YGYNO-977823; No.

of pages: 10; 4C:

Gynecologic Oncology xxx (xxxx) xxx

Contents lists available at ScienceDirect

Gynecologic Oncology

journal homepage: www.elsevier.com/locate/ygyno

Review Article

Ultrasound detection of endometrial cancer in women with postmenopausal bleeding:

Systematic review and meta-analysis☆
Beverly Long a,⁎, Megan A. Clarke b, Arena Del Mar Morillo b, Nicolas Wentzensen b, Jamie N. Bakkum-Gamez c
a
Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, George Washington University School of Medicine and Health Sciences, Washington, DC, United States of America
b
Clinical Epidemiology Unit, Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics (DCEG), National Cancer Institute (NCI), Bethesda, MD, United States of America
c
Department of Obstetrics and Gynecology, Division of Gynecologic Oncology Surgery, Mayo Clinic, Rochester, MN, United States of America

H I G H L I G H T S

• Fewer than 10% of women with PMB will be diagnosed with malignancy.
• A cut-off of ≥ 5 mm can detect endometrial cancer with a sensitivity of 96.3% and specificity of 21%.
• Endometrial volume, vascular flow index, vascular index, and flow index do not improve endometrial cancer detection.

a r t i c l e i n f o a b s t r a c t

Article history: Objective. To assess the performance of endometrial thickness (ET) cut-offs for detecting endometrial cancer
Received 25 November 2019 (EC) in women with postmenopausal bleeding (PMB) and evaluate the clinical utility of additional ultrasound
Received in revised form 16 January 2020 measures such as endometrial volume (EV), vascular flow index (VFI), vascularization index (VI), and uterine ar-
Accepted 20 January 2020
tery flow index (FI).
Available online xxxx
Methods. Clinicaltrials.gov and MEDLINE database via PubMed were queried for studies published between 1/
Keywords:
1990 and 3/2016 using specific MeSH terms. Original, peer-reviewed cohort studies reporting EC outcomes and
Ultrasound specific ultrasound findings by PMB status were included.
Postmenopausal bleeding Results. Study design, country, clinical setting inclusion/exclusion criteria, aggregate study-level demographic
Endometrial cancer and clinical data were extracted from 44 studies including 17,339 women with PMB and 1341 cases of EC (7.7%).
In women with PMB and EC (n = 417), pooled mean ET was 16.4 mm (95% CI, 14.8–18.1 mm). In women with
PMB without EC, pooled mean ET was 4.1 mm. 31 studies reported outcomes using different ET cut-off values
ranging from 3 to 20 mm. Compared to ≥3 or 4 mm, a cutoff of ≥5 mm had similar sensitivity (96.2, 95%CI
92.3, 98.1) with improved specificity for EC (51.5, 95%CI 42.3–60.7), allowing to reduce the rate of invasive
workup for PMB by 17%. EV, VI, VFI, and FI were significantly correlated with EC, but performance of specific
cut-offs was not analyzed due to limited data.
Conclusion. Among women with PMB mean ET is substantially higher in women with EC compared to those
without EC. An ET cutoff of ≥5 mm shows an acceptable tradeoff between sensitivity and specificity for diagnosis
of EC.
© 2020 Elsevier Inc. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2. Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2.1. Data sources and searches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2.2. Study selection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2.3. Data extraction and quality assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

☆ The authors report no conflicts of interest.

⁎ Corresponding author at: 2150 Pennsylvania Ave NW Ste 6A, Washington, DC 20035, United States of America.
E-mail address: Belong@mfa.gwu.edu (B. Long).

https://doi.org/10.1016/j.ygyno.2020.01.032
0090-8258/© 2020 Elsevier Inc. All rights reserved.

Please cite this article as: B. Long, M.A. Clarke, A.D.M. Morillo, et al., Ultrasound detection of endometrial cancer in women with postmenopausal
bleeding: Systematic review ..., Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2020.01.032
2 B. Long et al. / Gynecologic Oncology xxx (xxxx) xxx

2.4. Data synthesis and analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

3. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3.1. Quality of included studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3.1.1. Summary of QUADAS assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3.2. Endometrial thickness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3.3. Influence of study characteristics on endometrial thickness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3.4. Diagnostic accuracy of endometrial thickness for endometrial cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3.5. Influence of study characteristics and small-sample size effects (cut-off ≥ 5 mm) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3.6. Other ultrasound findings associated with endometrial cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3.6.1. Endometrial volume . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3.6.2. Vascularization index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3.6.3. Vascularity flow index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3.6.4. Flow index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
4. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Author contributions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Funding source . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

1. Introduction 2.2. Study selection

Postmenopausal bleeding (PMB) is a common condition, affect-
ing approximately 10% of postmenopausal women [1]. While its
work up requires ruling out endometrial cancer (EC), most PMB
has a benign etiology, and fewer than 10% of women with PMB will
be diagnosed with cancer [2]. Still, prompt work up is crucial since
five-year survival for patients with localized EC is approximately
95%, while regional and distant metastases decrease survival to
under 70% and 20%, respectively [3]. Transvaginal ultrasound
(TVUS) is usually the first step in the diagnostic work-up of PMB, as
specific ultrasound findings such as thickened endometrium, endo-
metrial fluid, or abnormal vascularity have been associated with an
increased risk of EC [4–11]. However, invasive diagnostic procedures
(endometrial biopsy (EMB), hysteroscopy, and/or dilation and curet-
tage) are necessary for definitive diagnosis. These procedures are as-
sociated with cost, patient discomfort, potential exposure to
anesthesia, and surgical risks including uterine perforation or infec-
tion [12]. Because EC risk is low in the setting of a thin endometrium,
many experts recommend a minimum cut-off for endometrial thick-
ness, below which invasive testing can be avoided [4–7]. However,
optimal cut-offs can be difficult to determine and may vary between
populations, since EC risk varies based on population characteristics
[2]. Few studies have examined the performance of other ultrasound
findings such as endometrial volume (EV), vascular flow index (VFI),
vascularization index (VI), and uterine artery flow index (FI) to de-
tect EC.
The primary objective of this systematic review and meta-analysis
was to evaluate the diagnostic accuracy of endometrial thickness at var-
ious cut-offs compared to endometrial sampling results to define a low
risk population among women with PMB in which further testing can be
avoided. We also reviewed the literature to identify studies reporting
specific ultrasound findings (EV, VFI, VI, and FI) to determine whether
these parameters can improve detection of EC beyond endometrial
thickness alone.
2. Methods
2.1. Data sources and searches
Our search was limited to English-language, peer-reviewed studies
published before March 2016. We searched the MEDLINE database via
PubMed as well as clinicaltrials.gov using combinations of the medical
subject headings (MeSH) and keyword search terms described in Sup-
plement 1. We also reviewed references from eligible articles for addi-
tional relevant studies.
This systematic review and meta-analysis was performed in accor-
dance with the Preferred Reporting Items for Systematic Reviews and
Meta-Analyses (PRISMA) guidelines [13]. Studies were included in this
analysis if they reported a mean endometrial thickness with a measure
of variance (standard error), and the measurement of endometrial
thickness was well-described/carried out with TVUS. All studies used
histological assessment of the endometrium for diagnosis. To estimate
diagnostic accuracy of endometrial thickness, we included a subset of
these studies that reported performance estimates for specific endome-
trial thickness cut-offs to detect EC. Articles were independently
screened for inclusion by ADM and BL using study titles and abstracts.
Studies were included if they contained original data and reported out-
comes by PMB status. Studies of pre- and postmenopausal women were
included if findings were reported separately by menopausal status, and
only the subset of postmenopausal women was included in the analysis.
In order to obtain representative prevalence estimates of EC, we ex-
cluded case series, case-control studies, and randomized controlled tri-
als. In the case of sequential or multiple publications where there was a
possibility of overlapping data, only data from the most recent or largest
publication were included.
2.3. Data extraction and quality assessment
Data abstraction was carried out by ADM, BL, and MC. Title, lead au-
thor, study design, country, clinical setting inclusion/exclusion criteria,
aggregate study-level demographic data (age, body max index (BMI)),
years since menopause, frequency of bleeding, use of hormone replace-
ment therapy (HRT) and/or tamoxifen, and histology were included
when available. Geographical regions were defined by the World Health
Organization criteria when more than one country was represented.
Studies were considered to be cohort studies if follow-up time was
specified, and further classified as retrospective or prospective, depend-
ing on the timing of study initiation and outcome and exposure assess-
ment, respectively. Data were recorded in a pre-defined spreadsheet. All
data were publicly-available/published, and Institutional Review Board
(IRB) approval was not required.
The quality of selected studies was independently evaluated by BL
and MC using the Quality Assessment of Diagnostic Accuracy Studies
(QUADAS) checklist [14]. The resulting QUADAS scores for each study
are presented in Supplement Material 2. Studies were considered to
have the potential for verification bias if disease verification
(e.g., EMB) differed based on TVUS results or if there was insufficient in-
formation to rule out potential verification bias (i.e., studies that

Please cite this article as: B. Long, M.A. Clarke, A.D.M. Morillo, et al., Ultrasound detection of endometrial cancer in women with postmenopausal
bleeding: Systematic review ..., Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2020.01.032
 B. Long et al. / Gynecologic Oncology xxx (xxxx) xxx 3

recorded a “no” or “unclear” on item #6 of the QUADAS checklist). Sen-
sitivity analyses were performed with and without these studies.
2.4. Data synthesis and analysis
A pooled estimate of the mean endometrial thickness overall and by
EC status was calculated using a random effects model with inverse var-
iance weighting and visualized using forest plots. The percentage of
total variation across studies due to heterogeneity was assessed with
the I2 index [15]. To estimate diagnostic accuracy of endometrial thick-
ness for EC, we selected studies that reported at least one cut-off value
for endometrial thickness for calculation of sensitivity and specificity
for the diagnosis of EC in women with PMB. We extracted information
on the number of true positives, false negatives, false positives, and
true negatives according to each reported endometrial thickness cut-
off. Calculations of summary sensitivity and specificity estimates for en-
dometrial thickness cut-offs required data from a minimum of four
studies and were carried out using a bivariate random effects model
with a bivariate normal model for the sensitivity and specificity be-
tween studies, fit with the Stata metandi and gllam packages [16–18].
If the study reported more than one cutoff, we estimated sensitivity
and specificity values for each reported cutoff. Sensitivity and specificity
estimates for each study were plotted in a summary receiver operator
characteristic (ROC) plot, where each point on the curve represents a
different study, weighted according to sample size. Crude estimates of
positive and negative predictive values were calculated by summing
the total of true positives, false positives, true negatives, and false nega-
tives across studies for a given cut-off. We calculated Youden's index for
each cutoff by adding the pooled sensitivity and specificity estimates for
each cutoff and subtracting one.
To evaluate potential sources of heterogeneity in our estimates, we
performed subgroup analyses according to exclusion criteria based on
hormone replacement therapy (HRT) and/or tamoxifen use, geographic
region, and publication date (b2000, ≥2000 based on median publica-
tion date (2000)) and we used meta-regression analyses to evaluate
the influence of continuous variables including mean age of study par-
ticipants. For the analysis of other abnormal ultrasound findings, we
used descriptive statistics and analysis of variance (ANOVA) tests
weighted by the sample size to summarize mean differences in
women with EC compared to those without EC. Spearman correlation
coefficients were used to assess the correlation between endometrial
thickness and other ultrasound findings to determine whether these
findings could potentially contribute information about EC risk inde-
pendent of endometrial thickness.
3. Results
An initial PubMed search identified 3203 titles. After review of ab-
stracts and removal of duplicates, the remaining 332 full text articles
were reviewed. Of these, 151 original studies met inclusion criteria,

Fig. 1. Articles identified and assessed for eligibility.

Please cite this article as: B. Long, M.A. Clarke, A.D.M. Morillo, et al., Ultrasound detection of endometrial cancer in women with postmenopausal
bleeding: Systematic review ..., Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2020.01.032
4 B. Long et al. / Gynecologic Oncology xxx (xxxx) xxx

Table 1
Study characteristics and exclusion criteria.

Author Year Country N EC EC prevalence Patient exclusion criteria

cases (%)

Osmers 1990 Germany 103 13 12.6 HRT

Granberg 1991 Sweden 205 18 8.8
Karlsson 1995 Sweden/Denmark 1138 114 10.0
Malinova 1995 Bulgaria 118 57 48.3
Emanual 1995 Netherlands 47 7 14.9
Chan 1994 Hong Kong 67 17 25.4 HRT
Sladkevicius 1994 Sweden 132 24 18.2
Dorum 1993 Norway 100 15 15.0
Wolman 1996 Israel 54 4 7.4 HRT, pelvic abnormalities on ultrasound
Ferrazzi 1996 Italy 930 107 11.5 HRT
Guner 1996 Turkey 192 19 9.9
Grigoriou 1996 Greece 250 24 9.6
GuisaChiferi 1996 Brazil 80 19 23.8
Gruboeck 1996 United Kingdom 97 11 11.3
Haller 1996 Croatia 81 16 19.8 HRT
Fistonic 1997 Croatia 103 14 13.6 HRT
Kekre 1997 India 44 8 18.2 HRT
O'connell 1998 United States 100 5 5.0
Weber 1998 Germany 159 62 39.0 HRT
Buyuk 1999 Turkey 54 9 16.7
Bakour 1999 United Kingdom 96 11 11.5
Amit 2000 United States 60 11 18.3
Sousa 2001 Portugal 69 9 13.0
Randelzhofer 2002 Germany 321 95 29.6 HRT, tamoxifen
Auslander 1993 Isreal 129 16 12.4 HRT
Bruchim 2004 Isreal 95 9 9.5 HRT
Phillip 2004 Jamaica 75 8 10.7 HRT, tamoxifen, serious medical conditions
Minagawa 2005 Japan 39 7 17.9
Taskin 2006 Turkey 103 9 8.7 HRT, tamoxifen
Sadoon 2009 United Kingdom 136 7 5.1 HRT, tamoxifen
Mansour 2007 Saudi Arabia 170 27 15.9 HRT
Tinelli 2008 Italy 752 18 2.4
Tsikouras 2008 Greece 275 18 6.5 HRT, tamoxifen, serious medical conditions,
known gynecologic malignancy
Ewies 2010 United Kingdom 326 18 5.5
Burbos 2010 United Kingdom 3548 201 5.7
Lee 2011 Korea 112 2 1.8
Menzies 2011 Canada 268 14 5.2 Tamoxifen
Cho 2013 Korea 163 17 10.4 Hematologic disease, non-uterine pelvic disease
Wong AW 2016 China 4383 168 3.8
Van den Bosch 2015 Belgium 454 30 6.6
Kim 2015 Korea 174 28 16.1
Seckin 2016 Turkey 274 8 2.9
Ozer 2016 Turkey 43 2 4.7 HRT, tamoxifen, fibroids, serious medical conditions,
vaginal bleeding from a non-uterine source
Ciatto 2002 Italy 1220 45 3.7
Total 17,339 1341 7.7

and 44 of these studies reported summary statistics for endometrial
thickness (Fig. 1). A search of clinicaltrials.gov did not return any addi-
tional studies with reported or published results available for analysis.
Thus, a total of 44 studies including 17,339 women with postmeno-
pausal bleeding from 25 countries were available for this analysis
(Table 1) [19–57,64–67].
3.1. Quality of included studies
3.1.1. Summary of QUADAS assessment
All included studies were considered moderate/good quality
(QUADAS score N 7; Supplement 2). The most common source of bias
was non-blinding to ultrasound results at the time of histologic assess-
ment. Other potential sources of bias included lack of information re-
garding withdrawals from the studies and/or the interval between
ultrasound and histologic diagnosis.
3.2. Endometrial thickness
Data on mean endometrial thickness in all women with PMB were
available from 10 studies from 9 countries and included a total of 1025
women ([19–28]; Fig. 2). Among these studies, the pooled estimate of
mean endometrial thickness was 9.3 mm (95% CI, 8.0–10.5 mm) with
an I2 = 91.9% (p-heterogeneityb0.001). In 20 studies from 14 countries
reporting a mean (±SD) endometrial thickness among 3440 women
with PMB and EC (n = 418, 12.2%), the pooled mean endometrial thick-
ness was 16.4 mm (95% CI, 14.8–18.1 mm) with an I2 = 82.8% (p-
heterogeneityb0.001) [9,20–22,24,27,29–42]. Among the 17 studies
from 13 countries reporting a mean (±SD) endometrial thickness for
women with PMB without EC (n = 1797) the pooled mean endometrial
thickness was 4.1 mm (95% CI, 3.5–4.7 mm) with an I2 = 98.4% (p-
heterogeneityb0.001) [9,20,22,23,25,29–31,33,34,36–42].
3.3. Influence of study characteristics on endometrial thickness
We did not observe a significant association between age and endo-
metrial thickness among all women with postmenopausal bleeding.
Among women with EC, endometrial thickness did not differ based on
year of publication (prior to 2000 vs. after 2000, p = 0.175). However,
among women without EC, endometrial thickness was significantly
higher in studies published after the year 2000. For studies published be-
fore the year 2000, endometrial thickness among women without EC

Please cite this article as: B. Long, M.A. Clarke, A.D.M. Morillo, et al., Ultrasound detection of endometrial cancer in women with postmenopausal
bleeding: Systematic review ..., Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2020.01.032
 B. Long et al. / Gynecologic Oncology xxx (xxxx) xxx 5

(a) Pooled Mean ET in Studies Reporting Mean (SD) for Women with PMB

Study

ID Mean ET (95% CI)

O'connell (1998) 7.60 (6.68, 8.52)

Weber (1998) 14.80 (13.04, 16.56)

Sousa, R (2001) 10.30 (7.73, 12.87)

Phillip (2004) 6.78 (5.73, 7.83)

Bruchim (2004) 7.30 (6.44, 8.16)

Minagawa (2005) 7.20 (5.44, 8.96)

Mansour (2007) 8.75 (8.14, 9.36)

Lee (2011) 9.40 (7.75, 11.05)

Cho (2013) 9.80 (8.95, 10.65)

Ozer (2016) 11.40 (10.35, 12.45)

Overall (I-squared = 91.9%, p = 0.000) 9.25 (8.04, 10.45)

NOTE: Weights are from random effects analysis

0 5 10 15 20

(b) Pooled Mean ET in Studies Reporting Mean (SD) for Endometrial Cancer Cases

Study
ID Mean ET (95% CI)

Granberg (1991) 18.20 (15.34, 21.06)

Auslander (1993) 18.10 (13.59, 22.61)
Chan F (1994) 10.08 (5.17, 14.99)
Karlsson (1995) 21.10 (18.93, 23.27)
Malinova (1995) 18.40 (16.27, 20.53)
Emanuel (1995) 14.30 (11.04, 17.56)
Guner (1996) 22.70 (18.11, 27.29)
Gruboeck (1996) 29.50 (22.06, 36.94)
Grigoriou (1996) 16.50 (14.02, 18.98)
Wolman (1996) 12.40 (7.21, 17.59)
Haller (1996) 22.00 (17.39, 26.61)
Fistonic (1997) 14.10 (12.79, 15.41)
Kekre (1997) 12.56 (8.50, 16.62)
O'connell (1998) 17.70 (9.90, 25.50)
Sousa, R (2001) 21.40 (15.19, 27.61)
Bruchim (2004) 10.30 (7.95, 12.65)
Minagawa (2005) 15.03 (10.24, 19.82)
Tsikouras (2008) 12.33 (8.53, 16.13)
Cho (2013) 16.00 (12.88, 19.12)
Kim A (2015) 14.29 (12.96, 15.62)
Overall (I-squared = 82.8%, p = 0.000) 16.43 (14.79, 18.07)

NOTE: Weights are from random effects analysis

0 5 10 15 20 25 30 35 40

Fig. 2. Mean endometrial thickness (ET) for women with PMB, with PMB and EC, and with PMB without EC.

Please cite this article as: B. Long, M.A. Clarke, A.D.M. Morillo, et al., Ultrasound detection of endometrial cancer in women with postmenopausal
bleeding: Systematic review ..., Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2020.01.032
6 B. Long et al. / Gynecologic Oncology xxx (xxxx) xxx

(c) Pooled Mean ET in Studies Reporting Mean (SD) for Non-Endometrial Cancer Cases

Study
ID Mean ET (95% CI)

Granberg (1991) 3.40 (3.23, 3.57)

Auslander (1993) 2.60 (2.34, 2.86)
Chan F (1994) 1.14 (0.82, 1.46)
Malinova (1995) 3.10 (2.67, 3.53)
Emanuel (1995) 2.70 (2.45, 2.95)
Gruboeck (1996) 5.30 (4.46, 6.14)
Grigoriou (1996) 3.40 (3.24, 3.56)
Wolman (1996) 4.00 (3.47, 4.53)
Haller (1996) 4.00 (3.56, 4.44)
Fistonic (1997) 6.20 (5.68, 6.72)
Kekre (1997) 2.30 (2.14, 2.46)
O'connell (1998) 4.40 (4.02, 4.78)
Phillip (2004) 3.90 (2.87, 4.93)
Bruchim (2004) 6.20 (5.31, 7.09)
Mansour (2007) 4.87 (4.31, 5.43)
Tsikouras (2008) 4.73 (4.46, 5.00)
Kim A (2015) 8.70 (8.07, 9.33)
Overall (I-squared = 98.4%, p = 0.000) 4.14 (3.54, 4.73)

NOTE: Weights are from random effects analysis

0 5 10

Fig. 2 (continued).

was 3.50 mm (95% CI 2.96, 4.05) compared to 5.69 mm (95% CI, 4.1–7.2)
in studies published after 2000 (p = 0.018). Mean endometrial thick-
ness did not differ based on the exclusion of HRT among patients with-
out EC (endometrial thickness = 4.29 mm (excluded HRT) vs. 3.71 mm
(did not exclude HRT), p = 0.634). Among women with EC, mean endo-
metrial thickness was significantly lower in studies that excluded pa-
tients taking HRT (endometrial thickness = 14.43 mm vs. 16.43 mm,
p = 0.026). The mean endometrial thickness was not significantly dif-
ferent according to geographic region among patients with or without
EC.
3.4. Diagnostic accuracy of endometrial thickness for endometrial cancer
A total of 30 studies reported at least one cut-off value to assess di-
agnostic accuracy of ultrasound to detect EC among women with PMB
[19,21,22,27,29,30,33,35–40,42–57,65]. Of the 12,008 women included
in these studies, 957 (8.0%) were diagnosed with EC. A total of 17 differ-
ent endometrial thickness cut-off values were reported, ranging from
N3 mm to N20 mm. At least 4 studies evaluated the following
cutoffs: ≥ 3 mm, ≥ 4 mm, ≥ 5 mm, ≥ 6 mm, N 8 mm, ≥ 10 mm, and N 15 mm
(Table 2).
Cut-offs of ≥3 mm, ≥ 4 mm, and ≥ 5 mm were all highly sensitive but
not specific for EC (Table 2). The endometrial thickness cut-off of ≥5 mm
was the most frequently studied, with 20 studies including 10,165
women with an 8.8% prevalence of EC. The sensitivity and specificity
of the ≥5 mm cut-off was 96.2% (95%CI 92.3–98.1) and 51.1% (95% CI
42.3–60.7), respectively. Based on this prevalence, the negative predic-
tive value of endometrial thickness b 5 mm was 99.27% with a positive
predictive value (PPV) of 16.1% for ET ≥ 5 mm. Based on the comple-
ment of the NPV (1 – NPV), the risk of EC in a woman with an endome-
trial thickness of b5 mm was 0.7%. Cut-offs of ≥3 mm and ≥ 4 mm had
similar NPV (99.68% and 99.41%, respectively) but lower PPV (7.35%
and 12.7%, respectively) to predict EC among women with PMB. A sum-
mary plot of reported sensitivity and specificity in each study for the
most commonly reported study cut-offs (≥4 mm and ≥ 5 mm) is
shown in Fig. 3. Interestingly, a ≥ 4 mm cut-off was less sensitive than
a ≥ 5 mm cut-off for detection of EC in our analysis. This was likely
due to heterogeneity between studies reporting variable cut-offs, as

Table 2
Summary estimates of sensitivity and specificity for different combined cut-off values of ET.

Cut-off Number of studies Sensitivity % Specificity % NPV PPV Youden's Index

(95% CI) (95% CI)

≥ 3 mm 4 96.2 (92.4–98.2) 42.1 (26.2–59.8) 99.7 7.3 0.38

≥ 4 mm 14 95.7 (88.1–98.5) 46.0 (36.7–55.6) 99.4 12.7 0.42
≥ 5 mm 20 96.2 (92.3–98.1) 51.5 (42.3–60.7) 99.3 21.1 0.48
≥ 6 mm 5 85.2 (70.2–93.3) 64.0 (53.0–73.6) 99.1 17.6 0.49
N 8 mm 6 88.0 (71.4–95.5) 66.2 (52.3–77.8) 98.8 22.3 0.54
≥ 10 mm 9 78.2 (64.7–87.5) 83.7 (74.4–90.1) 98.1 33.7 0.62
N 15 mm 4 58.9 (48.6–68.5) 94.2 (79.6–98.5) 94.0 55.7 0.53

Please cite this article as: B. Long, M.A. Clarke, A.D.M. Morillo, et al., Ultrasound detection of endometrial cancer in women with postmenopausal
bleeding: Systematic review ..., Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2020.01.032
 B. Long et al. / Gynecologic Oncology xxx (xxxx) xxx 7

this discrepancy was eliminated when analysis was restricted to the six
studies that included both the 4 mm and 5 mm cut-offs (Table 3).
(a)
3.5. Influence of study characteristics and small-sample size effects (cut-
off ≥ 5 mm)
1

Because the cut-off of ≥5 mm was the most frequently reported, we

evaluated the influence of study characteristics on the diagnostic accu-
.8

racy of this cut-off for detection of EC. We had insufficient power to an-
alyze other cut-offs in stratified analyses. There were no significant
differences in the sensitivity or specificity of endometrial thick-
ness ≥ 5 mm for detection of EC based on age, HRT use, publication
.6

date or geographic region.

We also performed sensitivity analysis after excluding studies with
potential verification bias based on QUADAS scoring. When 9 studies
were excluded for potential verification bias (based on question 6 in
.4

Supplement 2) there was no significant change in sensitivity or specific-

ity of the analyzed endometrial thickness cut-offs.

3.6. Other ultrasound findings associated with endometrial cancer

.2

3.6.1. Endometrial volume

Four studies including 434 patients assessed endometrial volume
0

(EV) as a predictor of EC in women with PMB [8–11], including 87 pa-

1 .8 .6 .4 .2 0 tients with EC and 347 without EC. EV was obtained using 3-
Specificity dimensional power Doppler ultrasound. Ultrasound methods were
well described in all studies, though power Doppler settings including
Study estimate Summary point power Doppler gain, pulse repetition frequency, and sweeping angle
95% prediction 95% confidence differed between studies. Of the four studies, three were restricted to
region region women with an endometrial thickness of ≥4 [7] or N 4.5 mm [10,11]
and three excluded women using HRT [8,9,11]. Among patients with
EC, mean EV was 7.74 mL (SD = 2.3; range, 5.6–10.2 mL) compared
to 2.79 mL (SD = 0.4 mL; range, 2.3–3.4 mL) among patients without
(b) cancer (p b 0.0001). Mean EV was also significantly correlated with en-
dometrial thickness overall (rho = 0.76, p-value = 0.0280).
1

3.6.2. Vascularization index

Vascularization index (VI) was evaluated in the same four studies
described above [8–11]. All studies used Virtual Organ Computer-
.8

Aided Analysis (VOCAL) software to measure vascular indices. One

study [8] defined VI as the “number of color voxels in the volume,
which represents the vessels in the tissue and is expressed as a percent-
age.” VI was not defined in the other 3 studies. Among patients with EC,
.6

mean VI was 15.3 (SD = 3.1; range, 11.7–17.9) compared to 4.77 (SD =
4.2; range, 1.2–10.6) in patients without EC (p b 0.0001). Mean endo-
metrial VI was non-significantly correlated with endometrial thickness
overall (rho = 0.67, p-value = 0.0710).
.4

3.6.3. Vascularity flow index

Vascularity flow index (VFI) was evaluated in three studies [8–10]
.2

including 372 patients, 74 with EC and 298 without EC. VFI was calcu-
lated using VOCAL software. It was defined in one study as the “mean
color value in all voxels in the volume, which represents both vascular-
ization and blood flow [8]” and was not defined in the other 2 studies
0

[9,11]. Among patients with EC, mean VFI was 5.52 (SD = 2.5; range,
1 .8 .6 .4 .2 0 36–9.2) (95% CI) compared to 1.49 (SD = 1.2; range, 0.3–2.8)) in pa-
Specificity tients without EC (p b 0.0001). Mean endometrial VFI was non-
significantly correlated with endometrial thickness overall (rho =
Study estimate Summary point 0.64, p-value = 0.0856).
95% confidence
95% prediction region 3.6.4. Flow index
region
Flow index (FI) was similarly evaluated in the same three studies as
VFI [8,9,11]. VOCAL software was used in all studies. FI was defined in
one study as “mean color value in the color voxels, which indicates
Fig. 3. Sensitivity and specificity in each study using endometrial thickness cut-offs of the average intensity of blood flow [8].” It was not expressly defined
(a) ≥4 mm and (b) ≥5 mm. in the other 2 studies [8,10]. Among patients with EC, mean FI was

Please cite this article as: B. Long, M.A. Clarke, A.D.M. Morillo, et al., Ultrasound detection of endometrial cancer in women with postmenopausal
bleeding: Systematic review ..., Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2020.01.032
8 B. Long et al. / Gynecologic Oncology xxx (xxxx) xxx
Table 3
Summary of estimates of sensitivity and specificity restricted to studies examining both ≥4 mm and ≥ 5 mm endometrial thickness cut-offs.
Cut-off Number of studies Sensitivity % (95 CI)
≥ 4 mm 6 94.8 (83.7–98.5)
≥ 5 mm 6 90.8 (79.0–96.3)
32.51 (SD = 1.7; range, 31.1–34.5) compared to 21.26 (SD = 5.4; range,
14.0–26.1) in patients without EC (p b 0.0001). Mean endometrial FI
was significantly correlated with endometrial thickness overall
(rho = 0.75, p-value = 0.0305).
4. Discussion
In this meta-analysis of 44 studies including 17,339 women, we
demonstrate that an endometrial thickness cutoff of ≥5 mm is the opti-
mal cut-off for detection of EC. The endometrial thickness cut-offs of ≥3,
≥4, and ≥ 5 mm were all highly sensitive for EC among women with
PMB, consistent with current American College of Obstetricians and Gy-
necologists (ACOG) guidelines, which state that an endometrial thick-
ness of ≤4 mm can reliably rule out EC in women with PMB [58]. The
negative predictive value of each of these cut-offs was over 99%, while
specificity varied from 42.1% to 51.5%. Therefore, a cut-off of ≥5 mm
may be a more appropriate threshold for further workup of PMB, due
to its comparable sensitivity and NPV and increased specificity com-
pared to less stringent cut-offs. Sensitivity of these thresholds did not
vary based on mean age, inclusion of patients using HRT, publication
date, or geographic region. There was also no change in sensitivity or
specificity when studies with potential verification bias were excluded.
Among the studies reporting a cut-off of ≥5 mm, use of this threshold
could have reduced the number of invasive diagnostic procedures by
up to 17%.
Mean endometrial thickness did not significantly differ based on age
or geographic region. However, there were differences in mean endo-
metrial thickness based on date of study publication and HRT exclusion.
In women without EC, mean endometrial thickness was higher for stud-
ies published after 2000 compared to those published before 2000. This
may be secondary to higher resolution imaging in more recent publica-
tions, changes in HRT-prescribing patterns, or intrinsic patient factors
that have changed over time, such as increasing obesity rates. Due to
limited reporting of potential confounders, we were unable to directly
examine the effects of BMI or HRT use on endometrial thickness in
these studies.
Our findings are consistent with previous, smaller reports. In a 1998
meta-analysis of 35 studies including 5892 women with PMB, Smith
Bindman et al. estimated a 1% risk of EC in women with PMB and endo-
metrial thickness b 5 mm [4]. The sensitivity of ultrasound to detect EC
was 96% (95% CI 94–98%) when this cut-off was used. Another meta-
analysis used original datasets from 13 studies including 2896 women
with PMB. The sensitivity of ultrasound to detect EC was 98%, 95%, and
90%, respectively, for cut-offs of 3, 4, and 5 mm. The authors estimated
a 0.6% post-test probability of EC when endometrial thickness was
b3 mm [7]. In our analysis, sensitivity was almost identical for cut-offs
of ≥3, ≥4, and ≥ 5 mm (96.2, 95.7, and 96.2%, respectively), as was NPV
(99.7, 99.4, 99.2%, respectively). The higher sensitivity for a ≥ 5 mm
compared to ≥4 mm cut-off is likely explained by small differences be-
tween the studies that included a 5 mm vs. 4 mm cut-off. The 95% con-
fidence intervals for the sensitivities of both cut-offs overlap almost
entirely, suggesting similar sensitivity with both cut-offs based on a
large number of studies.
Others have argued against the use of endometrial thickness cut-offs
in the work-up of EC. A meta-analysis by Tabor et al. reported similarly
high EC detection rates across studies; however, the authors calculated
a 4% false negative rate if the median endometrial thickness in each
study (range 2–6.4 mm) was used as a cut-off. They concluded that
this rate was unacceptably high for symptomatic postmenopausal
Please cite this article as: B. Long, M.A. Clarke, A.D.M. Morillo, et al., Ultrasound detection of endometrial cancer in women with postmenopausal
bleeding: Systematic review ..., Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2020.01.032
Specificity % (95 CI) NPV PPV Youden's Index
52.7 (38.0–70.0) 99.5 13.7 0.475
62.4 (47.9–75.0) 99.4 16.2 0.532
women [5]. However, even invasive methods such as dilation and curet-
tage and EMB have false negative rates of 2–6% and 5–15%, respectively
making ultrasound an attractive, non-invasive alternative to such test-
ing [59].
Given the false negative rate inherent in any diagnostic test, endo-
metrial thickness thresholds should be considered within the context
of clinical management. Using a ≥ 5 mm threshold for endometrial sam-
pling in women with PMB would result in fewer invasive procedures
compared to a more stringent cut-off, but many patients and providers
might prefer a lower false negative rate. In such cases, a more conserva-
tive cut-off could be used, as the false negative rate of a ≥ 3 mm thresh-
old is less than half of that of a ≥ 5 mm threshold (0.3 vs. 0.7%). While
patients with endometrial thickness b 3 mm could forego further follow
up in the absence of recurrent bleeding, patients with endometrial
thickness between 3 and 5 mm could continue short interval ultrasound
follow up to confirm their low-risk status. Patients with increasing en-
dometrial thickness, recurrent PMB, or other clinical risk factors could
be triaged to invasive diagnostic testing.
This meta-analysis is the first to include a summary of published
values for EV, VI, VFI, and FI in unselected women with PMB. While
these indices were all statistically significantly associated with EC, spe-
cific thresholds that could be used to guide further work-up of PMB
were not evaluated due to the limited number of studies. It is also un-
clear whether these indices provide independent information that
would improve detection of EC over endometrial thickness alone, as
EV and FI were significantly correlated with ET, and there was a trend
towards correlation of both VI and VFI with ET. Further, the reproduc-
ibility of these measurements has not been examined, as these are
newer imaging techniques that have not been widely adopted. While
these studies could be used in conjunction with ET to increase its sensi-
tivity to detect EC, more studies are needed to determine the role of ad-
vanced ultrasound imaging techniques in the detection of EC.
This meta-analysis has several strengths, including a large number of
studies from a wide range of geographic regions. Previous meta-
analyses of endometrial thickness cut-offs for the detection of EC have
been limited to studies published through 2006. Our analysis adds 14
more recent studies with an additional 7530 patients. The included
studies were of high quality based on QUADAS assessment, and our
findings were robust even when studies with potential for verification
bias were excluded. Because we abstracted data regarding age, HRT
use, geographic region, and publication date, we were able to assess po-
tential sources of heterogeneity in these studies. Still, many potential
confounders such as obesity, diabetes, and HRT use were inconsistently
reported, and their effect on the diagnostic accuracy of ultrasound could
not be assessed. Our analyses were also limited by inconsistent
reporting of outcomes across studies. For instance, we were unable to
assess the accuracy of endometrial thickness assessment in the diagno-
sis of benign or pre-malignant endometrial pathology because histo-
logic categories were inconsistently grouped across studies.
Due to the varying prevalence of EC among different study popula-
tions, the NPV of a 5 mm endometrial thickness cut-off varied from 88
to 100% among included studies. For instance, a study by Ciatto et al. re-
ported an overall EC prevalence of only 3.6%, with a negative ultrasound
(endometrial thickness b 5 mm) resulting in a 99% NPV despite a sensi-
tivity of only 77.8% [46]. Another study with a 39% prevalence of EC re-
ported only a 97% NPV despite 98% sensitivity [19]. This demonstrates
the importance of pretest probability on the utility of any diagnostic
test. While this meta-analysis supports the use of endometrial thickness
cut-offs in average-risk patients with PMB, patients at high risk for EC
 B. Long et al. / Gynecologic Oncology xxx (xxxx) xxx
likely require further workup even in the setting of a negative ultra-
sound. Importantly, these findings cannot be generalized to patients
with recurrent or persistent PMB, who should undergo further work-
up regardless of endometrial thickness. Underlying risk factors for EC,
such as obesity, diabetes, hypertension, recurrent bleeding, and family
history were inconsistently reported, so we were unable to analyze the
effect of these risk factors on the NPV of endometrial thickness cut-
offs. Prospective studies of women with PMB are necessary to evaluate
the long-term risk in higher risk patients and determine which patients
could forego invasive testing in the setting of a negative ultrasound.
Clinical EC risk scoring systems that have included both patient char-
acteristics and endometrial ultrasound assessment have typically used
higher endometrial thickness cut-offs than those in our analysis. For in-
stance, the Norwich DEFAB risk model utilizes an endometrial thickness
cut-off of ≥14 mm to assign one point for ultrasound findings. A Nor-
wich DEFAB score of ≥3 had an 81.8% sensitivity and 50.3% specificity
[60]. Notably, our results indicate a higher sensitivity (96.2%) and simi-
lar specificity (51.5%) for TVUS alone using an endometrial thickness
cut-off of ≥5 mm. Another risk model by Gianella et al. demonstrated a
sensitivity of 87.5% and a specificity of 80.1% when an endometrial
thickness cut-off of N8 mm was combined with clinical risk factors
[61]. Further refining guidelines for PMB workup has the potential to
optimize cost-effectiveness and improve the value of care. While our
data support the current role of TVUS to effectively rule out EC in aver-
age risk women with PMB and an endometrial thickness b 5 mm, the
specificity of TVUS remains limited. Invasive diagnostic procedures
could be further reduced by leveraging EC biomarkers and less invasive
sampling, such as a tampon-based tests [62].
In summary, the results of this meta-analysis support the use of an
endometrial thickness cut-off of 5 mm given its high sensitivity and im-
proved specificity for EC in unselected patients with postmenopausal
bleeding. Use of an intermediate threshold (3–5 mm) requiring repeat
imaging could further increase sensitivity of non-invasive testing.
These results should be generalizable to average-risk patients with
PMB, as factors such as age, geographic region, HRT use, and year of pub-
lication did not influence our results. We were unable to address the ef-
fects of comorbid conditions or other underlying risk factors on the
diagnostic yield of ultrasound in women with postmenopausal bleed-
ing. Our analysis suggests that TVUS may be effective to rule out EC in
average risk women with PMB.
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.ygyno.2020.01.032.
Author contributions
Beverly Long: writing and preparation of manuscript, systematic lit-
erature review, study design, data abstraction.
Megan Clarke: writing and preparation of manuscript methods and
results, data abstraction, statistical analysis.
Arena del Mar Morillo: data abstraction, study design, review of
manuscript.
Nicolas Wentzensen: manuscript editing/review, study design, data
analysis.
Jamie Bakkum-Gamez: manuscript editing/review, study design,
data analysis.
Funding source
No funding sources were utilized.
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