons on this subject and we used the most appropriate technique to summarize the sensiti vity and specifi city, to come to bett er esti mates than the formerly applied summary receiver operati ng characteristi c curve (sROC) technique for meta-regression in diagnosti c meta-analysis.10, 45-47 To our knowledge, there is no previously published review or meta-analysis on this subject.A limitati on of our study is that despite the thousands of women included in our analysis, the esti mates of sensiti vity and specifi city are very imprecise, especially the esti mates of sensiti vity. Another limitati on 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 asymptomati c 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 varied between 2.2% and 9.3%. In contrast to this analysis, which was a decision analysis in a theoreti cal cohort, we analyzed observati onal data. Unfortunately, we had insuffi cient data available from the published studies to calculate an opti mal threshold for endometrial thickness based on the sensiti vity and specifi city reported in the diff erent studies. Because of the low prevalence of the disease, the 95% CI for the summary esti mates of sensiti vity are very wide indicati ng a high inaccuracy. The use of TVS is not limited to women with PMB. The portability and improved resoluti on of TVS has contributed to the ubiquity of the test in routi ne gynecological practi ce. Postmenopausal women undergo TVS for a variety of gynecological indicati ons (e.g. pelvic pain, suspicion of a pelvic mass, uterine prolapse). During TVS for such non-bleeding indicati ons, images of the endometrium are frequently obtained and a thickened endometrium may be observed. This situati on of an apparently incidental fi nding of an abnormal endometrium will be familiar to all practi cing ultrasonographists. Faced with such

Chapter 8

110

a TVS finding, it is difficult for the physician to decide on the right management and usually results in a decision to undertake further, more invasive testing with endometrial sampling and / or hysteroscopy in keeping with current PMB pathways. Therefore, the findings 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 significance of an endometrial thickness beyond 4 mm is not the same as for a symptomatic PMB population and extrapolating protocols from PMB to an asymptomatic population is not justifiable in view of the poor performance of TVS in detecting serious endometrial disease at all cut-offs and the low overall disease prevalence. Because the prevalence of the target disease in an unselected postmenopausal population without bleeding symptoms and without HRT is very low, and endometrial thickness measurement in this population cannot achieve a sufficiently high sensitivity to provide additional reassurance to women with a negative test nor achieve a sufficiently high specificity 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 being asymptomatic have a prognostic advantage over postmenopausal endometrial cancer patients who visited their gynecologists immediately after bleeding had occurred.48 Thus, 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 any asymptomatic postmenopausal woman without 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 findings at physical examination, pelvic pain, distension, urinary and bowel complaints etc.), risk factors for endometrial disease (e.g. abnormal BMI, medical co-morbidities, family history etc.) and patient preference.49-54


111

8

REFEREnCES1. Brenner PF. Diff erenti al diagnosis of abnormal uterine bleeding. Am J Obstet Gynecol 1996;175(3 Pt 2):766-

769.

2. Parkin DM, Bray F, Ferlay J, Pisani P. Esti mati ng the world cancer burden: Globocan 2000. Int J Cancer 2001;94(2):153-156.

3. Smith-Bindman R, Kerlikowske K, Feldstein VA et al. Endovaginal ultrasound to exclude endometrial cancer and other endometrial abnormaliti es. JAMA 1998;280(17):1510-1517.

4. Epstein E. Management of postmenopausal bleeding in Sweden: a need for increased use of hydrosonography and hysteroscopy. Acta Obstet Gynecol Scand 2004;83(1):89-95.

5. Goldstein RB, Bree RL, Benson CB et al. Evaluati on of the woman with postmenopausal bleeding: Society of Radiologists in Ultrasound-Sponsored Consensus Conference statement. J Ultrasound Med 2001;20(10):1025-1036.

6. NVOG (Dutch Society of Obstetrics and Gynaecology). NVOG-richtlijn Abnormaal vaginaal bloedverlies in de menopauze [In Dutch]. NVOG Guideline: Abnormal vaginal bleeding during menopause . 2003.

7. Scotti sh Intercollegiate Guidelines Network. Investi gati on of postmenopausal bleeding. Scotti sh 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(5):558-565.

9. Whiti ng P, Rutjes AW, Reitsma JB, Bossuyt PM, Kleijnen J. The development of QUADAS: a tool for the quality assessment of studies of diagnosti c accuracy included in systemati c reviews. BMC Med Res Methodol 2003;3:25.

10. Reitsma JB, Glas AS, Rutjes AW, Scholten RJ, Bossuyt PM, Zwinderman AH. Bivariate analysis of sensiti vity and specifi city produces informati ve summary measures in diagnosti c reviews. J Clin Epidemiol 2005;58(10):982-990.

11. Andolf E, Dahlander K, Aspenberg P. Ultrasonic thickness of the endometrium correlated to body weight in asymptomati c postmenopausal women. Obstet Gynecol 1993;82(6):936-940.

12. Gull B, Karlsson B, Milsom I, Wikland M, Granberg S. Transvaginal sonography of the endometrium in a representati ve sample of postmenopausal women. Ultrasound Obstet Gynecol 1996;7(5):322-327.

13. Guven MA, Pata O, Bakaris S, Kafk asli A, Mgoyi L. Postmenopausal endometrial cancer screening: is there a correlati on between transvaginal sonographic measurement of endometrial thickness and body mass index? Eur J Gynaecol Oncol 2004;25(3):373-375.

14. Kasraeian M, Asadi N, Ghaff arpasand F, Karimi AA. Value of transvaginal ultrasonography in endometrial evaluati on of non-bleeding postmenopausal women. Climacteric 2011;13(6):126-131.

15. Malinova M, Pehlivanov B. Transvaginal sonography and progesterone challenge for identi fying endometrial pathology in postmenopausal women. Int J Gynaecol Obstet 1996;52(1):49-53.

16. Minagawa Y, Sato S, Ito M, Onohara Y, Nakamoto S, Kigawa J. Transvaginal ultrasonography and endometrial cytology as a diagnosti c schema for endometrial cancer. Gynecol Obstet Invest 2005;59(3):149-154.

17. Neele SJ, Marchien van BW, van der Mooren MJ, Kessel H, Netelenbos JC, Kenemans P. Ultrasound assessment of the endometrium in healthy, asymptomati c early post-menopausal women: saline infusion sonohysterography versus transvaginal ultrasound. Ultrasound Obstet Gynecol 2000;16(3):254-259.

18. Osmers R, Volksen M, Rath W, Teichmann A, Kuhn W. [Vaginosonographic measurement of the postmenopausal endometrium in the early detecti on of endometrial cancer]. Geburtshilfe Frauenheilkd 1989;49(3):262-265.

19. Pirhonen JP, Vuento MH, Makinen JI, Salmi TA. Long-term eff ects of hormone replacement therapy on the uterus and on uterine circulati on. Am J Obstet Gynecol 1993;168(2):620-630.

20. Warming L, Ravn P, Skouby S, Christi ansen C. Measurement precision and normal range of endometrial thickness in a postmenopausal populati on by transvaginal ultrasound. Ultrasound Obstet Gynecol 2002;20(5):492-495.

21. Bortolett o CC, Baracat EC, Goncalves WJ, Lima GR, Stavale JN. Transvaginal ultrasonography and the progestogen challenge test in postmenopausal endometrial evaluati on. Int J Gynaecol Obstet 1997;58(3):293-298.

22. Buccoliero AM, Caldarella A, Noci I et al. [Thin-layer cytology in endometrial diagnosis]. Pathologica 2003;95(4):179-184.

Chapter 8

112

23. Cohen MA, Sauer MV, Keltz M, Lindheim SR. Utilizing routine sonohysterography to detect intrauterine pathology before initiating hormone replacement therapy. Menopause 1999;6(1):68-70.

24. Elewa AMA. Correlation of vaginal ultrasound and hysteroscopy with endometrial histopathology in postmenopausal women. Middle East Fertility Society Journal 2001;6(1):26-33.

25. Gol K, Saracoglu F, Ekici A, Sahin I. Endometrial patterns and endocrinologic characteristics of asymptomatic menopausal women. Gynecol Endocrinol 2001;15(1):63-67.

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(4):344-348.

27. Langer RD, Pierce JJ, O’Hanlan KA et al. Transvaginal ultrasonography compared with endometrial biopsy for the detection of endometrial disease. Postmenopausal Estrogen/Progestin Interventions Trial. N Engl J Med 1997;337(25):1792-1798.

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(2):145-149.

29. Marello F, Bettocchi S, Greco P et al. Hysteroscopic evaluation of menopausal patients with sonographically atrophic endometrium. J Am Assoc Gynecol Laparosc 2000;7(2):197-200.

30. Martinez-Rubio MP, Alcazar JL. Ultrasonographic and pathological endometrial findings in asymptomatic postmenopausal women taking antihypertensive drugs. Maturitas 2003;46(1):27-32.

31. Paraskevaidis E, Papadimitriou D, Kalantaridou SN et al. Screening transvaginal uterine ultrasonography for identifying endometrial pathology in postmenopausal women. Anticancer Res 2002;22(4):2517-2520.

32. Tsuda H, Kawabata M, Yamamoto K, Inoue T, Umesaki N. Prospective study to compare endometrial cytology and transvaginal ultrasonography for identification of endometrial malignancies. Gynecol Oncol 1997;65(3):383-386.

33. 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(4):218-223.

34. Exacoustos C, Chiaretti M, Minghetti MC, Bianchi L, Arduini D, Romanini C. Endometrial Evaluation in Asymptomatic Postmenopausal Women by Transvaginal Sonography and Color Flow Doppler. J Am Assoc Gynecol Laparosc 1996;3(4, Supplement):S12.

35. Fernandez Parra JGP. Endometrial alterations on ultrasonography in asymptomatic postmenopausal women. Progresos en Obstetricia y Ginecologia 2008;51(7):398-403.

36. Fleischer AC, Wheeler JE, Lindsay I et al. An assessment of the value of ultrasonographic screening for endometrial disease in postmenopausal women without symptoms. Am J Obstet Gynecol 2001;184(2):70-75.

37. Pardo J, Aschkenazi S, Kaplan B, Orvieto R, Nitke S, Ben-Refael Z. Abnormal sonographic endometrial findings in asymptomatic postmenopausal women: possible role of antihypertensive drugs. Menopause 1998;5(4):223-225.

38. Psyllaki AN, I. Transvaginal sonographic prognostic value to detect endometrial pathology in postmenopausal asymptomatic women without hormone replacement therapy. Archives of Gynecology and Obstetrics 2010;Conference(Deutsche Gesellschaft fur Gynakologie und Geburtshilfe, DGGG):Munich-S112.

39. Ribeiro CT, Rosa-E-Silva JC, Silva-de-Sa MF et al. Hysteroscopy as a standard procedure for assessing endometrial lesions among postmenopausal women. Sao Paulo Med J 2007;125(6):338-342.

40. Schmidt TR. The role of hysteroscopy in the management of asymptomatic postmenopausal patients with suspicious ultrasound findings of the uterine endometrium - Correlation with sonographic and histologic findings. Geburtshilfe und Frauenheilkunde 1999;59(4):163-166.

41. Valadares S.Coutinho. Ambulatory hysteroscopy results post-menopause: Comparative study between patients with and without metrorrhagia. Gynecological Surgery 2005;2(4):259-263.

42. Zacchi V, Zini R, Canino A. [Transvaginal sonography as a screening method for the identification of patients at risk of postmenopausal endometrial pathology]. Minerva Ginecol 1993;45(7-8):339-342.

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(3):345-349.

44. Emanuel M, Verdel M, Wamsteker K, Lammes F. An audit of true prevalence of intrauterine pathology: the hysteroscopic findings, controled for patient selection in 1202 patients with abnormal uterine bleeding. Gynaecol Endosc 1995;4:237-241.


113

8

45. Deeks JJ. Systemati c reviews in health care: Systemati c reviews of evaluati ons of diagnosti c and screening tests. BMJ 2001;323(7305):157-162.

46. Leefl ang MM, Deeks JJ, Gatsonis C, Bossuyt PM. Systemati c reviews of diagnosti c test accuracy. Ann Intern Med 2008;149(12):889-897.

47. Shapiro DE. Issues in combining independent esti mates of the sensiti vity and specifi city of a diagnosti c test. Acad Radiol 1995;2 Suppl 1:S37-S47.

48. Gerber B, Krause A, Muller H et al. Ultrasonographic detecti on of asymptomati c endometrial cancer in postmenopausal pati ents off ers no prognosti c advantage over symptomati c disease discovered by uterine bleeding. Eur J Cancer 2001;37(1):64-71.

49. Anderson KE, Anderson E, Mink PJ et al. Diabetes and endometrial cancer in the Iowa women’s health study. Cancer Epidemiol Biomarkers Prev 2001;10(6):611-616.

50. McPherson CP, Sellers TA, Pott er JD, Bosti ck RM, Folsom AR. Reproducti ve factors and risk of endometrial cancer. The Iowa Women’s Health Study. Am J Epidemiol 1996;143(12):1195-1202.

51. Timmermans A, Opmeer BC, Veersema S, Mol BW. Pati ents’ preferences in the evaluati on of postmenopausal bleeding. BJOG 2007;114(9):1146-1149.

52. van Doorn LC, Dijkhuizen FP, Kruitwagen RF, Heintz AP, Kooi GS, Mol BW. Accuracy of transvaginal ultrasonography in diabeti c or obese women with postmenopausal bleeding. Obstet Gynecol 2004;104(3):571-578.

53. Weiderpass E, Persson I, Adami HO, Magnusson C, Lindgren A, Baron JA. Body size in diff erent periods of life, diabetes mellitus, hypertension, and risk of postmenopausal endometrial cancer (Sweden). Cancer Causes Control 2000;11(2):185-192.

54. Xu WH, Xiang YB, Ruan ZX et al. Menstrual and reproducti ve factors and endometrial cancer risk: Results from a populati on-based case-control study in urban Shanghai. Int J Cancer 2004;108(4):613-619.

Chapter 8

114

APPEnDIX

Appendix 1. Search Strategy

Medline#1. Postmenopause [MeSH]#2. Postmenopau* [tiab]#3. Post-menopau* [tiab]#4. #1 OR #2 OR #3#5. Asymptomatic [tiab]#6. Screening [tiab]#7. #5 OR #6#8. #4 AND #7#9. Ultrasonography [MeSH]#10. Utrasound* [tiab]#11. Ultrasonograph* [tiab]#12. Sonograph* [tiab]#13. Echograph* [tiab]#14. Ultrasonic imaging* [tiab]#15. #9 OR #10 OR #11 OR #12 OR #13 OR #14#16. Endometrium [MeSH]#17. Endometrial thickness [tiab]#18. #16 OR #17#19. #15 AND #18#20. #19 AND #8#21. Endometrial neoplasms [MeSH]#22. Endometrial neoplasm* [tiab]#23. Endometrial carcinoma* [tiab]#24. Endometrial cancer* [tiab]#25. Endometrial malignanc* [tiab]#26. Endometrial tumo* [tiab]#27. #21 OR #22 OR #23 OR #24 OR #25 OR #26#28. Endometrial hyperplasia [MeSH]#29. Endometrial hyperplasia* [tiab]#30. #28 OR # 29#31. #27 OR #30#32. # 8 AND # 31#33. # 20 OR # 32

Embase#1. Postmenopausal#2. Postmenopau$.ti,ab#3. Post-menopau$.ti,ab#4. #1 OR #2 OR #3#5. Asymptomatic.ti,ab#6. Screening.ti,ab#7. #5 OR #6#8. #4 AND #7#9. Ultrasound$.ti,ab#10. Ultrasonograph$.ti,ab#11. Sonograph$.ti,ab#12. Echograph$.ti,ab#13. Ultrasonic imaging$.ti,ab#14. #9 OR #10 OR #11 OR #12 OR #13#15. Endometri$.ti,ab#16. Endometrial thickness.ti,ab#17. #15 OR #16#18. # 14 AND #17#19. #18 AND #8#20. Endometrial carcinoma$.ti,ab#21. Endometrial neoplasm$.ti,ab#22. Endometrial cancer$.ti,ab#23. Endometrial malignanc$.ti,ab#24. Endometrial tumo$.ti,ab#25. #20 OR #21 OR #22 OR #23 OR #24#26. Endometrial hyperplasia$.ti,ab#27. #25 OR #26#28. #8 AND #27#29. #19 OR #28


115

8

Appendix 2. QUADAS checklist

Item Questi on Answer

Yes no Unclear

1 Was the spectrum of pati ents representati ve of the pati ents who will receive the test in practi ce?

2 Were selecti on criteria clearly described?

3 Is the reference standard likely to correctly classify the target conditi on?

4 Is the ti me period between reference standard and index test short enough to be reasonably sure that the target conditi on did not change between the two tests?

5 Did the whole sample or a random selecti on of the sample, receive verifi cati on using a reference standard of diagnosis?

6 Did pati ents receive the same reference standard regardless of the index test result?

7 Was the reference standard independent of the index test?

8 Was the executi on of the index test described in suffi cient detail to permit replicati on of the test?

9 Was the executi on of the reference standard described in suffi cient detail to permit its replicati on?

10 Were the index test results interpreted without knowledge of the results of the reference standard?

11 Were the reference standard results interpreted without knowledge of the results of the index test?

12 Were the same clinical data available when test results were interpreted as would be available when the test is used in practi ce?

13 Were uninterpretable / intermediate test results reported?

14 Were withdrawals from the study explained?

uva-dare (digital academic repository) management of ... · biopsy should be performed.8 they...

Documents