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Review
Endovaginal Ultrasound to Exclude
Endometrial Cancer and
Other Endometrial Abnormalities
Rebecca Smith-Bindman, MD; Karla Kerlikowske, MD; Vickie A. Feldstein, MD; Leslee Subak, MD;
Juergen Scheidler, MD; Mark Segal, PhD; Richard Brand, PhD; Deborah Grady, MD
Context.—Postmenopausal vaginal bleeding is a common clinical problem. En-
dovaginal ultrasound (EVUS) is a noninvasive diagnostic test that may help deter-
mine which women should undergo endometrial biopsy.
Objective.—To determine the accuracy of EVUS in detecting endometrial dis-
ease in postmenopausal women with vaginal bleeding according to hormone
replacement use.
Data Sources.—Literature search of English-language and non–English-
language articles published from 1966 through November 1996 using MEDLINE
and by a manual search of bibliographies of published articles.
Study Selection.—Studies were included if they prospectively collected EVUS
measurements of endometrial thickness prior to obtaining endometrial tissue for
histologic evaluation in postmenopausal women with vaginal bleeding. Of 85 stud-
ies that included data on EVUS and endometrial histology, 35 were included in the
meta-analysis and included 5892 women.
Data Extraction.—Articles were reviewed and independently selected and ab-
stracted by 2 reviewers. Disagreement was resolved by consensus.
Data Synthesis.—The overall summary mean weighted estimates of sensitivity
and specificity were calculated for thresholds of endometrial thickness from 3 to 10
mm.Usinga5-mmthresholdtodefineabnormalendometrialthickening,96%(95%
confidence interval [CI], 94%-98%) of women with cancer had an abnormal EVUS
result, whereas 92% (95% CI, 90%-93%) of women with endometrial disease
(cancer, polyp, or atypical hyperplasia) had an abnormal result. This did not vary
by hormone replacement use. However, the number of women with normal histol-
ogy who had an abnormal EVUS result did vary by hormone replacement use. In
women who were not using hormone replacement therapy, 593 (8%) with normal
histological findings had an abnormal EVUS result (specificity, 92%; 95% CI, 90%-
94%), whereas 1544 (23%) using hormone replacement therapy had an abnormal
EVUS result (specificity, 77%; 95% CI, 75%-79%). For a postmenopausal woman
with vaginal bleeding with a 10% pretest probability of endometrial cancer, her
probability of cancer is 1% following a normal EVUS result.
Conclusion.—Endovaginal ultrasound has a high sensitivity for detecting endo-
metrial cancer and other endometrial disease and can reliably identify postmeno-
pausal women with vaginal bleeding who are highly unlikely to have significant en-
dometrial disease so that endometrial sampling may be unnecessary.
JAMA. 1998;280:1510-1517
From the General Internal Medicine Section, San
Francisco Veterans Affairs Medical Center, San
Francisco, Calif (Drs Smith-Bindman, Kerlikowske,
and Grady); Departments of Radiology (Drs
Smith-Bindman, Scheidler, and Feldstein), Epidemiol-
ogy and Biostatistics (Drs Kerlikowske, Segal, Brand,
and Grady), and Obstetrics, Gynecology, and Repro-
ductive Sciences (Dr Subak), University of California,
San Francisco. Dr. Scheidler is now with the Depart-
ment of Diagnostic Radiology, University of Munich, Mu-
nich, Germany.
Reprints: Rebecca Smith-Bindman, MD, Department
of Radiology, University of California, San Francisco/Mt
Zion Medical Center, 1600 Divisidero St, San Francisco,
CA 94115 (e-mail: Rebecca.Smith-Bindman@Radiology
.UCSF.edu).
ENDOMETRIAL cancer is the fourth
most common malignancy in women in
the United States, with more than 36 000
cases and 6300 deaths occurring annu-
ally.1The majority of women with endo-
metrial cancer are postmenopausal and
present with vaginal bleeding. In most
women with abnormal vaginal bleeding,
endometrial sampling with an endome-
trial biopsy or dilatation and curettage
is performed. Endometrial cancer has
been detected in 5% to 60% of postmeno-
pausal women with vaginal bleeding, de-
pending on age and other risk factors.2-5
Office-based endometrial biopsy tech-
niques are uncomfortable,4,6,7 cannot be
performed or are nondiagnostic in 2% to
28% of attempts,4-6,8-11,12 and often yield
an inaccurate diagnosis, particularly for
women with endometrial polyps.13,14
For editorial comment see p 1529.
During the last decade, endovaginal
ultrasound (EVUS) has become widely
used to evaluate the endometrium in
postmenopausal women with vaginal
bleeding. Endovaginal ultrasound uses
an ultrasound probe that is placed di-
rectly in the vagina to obtain detailed
images of the endometrium. Thin endo-
metrium is generally considered normal,
whereas thickened endometrium may
represent cancer, hyperplasia, or polyps.
The chief goal of an EVUS examination
of the endometrium is to exclude patho-
logical conditions and thereby make en-
dometrial sampling unnecessary.
Many published studies have assessed
the accuracy of EVUS in evaluating
the endometrium for malignancy.3,11,13-96
While it has been suggested that cancer
can be excluded with a high degree of con-
fidence when the endometrial thickness is
less than 3 mm, a few studies have re-
ported cancer in women with a thin endo-
1510 JAMA, November 4, 1998—Vol 280, No. 17 Endovaginal Ultrasound to Exclude Endometrial Cancer—Bindman et al
©1998 American Medical Association. All rights reserved.
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metrial measurement.17,38,79 However,
most studies of the diagnostic accuracy of
EVUS have been small and included few
women with cancer. Additionally, studies
applied different thresholds of endome-
trial thickness for calling an EVUS result
abnormalandmany havenotreported the
results separately in women receiving
hormone replacement therapy.
To enhance the precision of estimates
of the accuracy of EVUS, we conducted
a critical review of the literature and
used meta-analytic techniques to deter-
mine the accuracy of EVUS in diagnos-
ing endometrial pathological conditions
in postmenopausal women with vaginal
bleeding according to hormone replace-
ment therapy use. Our main goal was to
determine if EVUS can reliably identify
women who are highly unlikely to have
significant endometrial disease and
therefore need no further evaluation.
METHODS
Data Sources
We performed a literature search us-
ing the MEDLINE database of all stud-
ies published from January 1966 through
November 1996 and manually searched
bibliographies of published articles.
MEDLINE search terms included en-
dometrium, endometrial cancer, ultra-
sound, endovaginal ultrasound, trans-
vaginal ultrasound, vaginal bleeding,
dilatation and curettage, and endome-
trial biopsy. Review articles, letters,
case reports, and comments were ex-
cluded. English-language and non–En-
glish-language articles were included.
We identified 85 studies that included
data on EVUS and endometrial sam-
pling. Of these, 12 were in German, 5 Ital-
ian, 3 French, 1 Chinese, 1 Dutch, and
the remainder in the English language.
Study Selection
Articles were independently selected
and reviewed by 2 reviewers. Studies
that prospectively evaluated EVUS on
patients prior to obtaining endometrial
tissue(endometrial biopsy, dilatation and
curettage, or hysterectomy) were in-
cluded. Retrospective studies,19,33,34,62,72,77
studies with selective histological sam-
pling,23,24,29,39,52,62,69 studies that reported
results pooled for premenopausal and
postmenopausal women,42,71,84,97 and stud-
ies that measured endometrial thickness
following tissue sampling13,17,23,42,49,58,62
were excluded. In addition, studies that
evaluated EVUS only in asymptomatic
women,16,35,67,69,81,93,98,99 women receiving
tamoxifen,31,32,51,56,59,75 and women with
known endometrial cancer43,58,100,101; stud-
ies not reporting endovaginal thickness
measurements15,26,52,71,72,74,76,77; and studies
where the crude data could not be ex-
tracted19,21,24,39,42,48,52,72,81,85,97 were ex-
cluded. When we could not extract data
from published articles, we wrote to the
correspondingauthor to obtain additional
information (18 authors, 5 of whom re-
sponded). Additional nonpublished re-
sults were obtained from 2 authors, and
these are included in our analysis with
publishedresults by the same authors.20,61
For studies that resulted in multiple pub-
lications, data from the most recent pub-
lication were used.34,69
Data Abstraction
We defined endometrial thickness as the
width of the combined thickness of the an-
terior and posterior sides of the endome-
trium. When a single-wall measurement
was reported, we doubled the measure-
ment. Three outcomes were considered:
cancer, benign endometrial abnormali-
ties (atypical and complex hyperplasia or
polyps), and normal (atrophy, normal). En-
dometrial disease was defined as includ-
ing cancer and benign endometrial abnor-
malities. Within each study, cases of
cervical cancer and cervical polyps were
excluded. For each outcome, 2 authors ab-
stracted and recorded the number of true-
positive, false-positive, true-negative, and
false-negative cases using all reported
thickness thresholds (3, 4, 5, 6, 7, 8, 9, and
10 mm). We also abstracted the mean en-
dometrial thickness among women with
atrophic endometrium, hyperplasia or pol-
yps, and cancer. For each study we also
recorded mean age, the number of wom-
en using hormone replacement therapy,
the number of women with vaginal bleed-
ing, frequency of the ultrasound probe,
whether fluid within the endometrial cav-
ity was included, and whether “,”or“#”
was considered as the dividing point be-
tween normal and abnormal. We also re-
corded the number of women who could
not tolerate or who had a nondiagnostic
EVUS result. Discrepancies among re-
viewers were resolved by consensus.
Data Synthesis
For each study, the sensitivity, speci-
ficity, and exact 95% confidence inter-
vals (CIs) were calculated for all EVUS
thickness measurements. When studies
did not explicitly state hormone replace-
ment therapy use,16,53,54,63,70,80,83,90 we ana-
lyzed these articles with those that in-
cluded women using hormone replace-
ment therapy, as we assumed some
women may have been using hormone
replacement therapy. In the studies that
included women using hormone replace-
ment therapy, the percentage of these
women varied from 3% to 60%.
Studies used endometrial thickness
measurements of 3 to 10 mm to define an
abnormal EVUS test result. Before we
combined the results across studies, we
tested whether there was a trade-off be-
tween sensitivity and specificity for each
thickness threshold.102 We found there
was no correlation of sensitivity and
specificity within any of the individual
thickness measurements used to define
abnormal (for example, #5 mm) across
the different studies. Therefore, we cal-
culated mean weighted pooled estimates
of sensitivity and specificity for each
threshold, for any endometrial disease,
and for cancer alone.
The summary estimates were calcu-
lated as a weighted average. Individual
study findings were weighted by sample
size.For example, the summary weighted
sensitivity was calculated as the sum of
the sensitivities reported for each study
multiplied by the number of subjects in
that study, divided by the total number of
subjects in all of the studies: S[(sensitivi-
tyi)(ni)]/(n1+n
2+ ... n
i
). Sensitivity for
cancer was weighted by the number of
cases of cancer, sensitivity for endome-
trial disease was weighted by the number
of endometrial abnormalities, and speci-
ficity was weighted by the number of nor-
mal women without endometrial abnor-
malities. The 95% CIs for the mean
weighted results were calculated using
exact methods.
A test for homogeneity was performed
to evaluate the consistency of findings
across studies. We used the CIs of the
individual study findings to determine if
the results were homogeneous; if the 95%
CI from a study did not overlap the
weighted summary point estimate, the
result of that study was considered het-
erogeneous.103 Possible reasons for het-
erogeneity, such as whether the study
was published in the English languge or a
non–English language, use of hormone
replacement therapy, patient symptoms,
whetherfluid within the endometrial cav-
ity was included or excluded in determin-
ing endometrial thickness, and specialty
of the examiner were studied by strati-
fying the summary estimate according to
these factors to determine if homogene-
ity improved.
Positive and negative likelihood ratios
were calculated for each endometrial
thickness. The posttest risk of endome-
trial disease was calculated using the 5-
mm-thicknessthreshold, varying the pre-
test risk of disease from 1% to 50%. A
summary receiver operating character-
istic curve (ROC) was generated using
the data from all thresholds using the
methodof Moses and colleagues104 to com-
bine the results across the range of endo-
metrial thicknesses. We tested for differ-
ences between the summary ROC curves
of women who used hormone replace-
ment therapy and women who did not.
We also tested for differences between
the summary ROC curves of women who
JAMA, November 4, 1998—Vol 280, No. 17 Endovaginal Ultrasound to Exclude Endometrial Cancer—Bindman et al 1511
©1998 American Medical Association. All rights reserved.
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used hormone replacement therapy and
women in whom hormone replacement
therapy use was not stated.
We excluded many studies on the ba-
sis of methodologic criteria. A sensitiv-
ity analysis was performed to determine
if including these studies would have had
a significant impact on the overall re-
sults. All studies that were excluded
were included in the sensitivity analysis
if data could be extracted (n = 8), except
studies that evaluated EVUS in asymp-
tomatic women as a screening test for
cancer and studies that evaluated EVUS
in women receiving tamoxifen.
RESULTS
A total of 35 studies (14 non–English
language) including 5892 women met in-
clusion criteria (Table 1). The mean age of
the women was 61 years, and 94% were
symptomatic with vaginal bleeding. The
prevalence of endometrial cancer was
13% and of endometrial polyps or hyper-
plasia 40%. Within the studies that in-
cluded women using hormone replace-
ment therapy, 471 (26%) of the 1781 wom-
en were currently using such therapy.
Sixteen studies reported the number of
women who could not tolerate EVUS
(mean, 0; SD, 2%) and 14 studies reported
the number of women who had a nondi-
agnostic EVUS result (mean, 0; SD, 2%).
The mean (SD) endometrial thickness
was 4 (1) mm for women with normal
histological findings, 10 (3) mm for wom-
en with endometrial polyps, 14 (4) mm
for women with hyperplasia, and 20 (6)
mm for women with cancer.
Sensitivity
Endovaginal ultrasound was better at
detecting cancer than it was at detecting
polyps or hyperplasia (Table 2). For ex-
ample, using a 5-mm threshold, 96% (95%
CI, 94%-98%) of women with cancer had
an abnormal EVUS result, whereas 92%
(95% CI, 90%-93%) of women with endo-
metrial disease had an abnormal EVUS
result. Endovaginal ultrasound was
equally accurate at identifying women
with endometrial disease regardless of
whether they were using hormone re-
placement therapy (Table 3). For ex-
ample, at a 5-mm thickness, EVUS
identified 95% (95% CI, 93%-97%) of
endometrial disease among women not
using hormone replacement therapy, and
91% (95% CI, 89%-93%) of endometrial
disease among women who were using
hormone replacement therapy.
Specificity
In general, specificity was higher for
endometrial disease than cancer (Table
2). For all endometrial thickness thresh-
Table 1.—Prospective Studies ComparingEndovaginal UltrasoundMeasurements WithEndometrial Histologyin PostmenopausalWomen Included in Meta-analysis
Source, y
No. (%)
Endometrial Thickness
Cutoffs, mm‡
Vaginal
Bleeding Hormone Replacement
Therapy*Endometrial
Disease† Cancer
Abu Hmeidan et al,16 1992§ 545 (100) NS 274 (50) 86 (16) 5
Aleem et al,18 1995 42 (33) 0 23 (55) 14 (33) 8
Auslender et al,20 1993 134 (100) 0 66(49) 16 (12) 3, 4, 5, 6, 7, 8, 10
Botsis et al,22 1992 120 (100) 0 22 (18) 8 (7) 5, 10
Brolmann et al,27 1993§ 54 (100) 0 32 (59) 10 (19) 6, 8
Cacciatore et al,28 1994 45 (100) 20 (44) 23 (51) 4 (9) 5
Chan et al,30 1994 67 (100) 0 29 (43) 17 (25) 4, 5, 6, 7
Degenhardt et al,36 1991§ 37 (100) NS 37 (27)\37 (100) 6
Dijkhuizen et al,37 1996 69 (100) 0 31 (45) 8 (12) 6, 8, 10
Dorum et al,38 1993 100 (100) 12 (12) 25 (25) 15 (15) 5
Goldstein et al,44 1990 28 (100) 18 (64) 6 (21) 1 (4) 5
Granberg et al,45 1991 175 (100) 0 48 (27) 18 (10) 5
Hanggi et al,50 1995§ 89 (100) 0 25 (28) 21 (24) 5
Karlsson et al,53 1993 105 (100) NS 35 (33) 15 (14) 5
Karlsson et al,54 1994 51 (100) NS 35 (69) 0 (0) 4
Karlsson et al,55 1995 1129 (100) 351 (31) 385 (34) 114 (10) 4, 5, 6, 7
Klug and Leitner,57 1989§ 179 (100) 11 (6) 21 (12) 8 (4) 5, 10
Malinova and Pehlivanov,61 1995 118 (100) 0 81 (69) 57 (48) 5, 6, 7, 8
Mascaretti et al,63 1993§ 25 (100) NS 6 (24) 3 (12) 4
Nasri and Coast,64 1989 90 (100) 3 (3) 25 (28) 6 (7) 5, 6
Nasri et al,65 1991 59 (100) 0 22 (37) 7 (12) 5, 6
Osmers et al,68 1990 98 (100) 0 65 (66) 13 (13) 6
Osmers et al,70 1992§ 233 (100) NS 158 (68) 27 (12) 6
Pertl et al,73 1996§ 150 (100) 35 (23) 67 (45) 19 (13) 5, 10
Schramm et al,79 1995§ 195 (100) 0 107 (55) 29 (15) 4
Seelbach-Gobel et al,80 1995§ 232 (100) NS 100 (43) 39 (17) 6, 8
Smith et al,82 1991 45 (100) 12 (27) 9 (20) 4 (9) 6
Taviani et al,83 1995§ 41 (100) NS 16 (39) 2 (5) 5
Van den Bosch etal,87 1995 126 (100) 0 56 (44) 6 (5) 4
Varner et al,88 1991 15 (100) 9 (60) 6 (40) 2 (13) 4, 5, 6
Volgger et al,89 1996§ 380 (44) NS 174 (46) 41 (11) 6
Weigel et al,90 1990§ 101 (58) NS 48 (48) 15 (15) 3, 6, 8
Weigel et al,91 1995 200 (50) 0 112 (56) 37 (19) 4, 5, 6, 7
Wolman et al,92 1996 54 (100) 0 18 (33) 4 (7) 4, 5, 6, 7
Zannoni et al,95 1994§ 761 (100) 0 181 (24) 56 (7) 4
Total 5892 (94) 2368 (40) 759 (13)
*NS indicates not stated.
†Includes cancer, atypical and complex hyperplasia, and polyps in this definition of endometrial disease.
‡Thickness threshold used to define an abnormal test result.
§Non–English-language studies.
\Overall, 137 patients were included in this study (prevalence of cancer, 37/137), although only the results for cancer were abstracted and included in Table 2. These patients
were not included in the calculations of any endometrial disease.
1512 JAMA, November 4, 1998—Vol 280, No. 17 Endovaginal Ultrasound to Exclude Endometrial Cancer—Bindman et al
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olds tested, specificity was better among
women who did not use hormone re-
placement therapy (Table 3). For ex-
ample, using a 5-mm thickness, among
women with normal histological find-
ings, 23% (95% CI, 21%-25%) of women
using hormone replacement therapy had
an abnormal EVUS result, whereas only
8% (95% CI, 6%-10%) of women who
were not using hormone replacement
therapy had an abnormal EVUS result.
Homogeneity
The estimates for sensitivity were
highly consistent across studies. For ex-
ample, for the outcome of cancer, using
the 5-mm thickness, the studies were ho-
mogeneous. For the outcome of any en-
dometrial disease, 2 of 20 studies were
heterogeneous (Figure 1, A). In con-
trast, the specificity estimates were in-
consistent across studies. For example,
at a thickness threshold of 5 mm, 7 of the
20 articles were heterogeneous for the
outcome of cancer, and 8 of the 20 ar-
ticles were heterogeneous for the out-
come of any endometrial disease (Figure
1, B). The estimates of specificity became
less heterogeneous when the studies
were stratified by use of hormone re-
placement therapy (Figure 2, A, and 2,
B). Heterogeneity improved among
women who were not using hormone re-
placement therapy (Figure 2, A) but re-
mained among women who used hor-
mone replacement therapy (Figure 2, B).
Stratifying by other factors, including
whether studies were English language
or non–English language, patient symp-
toms, specialty of the examiner, whether
fluid was included or excluded from the
endometrial thickness measurement,
whether a single or double wall measure-
ment was used, and whether “,”or“#”
was used as the upper limit of normal did
not improve consistency across studies.
Summary ROC Curves
Changing the threshold of endome-
trial thickness used to define an abnor-
mal examination resulted in the ex-
pected trade-off between sensitivity and
specificity. (There was no trade-off
within the individual thickness thresh-
olds.) By increasing the thickness used
to define an abnormal EVUS result,
more abnormalities were missed, but
there were fewer false-positives (Table
2). For example, at a 3-mm cutoff, the
test detected 98% of women with endo-
metrial disease, but identified 38% of
women with normal histological findings
as abnormal. At a 10-mm thickness the
test detected fewer women with disease
(66%) and identified fewer women with
normal histological findings as abnormal
(12%). In general, EVUS was more ac-
curate in women who were not using hor-
mone replacement therapy (Table 3).
The summary ROCs that combine data
from all of the thickness thresholds were
significantly different between women
who were using hormone replacement
therapy and women who were not (P= .02;
Figure 3), and there was greater accu-
racy among women who were not using
hormone replacement therapy. The sum-
mary ROCs were not significantly differ-
ent among women who were using hor-
mone replacement therapy and women in
whom hormone replacement therapy use
was not stated (P= .36).
Positive and Negative Likelihood
Ratios and the Risk of Abnormality
Because the sensitivity of EVUS did
not vary significantly with hormone use,
EVUS is equally accurate in excluding
endometrial disease regardless of hor-
mone use. For example, at a 5-mm
threshold, the negative likelihood ratio
was 0.05 for women who did not use hor-
mone replacement therapy and 0.12 for
Table 2.—Summary Sensitivity and Specificity for Endometrial Disease and Cancer Using Different Endovaginal Thickness Measurements to Define an Abnormal
Result*
Threshold,
mm‡
Endometrial Disease† Cancer
No. of
Women§ Sensitivity
(95% CI), % No. of
Women§ Specificity
(95% CI), % No. of
Women§ Sensitivity
(95% CI), % No. of
Women§ Specificity
(95% CI), %
3 114 98 (94-100) 121 62 (53-71) 31 100 (89-100) 204 38 (32-45)
4\1001 91 (89-93) 1756 69 (67-71) 284 96 (93-98) 2422 53 (51-55)
5 1306 92 (90-93) 2137 81 (79-83) 457 96 (94-98) 2986 61 (59-63)
6¶ 1361 87 (85-89) 1717 82 (80-84) 454 95 (92-97) 2661 55 (53-57)
7# 691 85 (82-88) 1011 90 (88-92) 131 95 (89-98) 442 64 (59-69)
8** 381 85 (81-88) 369 80 (75-84) 151 97 (92-99) 530 60 (56-64)
10** 207 66 (59-73) 445 88 (85-91) 51 90 (79-97) 532 79 (75-82)
*CI indicates confidence interval.
†Includes cancer, atypical and complex hyperplasia, and polyps in this definition of endometrial disease.
‡Thickness threshold used to define an abnormal test result.
§The number of women for whom data were available.
\Results from Karlsson et al54 are included only for endometrial disease.
¶Results from Dengenhardt et al36 are not included for endometrial disease.
#Results from Karlsson et al55 are not included for cancer.
**Results from Dijkhuizen et al37 are not included for cancer.
Table 3.—Accuracy of Endovaginal Ultrasound for Detecting Endometrial Disease, Stratified by Hormone Replacement Therapy at Various Endometrial
Thickness Thresholds*
Thickness, mm Hormone Replacement
Therapy No. of
Women† Sensitivity
(95% CI), % No. of
Women† Specificity
(95% CI), % Positive
Likelihood Ratio Negative
Likelihood Ratio
3 No 66 98 (92-100) 68 71 (58-81) 3.4 0.03
Yes 48 98 (89-100) 53 51 (37-65) 2.0 0.04
4 No 569 86 (83-89) 968 70 (67-73) 2.9 0.20
Yes 432 97 (95-98) 788 68 (65-71) 3.0 0.04
5 No 423 95 (93-97) 593 92 (90-94) 11.9 0.05
Yes 883 91 (89-93) 1544 77 (75-79) 4.0 0.12
6 No 456 89 (86-92) 397 90 (87-93) 8.9 0.12
Yes 905 86 (84-88) 1320 79 (77-81) 4.1 0.18
7 No 306 88 (84-91) 267 95 (92-97) 17.6 0.13
Yes 385 83 (79-87) 744 88 (85-90) 6.9 0.19
*Endometrial disease includes cancer, atypical and complex hyperplasia, and polyps. CI indicates confidence interval.
†The number of women for whom data were available.
JAMA, November 4, 1998—Vol 280, No. 17 Endovaginal Ultrasound to Exclude Endometrial Cancer—Bindman et al 1513
©1998 American Medical Association. All rights reserved.
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women who used hormone replacement
(Table 3). Thus, a woman with a 10% pre-
test probability of endometrial disease
has a 1% risk of disease following a nor-
mal EVUS result (Table 4). Because
specificity of EVUS varied with hor-
mone use, the ability of EVUS to predict
endometrial disease varies by hormone
therapy use. At a 5-mm threshold, the
positive likelihood ratio was 11.9 among
women who did not use hormone re-
placement but only 4.0 among women
who used hormone replacement (Table
3). Thus, a woman with a 10% pretest
probability of any endometrial disease
has a 57% risk of disease following an
abnormal EVUS result if she is not using
hormone replacement therapy but only
a 31% risk of disease if she is using hor-
mone replacement therapy (Table 4).
The risk of having endometrial disease
following a normal and abnormal EVUS
result is shown for a range of pretest
probabilities (Table 4).
Sensitivity Analysis
Inclusion of results from excluded
studies had little impact. For example,
at a threshold of 5 mm, the sensitivity for
cancer alone was 96% among the in-
cluded studies (n = 457) and was 95%
among the excluded studies (n = 75).
Similarly at 5 mm, the specificity for can-
cer alone was 61% among the included
studies (n = 2986) and was 59% among
the excluded studies (n = 719). One study
contributed approximately 25% of the
patients to the pooled results.55 When
the findings of this article were elimi-
nated, the results changed slightly; the
sensitivity for endometrial disease de-
creased from 92% to 88%, and the sensi-
tivity for cancer alone decreased from
96% to 95%.
COMMENT
We found that EVUS is a sensitive
test for detecting endometrial disease.
Using a thickness of 5 mm, the sensitiv-
ity for detecting any endometrial dis-
ease was 92%, and the sensitivity for de-
tecting cancer was 96%. These estimates
did not vary by use of hormone replace-
ment therapy. The high sensitivity of
EVUS makes it an excellent noninva-
sive test for determining which women
with vaginal bleeding do not require en-
dometrial biopsy. The specificity is low,
and thus ultrasound is not very accurate
in predicting endometrial disease.
Therefore, an abnormal EVUS result in
a woman with vaginal bleeding needs to
be followed by a histological biopsy.
Like all techniques, EVUS imaging
will fail to detect cancer and other ab-
normalities in some women. However, a
false-negative rate of 8% must be com-
pared with endometrial biopsy tech-
niques. Office-based endometrial biopsy
devices, the most commonly used means
to sample the endometrium, have false-
negative rates of 5% to 15%,4-7,105-107 and
dilation and curettage, an invasive pro-
cedure, has false-negative rates of 2% to
6%.106,108-111 It is not surprising that
EVUS misses fewer abnormalities than
office-based endometrial biopsy because
ultrasound imaging allows visualization
of the entire endometrial cavity,
whereas most biopsy techniques rely on
blind sampling.7,105,106,109-111 This meta-
analysis suggests that the sensitivity of
EVUS is at least as good as office-based
endometrial biopsy techniques.
There are several benefits of EVUS
compared with endometrial biopsy. En-
dovaginal ultrasound is less invasive,
well tolerated, generally painless, with-
out complications, and nondiagnostic in
a small percentage of cases. Some wom-
en cannot undergo successful office en-
dometrial biopsy secondary to cervical
stenosis because of a small introitus,
pain, or intolerance of the procedure. An
invasive dilatation and curettage is then
required to obtain a diagnosis. Post-
menopausal women with vaginal bleed-
ing often undergo multiple biopsies, be-
cause insufficient tissue is obtained for
diagnosis or because of recurrent bleed-
ing.40 A negative EVUS could reduce the
need to undergo multiple biopsies. En-
dovaginal ultrasound is well suited to
evaluate persistent bleeding despite a
histological diagnosis of atrophy. A thin
endovaginal thickness measurement
supports the diagnosis of atrophy,
whereas a thickened measurement
would suggest that there was inade-
quate sampling of the endometrium and
that a pathologic diagnosis may have
been missed.13,14 Lastly, the cost of
EVUS has compared favorably with en-
dometrial biopsy in the evaluation of
postmenopausal bleeding.12
Ultrasound cannot discriminate be-
tween proliferative endometrium, be-
nign endometrial disease, and cancer, all
of which cause an increase in endome-
trial thickness. Because postmenopausal
0 0.2 0.4
Summary Estimate (95% CI)
Abu Hmeidan et al16
Auslender et al20
Botsis et al22
Cacciatore et al28
Chan et al30
Dorum et al38
Goldstein et al44
Granberg et al45
Hanggi et al50
Karlsson et al53
Karlsson et al55
Klug and Leitner57
Malinova and Pehlivanov61
Nasri and Coast64
Nasri et al65
Pertl et al73
Taviani et al83
Varner et al88
Weigel et al91
Wolman et al92
0.6
Sensitivity (95% CI) 1.00.1 0.3 0.5 0.80.7 0.9 0 0.2 0.4
Summary Estimate (95% CI)
Abu Hmeidan et al16
Auslender et al20
Botsis et al22
Cacciatore et al28
Chan et al30
Dorum et al38
Goldstein et al44
Granberg et al45
Hanggi et al50
Karlsson et al53
Karlsson et al55
Klug and Leitner57
Malinova and Pehlivanov61
Nasri and Coast64
Nasri et al65
Pertl et al73
Taviani et al83
Varner et al88
Weigel et al91
Wolman et al92
0.6
Specificity (95% CI) 1.00.1 0.3 0.5 0.80.7 0.9
A B
Figure 1.—Sensitivity (A) and specificity (B) for endometrial disease using a 5-mm endometrial thickness. CI indicates confidence interval. The vertical line rep-
resents the summary estimate (95% CI).
1514 JAMA, November 4, 1998—Vol 280, No. 17 Endovaginal Ultrasound to Exclude Endometrial Cancer—Bindman et al
©1998 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ on 02/25/2013
hormone replacement therapy may
cause proliferation of the endometrium,
EVUS is less specific in women using
hormone replacement therapy. The fact
that different regimens of estrogen and
progestins affect the endometrium dif-
ferently may account for the variability
in reported specificity of EVUS in wom-
en using hormone replacement therapy.
Additionally, the different rates of re-
ported hormone replacement therapy
use may have contributed to the vari-
ability in reported specificity. It is pos-
sible that if 100% of the women were us-
ing hormone replacement therapy that
the specificity would be substantially
less than we report.
Fewer than half of the studies re-
ported the rate of nondiagnostic EVUS
examinations. A nondiagnostic test may
occur more often in women with inva-
sive carcinoma in whom the endometrial
cavity can be difficult to visualize. In
cases where the endometrium is incom-
pletely visualized, it is important for the
examination to be interpreted as nondi-
agnostic. In these cases, dilation and cu-
rettage, hysteroscopy, sonohysterogra-
phy, or magnetic resonance imaging can
be performed to further evaluate the en-
dometrium.
Positive and negative likelihood ratios
can be used to estimate a patient’s post-
test probability of disease. The positive
likelihood ratio is used to calculate the
probability of disease after a positive test
result (rule in disease), whereas the nega-
tive likelihood ratio is used to calculate the
probability of disease after a negative test
result (rule out disease). At a 5-mm-
thickness cutoff, the negative likelihood ra-
tios were approximately 0.1 regardless of
hormone use. Thus, a negative EVUS re-
sult can decrease a pretest odds of cancer
by approximately 90% in women regard-
less of hormone use. A woman with a 1%
risk of cancer, which is the risk associated
with vaginal bleeding in a postmeno-
pausal woman using combined hormone re-
placement therapy, will have a 0.1% risk
of cancer following a negative ultrasound
examination result. A woman with a 10%
pretest probability of cancer, which is the
risk associated with vaginal bleeding in a
postmenopausal woman who is not using
hormone replacement therapy, will have
a 1% probability of cancer following a nega-
tive ultrasound examination result.
Tests of homogeneity are important
in evaluating the appropriateness of
combining the results of different stud-
ies. We found that the sensitivity of
EVUS was high, independent of hor-
mone replacement therapy, and consis-
tent across studies. One study contrib-
uted the majority of the heterogeneity
noted for the estimate of sensitivity.79
The low sensitivity for detecting endo-
metrial disease using the 4-mm cutoff
(Tables 2 and 3) is a reflection of this
study. If this study was excluded, the
sensitivity for endometrial disease im-
proved from 92% to 94% using the 4-mm
cutoff. One study contributed approxi-
mately 25% of the patients in our pooled
results.55 When this study was excluded,
the results changed only slightly.
We excluded studies that evaluated the
endometrium in women taking tamoxi-
fen, which causes marked thickening of the
endometrium and increases the risk of en-
04080
0
20
40
60
80
100
False-Positive Rate, %
Sensitivity, %
10020 60
Hormone Replacement Therapy
No Hormone Replacement Therapy
Figure 3.—Summary receiver operating curves stratified by hormone replacement therapy use.
Table 4.—Risk of a Woman Having Endometrial
Disease Following an Endovaginal Ultrasound
(EVUS) Using a Cutoff of 5 mm to Define an Ab-
normal Test Result, Stratified by Hormone
Replacement Therapy (HRT) Use and Pretest
Probability of Disease*
HRT Pretest
Probability, %
Posttest Probability of
Endometrial Disease
After an EVUS, %
Normal
Result Abnormal
Result
No 1 0.1 11
Yes 0.1 4
No 5 0.3 39
Yes 0.6 17
No 10 0.6 57
Yes 1.3 31
No 20 1.3 75
Yes 2.9 50
No 50 5.1 92
Yes 11.0 80
*Includes cancer, atypical and complex hyperplasia,
and polyps in this definition of endometrial disease.
0 0.2 0.4
Summary Estimate (95% CI)
Auslender et al20
Botsis et al22
Chan et al30
Granberg et al45
Hanggi et al50
Malinova and Pehlivanov61
Nasri and Coast65
Weigel et al91
Wolman et al92
0.6
Specificity (95% CI) 1.00.1 0.3 0.5 0.80.7 0.9 0 0.2 0.4
Summary Estimate (95% CI)
Abu Hmeidan et al16
Cacciatore et al28
Dorum et al38
Goldstein et al44
Karlsson et al54
Karlsson et al55
Klug and Leitner57
Nasri and Coast64
Pertl et al73
Taviani et al83
Varner et al88
0.6
Specificity (95% CI) 1.00.1 0.3 0.5 0.80.7 0.9
A B
Figure 2.—Specificity for endometrial disease (A, without hormone replacement therapy; B, with horomone replacement therapy) using a 5-mm endometrial thick-
ness. CI indicates confidence interval. The vertical line represents the summary estimate (95% CI).
JAMA, November 4, 1998—Vol 280, No. 17 Endovaginal Ultrasound to Exclude Endometrial Cancer—Bindman et al 1515
©1998 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ on 02/25/2013
dometrial abnormality.41,112 We did not in-
clude the results of studies that focused
on the use of EVUS as a screening test
for cancer in asymptomatic women be-
cause endometrial cancer is rare, most
women with endometrial cancer have
vaginal bleeding, and the false positives
would outnumber the true positives in an
asymptomatic population.96
While we included 2 unpublished stud-
ies, we may have missed other unpub-
lished work with negative results, whose
inclusion may have lowered overall test
accuracy. However, it is unlikely that we
missed any large studies, and smaller
studies are unlikely to substantially af-
fect the results. Additionally, the results
may reflect the accuracy of specialized
centers that have published data, and
this may inflate the accuracy available in
a general community setting.
In summary, we found that a thin
(#5-mm) endometrial measurement on
EVUS can exclude endometrial disease
in the majority of postmenopausal wom-
en with vaginal bleeding, regardless of
hormone replacement use. Endovaginal
ultrasound has similar sensitivity as en-
dometrial biopsy and can be used when
endometrial biopsy is not available, non-
diagnostic, or unsuccessful.
We thank Warren Browner, MD, and Andrew
Bindman, MD, for their review of the manuscript
and Loreto Carmona, MD, for her helpful review of
studies included in the meta-analysis.
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