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ABSTRACT
Objectives The aim of this study was to estimate the
rate of malignancy in adnexal lesions described as
unilocular cysts at transvaginal ultrasound examination
and to investigate if there are differences in clinical and
ultrasound characteristics between benign and malignant
unilocular cysts.
Methods A total of 3511 patients with an adnexal mass
underwent transvaginal ultrasound examination between
1999 and 2007. Sonologists used the International
Ovarian Tumor Analysis terms and definitions to describe
their ultrasound findings. Only masses operated on within
120 days after the ultrasound examination were included
in the analysis and the histopathological diagnosis of the
mass was used as the gold standard.
Results Of the 3511 masses, 1148 (33%) were classified
as unilocular cysts on ultrasound. Of these, 11 (0.96%
(95% CI, 0.481.71)) were malignant. The malignancy
rate was lower in premenopausal than in postmenopausal
women: 0.54% (5/931; 95% CI, 0.171.25) vs 2.76%
(6/217; 95% CI, 1.025.92); P = 0.009. More patients
with malignant unilocular cysts had a personal history of
breast cancer (18% vs 2%; P = 0.02) or ovarian cancer
(18% vs 0.6%; P = 0.003). Hemorrhagic cyst contents
on ultrasound were more common in malignant than in
benign unilocular cysts (18% vs 2%; P = 0.03). In seven of
INTRODUCTION
The risk of a unilocular ovarian cyst being malignant
is considered to be very low, irrespective of whether
the cyst is described on the basis of macroscopic
inspection by a pathologist1 or on the basis of
an ultrasound image of the cyst2 5 . It has been
suggested that unilocular cysts < 5 cm in diameter in
postmenopausal women do not require intervention
other than possibly follow-up scans. For example, in
the United Kingdom Collaborative Trial on Ovarian
Cancer Screening (UKCTOCS), women with a unilocular
cyst with anechoic contents and a volume < 60 mL
ORIGINAL PAPER
METHODS
This is a retrospective analysis of prospectively collected
information in the International Ovarian Tumor Analysis
(IOTA) database. The IOTA study is a prospective
observational international multicenter study including
21 ultrasound centers in nine countries, in which
patients with adnexal masses were scanned transvaginally
using a standardized research protocol8 10 . Ultrasound
examiners were radiologists or gynecologists highly
experienced in gynecological ultrasound and with a special
interest in adnexal masses. The study was conducted
in accordance with precepts established by the Helsinki
Declaration, the research protocol was ratified by the
local Ethics Committee at each center and all participants
gave informed consent to participate. Recruitment took
place between 1999 and 2007. The IOTA terms and
definitions11 were used to describe ultrasound findings.
Both gray-scale and color/power Doppler ultrasound
examination were carried out, and information on
more than 40 clinical and ultrasound variables was
collected. In addition, the ultrasound examiner classified
each mass as benign or malignant using subjective
evaluation of gray-scale and Doppler ultrasound findings
(subjective assessment) and stated the confidence with
which the classification was made (certainly benign,
probably benign, uncertain, probably malignant, certainly
malignant). In the case of bilateral adnexal masses, the
mass with the most complex ultrasound morphology was
included in the database. If both masses had similar
ultrasound morphology the largest or the one most easily
accessible by ultrasound was included. Only women with
masses who were operated on within 120 days after the
ultrasound examination were included in the analysis.
The gold standard was histological diagnosis of the
surgically removed adnexal mass. Staging of malignancies
was done in accordance with the International Federation
of Gynecology and Obstetrics (FIGO)12,13 .
For the purpose of the current study, the IOTA database
was searched for tumors classified as unilocular cysts
at ultrasound examination. The unilocular cysts in the
database comprised our study population. The IOTA
definition of a unilocular cyst is a cyst with one cyst
81
RESULTS
The IOTA database contains information on 3511
patients with at least one adnexal mass. The number
of masses contributed by each center is shown in Table S1
(online) and the histology of the masses in Table S2
(online). Of the 3511 masses, 1148 (33%) were classified
as unilocular cysts on ultrasound examination. The
proportion of adnexal masses classified as unilocular
cysts ranged from 12% to 67% in the different centers.
Of 186 borderline tumors in the entire IOTA database,
five (2.76% (95% CI, 0.886.16)) were classified as
unilocular cysts on ultrasound, and of 764 invasive
malignancies, six (0.79% (95% CI, 0.291.70)) were
classified as unilocular cysts on ultrasound.
Of the 1148 unilocular cysts in the IOTA database,
11 (0.96% (95% CI, 0.481.71)) were malignant
vs 40% (939/2363; 95% CI, 3842) of all other
adnexal masses (P < 0.001). Five of the malignant
unilocular cysts were borderline tumors and six were
primary invasive malignancies, i.e. the rate of borderline
malignancy was 0.44% (95% CI, 0.141.01) and that
of invasive malignancy was 0.52% (95% CI, 0.191.13)
(Table S2). The malignancy rate in unilocular cysts was
lower in premenopausal women than in postmenopausal
women: 0.54% (5/931; 95% CI, 0.171.25) compared
to 2.76% (6/217; 95% CI, 1.275.92); P = 0.009. In
premenopausal women, four of 931 unilocular cysts were
borderline malignant (0.43% (95% CI, 0.121.10)) and
one was invasively malignant (0.11% (95% CI, 00.60)).
The corresponding figures for postmenopausal women
were one (0.46% (95% CI, 0.012.54)) and five (2.30%
(95% CI, 0.755.29)) of 217 unilocular cysts.
The malignancy rate in unilocular cysts with anechoic
cyst fluid and regular walls on ultrasound was 1.22%
(4/326; 95% CI, 0.343.11) and that in unilocular
cysts with another type of cyst fluid, with or without
irregular walls on ultrasound, was 0.85% (7/822; 95%
Valentin et al.
82
DISCUSSION
We found the risk of malignancy in surgically removed
adnexal lesions judged to be unilocular cysts at
transvaginal scan to be 0.96%; it was 0.54% in
premenopausal women and 2.76% in postmenopausal
women and the difference in malignancy rate between preand postmenopausal women was statistically significant.
Hemorrhagic cyst contents on ultrasound increased the
risk of malignancy, as did a personal history of ovarian
or breast cancer. However, seven of the 11 malignant
cysts described as unilocular on ultrasound proved to
contain papillary projections or other solid components
at macroscopic inspection of the corresponding surgical
specimen by the pathologist.
The strength of our study is that it is large and
multicenter and that data were prospectively collected
following a standardized research protocol and using
standardized terminology to describe the masses. This
increases the likelihood that our results are generalizable.
A limitation of our study is that it includes only women
who were operated on. The true malignancy rate in cysts
judged to be unilocular on ultrasound is likely to be much
lower than that in our study, because many unilocular
cysts are left in situ4,5,14 23 . In studies in which (mostly
asymptomatic) women with adnexal cysts judged to be
unilocular on ultrasound were recommended for followup with ultrasound examination or were indeed followed
with ultrasound examination for up to 13 years, four of
4361 (0.09%) unilocular cysts in 3797 (0.11%) patients
(most postmenopausal) were found to be malignant
83
Table 1 Prospectively collected clinical and ultrasound information for benign and malignant unilocular cysts (n = 1148)
Variable
Clinical characteristics
Age (years)
Postmenopausal
Nulliparous
Hysterectomy
Current hormonal treatment
Personal history of ovarian cancer
Personal history of breast cancer
Family history of ovarian cancer
Family history of breast cancer
CA 125 (U/mL)*
Ultrasound characteristics
Bilateral
Largest diameter (mm)
Mean diameter (mm)
Volume (cm3 )
Echogenicity of cyst contents
Anechoic
Homogeneous low level
Ground glass
Hemorrhagic
Mixed
Irregular walls
Fluid in pouch of Douglas
Fluid in pouch of Douglas (mm)
Ascites
Acoustic shadows
Color Doppler blood flow
No flow
Minimal flow
Moderate flow
Strong flow
Venous blood flow only
Spectral Doppler results
Pulsatility index
Resistance index
Peak systolic velocity (cm/s)
Time averaged maximum velocity (cm/s)
Diagnosis on basis of subjective assessment
Certainly benign
Probably benign
Uncertain
Probably malignant
Certainly malignant
Benign (n = 1137)
Malignant (n = 11)
36 (1590)
211 (19)
611 (54)
43 (4)
172 (15)
7 (< 1)
23 (2)
20 (2)
77 (7)
19 (23500)
60 (2682)
6 (55)
6 (55)
1 (9)
1 (9)
2 (18)
2 (18)
0 (0)
0 (0)
20 (7147)
0.002
0.009
1
0.35
1
0.003
0.02
1
1
0.50
165 (15)
56 (8760)
48 (8340)
54 (0.220 525)
1 (9)
57 (25171)
48 (23156)
58 (71940)
1
0.49
0.49
0.48
322 (28)
154 (14)
412 (36)
28 (2)
221 (19)
161 (14)
162 (14)
14 (161)
9 (< 1)
169 (15)
4 (36)
1 (9)
4 (36)
2 (18)
0 (0)
3 (27)
3 (27)
18 (1038)
0 (0)
0 (0)
0.52
603 (53)
384 (34)
138 (12)
12 (1)
81 (7)
5 (45)
6 (55)
0 (0)
0 (0)
2 (18)
0.19
1.00 (0.135.09)
0.61 (0.121.00)
10.20 (0.1979.85)
6.00 (0.0252.78)
1.68 (0.763.21)
0.72 (0.520.92)
12.72 (6.1827.60)
5.85 (1.7718.20)
0.41
0.39
0.60
0.93
938 (83)
188 (17)
9 (< 1)
1 (< 1)
1 (< 1)
4 (36)
6 (55)
1 (9)
0 (0)
0 (0)
0.03
0.20
0.20
0.46
1
0.38
0.76
0.38**
< 0.001
Data are given as n (%) or median (range). *CA 125 was measured in 742 (65%) patients with a benign mass and in 11 (100%) patients
with a malignant mass. Pulsatility index, resistance index, peak systolic velocity and time-averaged maximum velocity were measured in
cases with detectable color Doppler signals and detectable arterial blood flow, i.e. in 453 (39%) patients with a benign mass and in four
(36%) patients with a malignant mass. Anechoic vs others. Hemorrhagic vs others. No flow vs others. **No or minimal flow vs
moderate or strong flow. Certainly benign vs others.
No
No
No
41
26
43
82
Yes
Yes
60
65
No
69
No
No
50
71
No
42
No
No
Age
(years)
62
Personal
history of
ovary cancer
No
No
No
Yes
No
No
No
No
Yes
No
No
Personal
history of
breast cancer
13
84
68
20
147
13
78
10
26
14
CA 125
(U/mL)
Certainly
benign
Probably
benign
Uncertain
Certainly
benign
Probably
benign
Probably
benign
Probably
benign
Probably
benign
Probably
benign
Certainly
benign
Certainly
benign
25
37
57
75
45
140
53
48
171
128
58
Diagnosis on
basis of
Largest
subjective
diameter
assessment
(mm)
Hemorrhagic
Hemorrhagic
Ground glass
Ground glass
Anechoic
Anechoic
Ground glass
Anechoic
Ground glass
Low-level
Anechoic
Echogenicity
of cyst fluid
10
38
18
Fluid in
POD
(mm)
No
No
Yes
No
No
No
No
No
No
No
No
Bilateral
Yes
Yes
Yes
No
No
No
No
No
No
No
No
Irregular
cyst walls
Non-optimal
specimen
No (solid part
missed)
No (solid tumor)
No (papillations
missed)
No (papillations
missed)
No (papillations
missed)
No (solid part
missed)
No (papillations
missed)
Yes
Yes
Yes
Agreement with
macroscopy
Borderline, mucinous
(pseudostratification
and atypia), Stage 1
Borderline, mucinous,
Stage 1
Mature teratoma with
microcarcinoma of
struma type
Borderline (focus of
atypical cells), serous,
Stage 1
Borderline, serous,
Stage 1
Borderline, serous,
Stage 1
Seropapillary peritoneal
cancer, Stage 3
Infiltration of
neuroendocrine
carcinoma in a
benign cystic
teratoma (previous
breast cancer of
neuroendocrine type)
Carcinoma,
endometrioid, Stage 3
Carcinoma, tubal,
Stage 3
Recurrent mucinous
invasive cancer in the
ovary, Stage 1
Final diagnosis
84
Valentin et al.
PostMP
PostMP
19901994
19911998
19952002
19952000
19972012
19872002
19972002
Auslender et al.15
Conway et al.16
Valentin and
Akrawi17
Castillo et al.18
Nardo et al.19
Modessit et al.5
Alcazar et al.23
> 50 years
(mixed)
PreMP
PostMP
PostMP
PostMP
Any?
Anechoic
Anechoic
Any
Anechoic
Hypoechogenic
Anechoic?
Echogenicity
of cyst fluid
Smooth, no
papillae
No papillae
? (no
papillae)
Smooth
Smooth
Smooth
Wall
regularity
13219 mL;
50 mm in
84%
< 50 mm
(1850 mm)
0.1860.4 mL
(mean, 16.3 mL)
< 100 mm
(mean, 27 mm)
< 60 mm
(1560 mm)
380 mm*
1550 mm
1550 mm
1550 mm
Size
3797 women
(4361 cysts)
314 (378
cysts)
2763 (3259
cysts)
32
226
149 (153
cysts)
60
36
4 days14 years
(mean, 6 years)
1894 months
(median,
42 months)
3 weeks13 years
5 years
0.38 years
(median, 3 years)
87 months
470 months
(mean,
31.5 months)
372 months
(mean,
31 months)
5 years (?)
Time in
follow-up
364
133
138
45
12
18
Women
operated
on (n)
0/133
1**/9
2/138
1/45
0/12
0/18
0/9
Malignancy in
surgical
specimen (n/n)
0.11
(4/3797
women)
(0.09,
4/4361
cysts)
0/32
0 (0/2763)
0.32 (1/314)
0.88 (2/226)
0.67 (1/149)
0 (0/121)
0 (0/96)
0 (0/60)
0 (0/36)
Malignancy
rate per
woman in
study
population
(% (n/n))
*Refers to all adnexal lesions included in the study; this study includes also cysts other than unilocular ones. The study includes an additional 39 cysts with more complicated but benign ultrasound
morphology. Not all 12 cysts operated on were unilocular. Squamous cancer in a papillation overlooked at scan in a dermoid cyst. Indication for surgery was cyst growth. **At surgery this cyst
was no longer unilocular; a papillary projection had developed. 95% CI, 0.040.28. 95% CI, 0.040.24. ?, unequivocal information not available; MP, menopausal.
Total of nine
studies
PostMP
19871993
Aubert et al.14
PostMP
19911996
Study
MP status
Years of
recruitment
Women
with
unilocular
cysts (n)
Table 3 Malignancy rates in adnexal lesions judged to be unilocular cysts at transvaginal scan and managed by follow-up: literature review
26
2835
8760 mm 1148
134
5/1572
(0.32)
3/1572
(0.19)
1/931
(0.11)
2/641
(0.31)
2/641
(0.31)
3/641
(0.47)
13/1985
(0.65)
5/931
(0.54)
8/1054
(0.76)
3/413
(0.73)
5/641
(0.78)
All
2/437
(0.46)
1/217
(0.46)
1/220
(0.45)
18/437
(4.1)
5/217
(2.3)
13/220
(5.9)
13/134
(9.7)
1/134
(0.75)
0/43
0/43
Inv
0/43
0/43
Bord
PostMP
24/684
(3.5)
6/217
(2.8)
18/467
(3.9)
14/134
(10.4)
0/43
4/247
(1.6)
0/43
All
13/2835
(0.46)
5/1148
(0.44)
8/1687
(0.47)
0/45
0/41
0/43
1/35 (2.6)
3/660
(0.45)
3/641
(0.47)
1/134
(0.75)
0/43
0/45
Bord
25/2835
(0.88)
6 /1148
(0.52)
19/1687
(1.1)
0/45
0/41
0/43
0
4/660
(0.61)
2/641
(0.31)
13/134
(9.7)
0/43
0/45
Inv
All
38/2835
(1.34)
11/1148
(0.96)
27/1687
(1.6)
0/45
0/41
0/43
1/35 (2.6)
7/660
(1.1)
5/641
(0.78)
14/134
(10.4)
0/43
0/45
All
*Cysts with protrusions of solid tissue < 3 mm in height are classified as unilocular (with wall irregularity). 95% CI, 0.981.83%. ?, unequivocal information not available; Bord, borderline tumor;
Inv, invasive malignancy; IOTA, International Ovarian Tumor Analysis; MP, menopausal.
Any
> 30 mm
641
45
41
43
35
660
43
45
Inv
PreMP
Bord
4/931
(0.43)
19992007 Mixed
Smooth
> 30 mm
?
8990 mL
> 10 mm
?
18200 mm
< 50 mm
< 100 mm
Current study
Any
?
?
Smooth
IOTA*
?
?
?
Size
3/641
(0.47)
19871993 PostMP
Osmers et al.30
Any
?
?
Anechoic
Any
Anechoic
Anechoic
?
Echogenicity Wall
of cyst fluid regularity
19871993 PreMP
19831992 PostMP
19871995 PostMP or
> 50 years
19871988 Mixed
19911993 Mixed
19881993 PostMP
20042006 Mixed
19921997 Mixed
Osmers et al.25
Granberg et al.2
Valentin et al.3
Shalev et al.24
Gramellini et al.29
Ekerhovd et al.28
Study
Years of
recruitment MP status
Table 4 Malignancy rates in surgically removed adnexal lesions judged to be unilocular cysts at transvaginal scan: literature review
86
Valentin et al.
87
Table 5 Proportion of borderline and invasive adnexal malignancies classified as unilocular cysts on ultrasound: literature review
Proportion of unilocular cysts in malignant adnexal masses (n/n (%))
Study
Borderline
Invasive
3/33
4/113
0/1
0/5
0/5
0/9
0/6
No information
0/82
No invasive
0/27
0/15
0/19
0/42
0/21
No information
3/115
4/113
0/28
0/20
0/24
0/51
0/27
0/39
7/172 (4.1)
0/206
7/417 (1.7)
Current study
5/186 (2.7)
6/764 (0.8)
11/950 (1.2)
12/358 (3.4)
6/970 (0.6)
18/1367 (1.3)
Exacoustos et al.31
Fruscella et al.32
Valentin et al.3
Gramellini et al.29
Valentin33
Hata et al.35
Jokubkiene et al.34
Granberg et al.2
Valentin et al.
88
7.
8.
9.
10.
ACKNOWLEDGMENTS
This work was supported by the Swedish Medical
Research Council: grant numbers K2001-72X 1160506A, K2002-72X-11605-07B, K2004-73X-11605-09A
and K2006-73X-11605-11-3; funds administered by
Malmo University Hospital; two Swedish governmental
grants: ALF-medel and Landstingsfinansierad Regional
Forskning; and Reasearch supported by Research Council
KU Leuven: GOA-MANET; IWT-TBM 070706 (IOTA);
Belgian Federal Science Policy Office: IUAP P6/04
(DYSCO); Research Foundation Flanders (FWO
Vlaanderen, 2151609 N, 1251612 N; research project
grant G049312N); Research Council KUL: GOA MaNet,
IBBT: Future Health Dept., Belgian Federal Science Policy
Office: IUAP P7/ (DYSCO, Dynamical systems, control
and optimization, 20122017).
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