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Article

Diagnostic Parameters to Differentiate

Benign From Malignant Ovarian
Masses With Contrast-Enhanced
Transvaginal Sonography
Arthur C. Fleischer, MD, Andrej Lyshchik, MD, PhD, Howard W. Jones, III, MD,
Marta A. Crispens, MD, Rochelle F. Andreotti, MD, Phillip K. Williams, RDMS,
David A. Fishman, MD

Objective. The aim of this study was to evaluate diagnostic parameters to differentiate between
benign versus malignant ovarian masses using contrast-enhanced transvaginal sonography (TVS).
Methods. Thirty-three consecutive patients with 36 morphologically abnormal ovarian masses (solid
or cystic with papillary excrescences, focally thickened walls, or irregular solid areas) smaller than 10
cm received a microbubble contrast agent intravenously while undergoing pulse inversion harmonic
TVS. The following parameters were assessed: presence of contrast enhancement, time to peak
enhancement, peak contrast enhancement, half wash-out time, and area under the enhancement
curve (AUC). Tumor histologic analysis was used to distinguish benign from malignant ovarian tumors.
Results. Twenty-six benign masses and 10 malignancies were studied. Of all examined criteria, an AUC
of greater than 787 seconds1 was the most accurate diagnostic criterion for ovarian cancer, with
100.0% sensitivity and 96.2% specificity. Additionally, peak contrast enhancement of greater than
17.2 dB (90.0% sensitivity and 98.3% specificity) and half wash-out time of greater than 41.0 seconds
(100.0% sensitivity and 92.3% specificity) proved to be useful. Conclusions. Our data suggest that
the AUC, peak enhancement, and half wash-out time had the greatest diagnostic accuracy for con-
trast-enhanced TVS in differentiation between benign and malignant ovarian masses. Key words:
ovarian cancer; contrast-enhanced transvaginal sonography; pulse inversion harmonic imaging.

T
Abbreviations
AUC, area under the enhancement curve; CI, confi-
dence interval; CT, computed tomography; PET, positron
emission tomography; PIH, pulse inversion harmonic;
ROI, region of interest; TVS, transvaginal sonography
Received April 21, 2009, from the Departments
of Radiology (A.C.F., A.L., R.F.A., P.K.W.) and
Obstetrics and Gynecology (A.C.F., H.W.J., M.A.C.,
R.F.A.), Vanderbilt University Medical Center,
Nashville, Tennessee USA; and Department of
Obstetrics and Gynecology, Mount Sinai School
of Medicine, New York, New York USA (D.A.F.).
Revision requested April 23, 2009. Revised
manuscript accepted for publication May 5, 2009.
This study was supported by National Institutes
of Health/National Cancer Institute grant R21 CA
125227-01.
Address correspondence to Arthur C. Fleischer, MD,
Department of Radiology, Vanderbilt University
Medical Center, RR-1213 MCN, 1161 21st Ave N,
Nashville, TN 37232-2675 USA.
E-mail: arthur.fleischer@vanderbilt.edu
ransvaginal sonography (TVS) is the initial diag-
nostic modality of choice for the evaluation of
most pelvic masses. However, the sensitivity and
specificity of TVS for the definitive diagnosis of
ovarian cancer are limited. Because of this, the differen-
tial diagnosis of morphologically suspicious adnexal
masses, especially in postmenopausal women, typically
includes ovarian cancer. Up to now, there has been no
universally available test with high sensitivity or specifici-
ty for ovarian cancer. Ovarian cancer is a disease with a
poor prognosis. Women commonly have diagnoses of
stage III and IV disease, for which 5-year survival rates are
around 27% and 16%, respectively.1 Although advances in
therapy have improved median survival during the past
decade, there has been little or no change in the overall
mortality rate.2 It has been the hope that early detection
of early-stage disease could have a positive impact on the
prognosis of this dreaded disease.

2009 by the American Institute of Ultrasound in Medicine J Ultrasound Med 2009; 28:12731280 0278-4297/09/$3.50
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Differentiating Benign From Malignant Ovarian Masses
Women with adnexal masses are often offered
additional investigations, such as nondiagnostic
tumor marker tests (ie, cancer antigen 125) and
TVS to clarify the nature of the tumor.3 However,
the accuracy of morphologic assessment of ovar-
ian masses with transabdominal sonography
and TVS is relatively limited; thus, the nature of
adnexal tumors often remains uncertain, and as
a result, many patients undergo surgical proce-
dures for both diagnosis and treatment of benign
and malignant disease.4,5
A few studies have evaluated the use of contrast-
enhanced TVS in the differentiation of benign and
malignant ovarian tumors by showing more
prominent enhancement of malignant lesions.610
However, some of these studies were performed
with Doppler imaging to assess tumor enhance-
ment after contrast agent administration.7,8 This
method has low contrast and resolution, substan-
tial background noise, and considerable operator
dependence. These limitations can be addressed
by new sonographic imaging methods, such as
pulse inversion harmonic (PIH) imaging. Pulse
inversion harmonic imaging is a new sonograph-
ic technique that consists of a sequence of 2 recip-
rocal ultrasound waves transmitted into the
tissue to subtract the signal from a linear medium
such as tissue. Pulse inversion harmonic imaging
enhances the properties of microbubble contrast
materials, which are based on the generation of
harmonics from nonlinear oscillation of bubbles
and on stimulated acoustic emission effects from
the destruction of bubble walls.
Recently, studies performed at our medical
centers in the United States and a few from
Europe have shown the potential use of contrast-
enhanced TVS for the differential diagnosis of
benign versus malignant ovarian masses.68 Our
preliminary data showed that contrast-enhanced
PIH sonography was a more appropriate method
for characterizing blood flow dynamics in ovarian
tumors, and it could be an important tool to aid in
the differential diagnoses between benign and
malignant ovarian masses.9 Ovarian tumors were
characterized by higher peak contrast enhance-
ment, a longer half wash-out time, and a greater
area under the enhancement curve (AUC) when
compared with benign disease. It is theorized
that these differences occur because of the com-
plex and tangled arrangement of the microvas-
1274
cularity and overall increased vascularity within
malignant ovarian tumors. However, this needs
to be verified in larger series.
This retrospective study analyzed the diagnos-
tic accuracy of contrast enhancement parameters
in an attempt to identify those that have the high-
est predictive value. It is hoped that this analysis
will enhance the use of this technique for the dif-
ferentiation of benign versus malignant ovarian
masses in an attempt to provide an accurate
means for the early detection of ovarian cancer.
Materials and Methods
Thirty-three consecutive patients ages 24 to 73
years (average SD, 48.3 2.1 years) who had
morphologically abnormal ovarian masses (solid
or cystic with papillary excrescences, focally
thickened walls, or irregular solid areas) smaller
than 10 cm who were referred for surgical treat-
ment were studied over a 2-year period from
January 2007 to January 2009. Retrospective anal-
ysis included data obtained from our previously
reported published series as well as from 10 addi-
tional patients.9 All patients were scheduled for
surgical treatment after evaluation by gynecolog-
ic oncologists and radiologists and were screened
for major intercurrent disease, particularly right-
to-left, bidirectional, or transient right-to-left car-
diac shunts, and hypersensitivity to perflutren,
which are contraindications to the administra-
tion of this ultrasound contrast agent.
This study was approved by the Institutional
Review Board, and written informed consent was
obtained from each patient. All women included
in this study were treated by bilateral salpingo-
oophorectomy using surgical laparoscopy or
laparotomy within 3 days of the sonographic
examination. Final histologic diagnoses were
obtained for all lesions included in this study and
used as reference standards.
As the first part of the examination, transvagi-
nal gray scale sonography was performed with
an iU22 scanner (Philips Healthcare, Bothell, WA)
and an 85 MHz convex transvaginal probe to
identify an ovarian mass. All scans were per-
formed by a single sonographer (P.K.W.). After
that, color Doppler sonography was used to
identify the area of the tumor with most promi-
nent vascularity. Once a region of interest (ROI)
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Fleischer et al

was assigned on the basis of the gray scale and time between the peak intensity and the point
color Doppler sonographic findings, a contrast- corresponding to the return to the baseline. The
enhanced study of the area was performed using half wash-out time (in seconds) was defined as
lowmechanical index (0.06) harmonics with the time between the peak enhancement and the
pulse inversion to optimize depiction of intra- time when half of the enhancement had disap-
venous contrast. peared. The AUC (in seconds1) was calculated
A 3-L/kg dose of a perflutren microbubble from the arrival of the contrast agent, defined as
contrast agent (Definity; Lantheus Medical the point of the increase in image intensity
Imaging, North Billerica, MA) was injected intra- greater than 10% above the baseline to the end of
venously as a bolus. Subsequently, a bolus of 10 the wash-out period. This parameter correlates
mL of 0.9% sodium chloride solution was given with the vascular volume of the mass.
to flush the vessel. The patients blood pressure, Statistical analysis was performed with means
respiration, heart rate, and oxygen saturation and 95% confidence intervals (CIs). The analysis
were monitored during and for 15 to 20 minutes of variance test was used to compare the contrast
after the procedure as per the manufacturers parameters of enhancing benign versus malig-
recommendation for Definity. A 3-minute cine nant ovarian masses. The results were consid-
loop recording in the PIH mode was started at ered significant at P < .05.
the time of the intravenous injection. The sonog-
rapher was instructed not to move the transduc- Results
er during the 3-minute recording. The acquired
3-minute cine loops were stored on the scanners A total of 36 masses in 33 consecutive patients
internal hard drive and exported to a computer were studied. Of them, 10 were malignant and
workstation for later analysis. After that, the 26 benign. The histologic types of the ovarian
injection was repeated (up to 2 injections of the masses are listed in Table 1. Of 8 primary ovari-
contrast agent per examined tumor). Both cine an neoplasms, 6 were classified as stage I or II
loops were analyzed, and the one that showed and 2 as stage III. Two tumors were breast can-
the most prominent enhancement for each cer metastases.
tumor was chosen for further evaluation.
Each 3-minute video clip was then analyzed
Figure 1. Contrast enhancement quantification parameters. The time to peak is the
offline. Late-phase microvascular imaging pro- time from injection to the peak intensity. The wash-out time is the time between the
jections were reconstructed with QLAB software peak intensity and the point corresponding to the return to the baseline. The half
(Philips Healthcare) and analyzed to improve wash-out time is the time between the peak enhancement and the time when half
of the enhancement had disappeared. The AUC (in seconds1) is calculated from the
lesion detectability. These maximum-intensity
arrival of the contrast agent to the end of the wash-out period.
projection images depict the overall vascularity of
selected ROIs. The ROI was manually selected to
cover the entire mass on the harmonic image.
The gray scale intensity of the signals inside the
selected ROI were analyzed, and the contrast
enhancement time-intensity curves for each
tumor were plotted and analyzed with the QLAB
software. The time-intensity curves were normal-
ized by subtracting the mean preinjection (base-
line) intensity value from each intensity level
(Figure 1). After that, the following parameters
were assessed: The detectable contrast enhance-
ment (in decibels) was defined as the increase in
image intensity greater than 10% above the base-
line. The time to peak (in seconds) was defined as
the time from injection to the peak intensity. The
wash-out time (in seconds) was defined as the

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Differentiating Benign From Malignant Ovarian Masses

Table 1. Histologic Types of Ovarian Masses When contrast enhancement dynamics were
Type n assessed, we found that malignant lesions had a
similar time to peak (26.2 5.9 versus 29.8 13.4
Benign (n = 26)
Endometrioma 10 seconds; P = .4), greater peak enhancement (21.3
Corpus luteum cyst 4 4.7 versus 8.3 5.7 dB; P < .001 ), a longer half
Serous cystadenofibroma 3 wash-out time (104.2 48.1 versus 32.2 18.9 sec-
Paraovarian/paratubal cyst 2
onds; P < .001), and a greater AUC (1807.2 588.3
Mucinous cystadenoma 2
Teratoma 2 versus 413.8 294.8 seconds1; P < .001) when
Serous cystadenoma 2 compared with enhancing benign lesions.
Fibroma 1 Examples of contrast enhancement and enhance-
Malignant (n = 10)
Serous adenocarcinoma 5
ment kinetics in both malignant and benign
Endometrioid adenocarcinoma 2 tumors are presented in Figures 2 and 3.
Breast cancer metastasis 2 The diagnostic accuracy of all examined criteria
Borderline mucinous cystadenocarcinoma 1 was evaluated by ROC analysis and is presented
in Table 2 and Figure 4. An AUC of greater than
787 seconds1 was the most accurate diagnostic
criterion for ovarian cancer, with 100.0% sensi-
All malignant tumors (100%) and 13 benign tivity and 96.2 specificity. Additionally, peak
lesions (50%) showed detectable contrast contrast enhancement of greater than 17.2 dB
enhancement (image intensity >10% above the (90.0% sensitivity and 98.3% specificity) and a
baseline) after Definity injection. Enhancing half wash-out time of greater than 41.0 seconds
benign lesions included 4 endometriomas, 2 (100.0% sensitivity and 92.3% specificity) proved
mucinous cystadenomas, 2 corpus luteum cysts, to be useful.
2 teratomas, 1 serous cystadenofibroma, 1 para- The criterion of peak enhancement of greater
ovarian cyst, and 1 fibroma. than 17.2 dB showed 1 false-negative result in a
case of endometrioid adenocarcinoma (peak
enhancement, 10.6 dB). A half wash-out time of
Figure 2. Ovarian fibroma (benign). Top right, Gray scale image showing a well- greater than 41.0 seconds showed 2 false-positive
circumscribed hypoechoic lesion within the left adnexa (ROI shown). Top left, Peak
results in a teratoma (half wash-out time, 64.2
enhancement PIH image showing severely diminished vascularity within the
tumor. Bottom, Pulse inversion harmonic time-intensity curve showing a time to seconds) and a corpus luteum cyst (75.8 sec-
peak of 31 seconds, very low peak intensity (0.41 dB), a short half wash-out time onds). An AUC of greater than 787 seconds1
(6 seconds), and a low AUC (15.3 seconds1). showed 1 false-positive result in a patient with an
endometrioma (AUC, 1085.2 seconds1).

Discussion

Our previous study explored differences in

enhancement parameters in benign versus
malignant ovarian masses.9 This expanded study
retrospectively analyzed receiver operator char-
acteristics for the time to peak, peak enhance-
ment, wash-out, and AUC (vascular volume). The
data obtained in this study and those reported
earlier suggest that, except for the wash-in time,
contrast enhancement parameters are signifi-
cantly different in benign versus malignant ovar-
ian masses. The wash-in time probably reflects
intrinsic circulation depending on cardiac con-
traction, blood pressure, and overall vascular
tone. Once blood circulates through the tumor,

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Fleischer et al

however, differences may reflect the unique A recent study using PET and CT that showed
branching patterns and vessel morphologic areas of abnormal increased metabolic activity
characteristics in the microvascularity of the considered highly suspicious for malignant
tumors. However, additional studies will be nec- tumors in preoperative discrimination of benign
essary to determine whether the parameters are versus malignant ovarian diseases found sensitiv-
indeed unique to most ovarian malignancies. ity of 100% and specificity of 92.5%.15 However,
The lack of screening tests for diagnosis of early- because of relative expense and limited availabili-
stage ovarian cancer is an important determinant ty as well as possible delays in referral and surgery
of the mortality rate for this disease.10 Because of that can result, routine use of fluorodeoxyglucose
the absence or subtlety of early symptoms, more PET and CT is not recommended.
than 70% of patients have a diagnosis of advanced Proteomic technologies have identified hun-
stage ovarian cancer.11 If diagnosed early, the 5- dreds of proteins that may have value for the
year survival rate for stage I disease is approxi- detection of ovarian cancer, but none as yet
mately 89.6%; for stage II disease, it is 70.7%; for have achieved clinical validation. Although this
stage IIIC disease, it is 32.5%; and for stage IV dis- promising technology has reported impressive
ease, it is 18.6%.12 The main goal of imaging tech- results, with sensitivities and specificities of up to
niques in this setting is to identify tumors that are 93% and 97%, respectively, it has varying repro-
likely to be malignant during early stages. ducibility, and results may be biased by the
Preoperative evaluation of adnexal masses has model of overfitting and artifacts in the sample
been performed by several methods. Notable preparation, processing and, patient selection.16
among these are the noninvasive diagnostic Transvaginal and transabdominal sonography
radiologic modalities such as transabdominal is the most commonly used imaging technique
and transvaginal gray scale sonography, for assessing the characteristics of various
3-dimensional sonography, color and power pelvic masses. Sonography often fails to differ-
Doppler sonography, computed tomography entiate between benign and malignant lesions,
(CT), magnetic resonance imaging, and positron
emission tomography (PET).
Computed tomography has not been clinically Figure 3. Ovarian adenocarcinoma (malignant). Top right, Gray scale image show-
ing a large solid/cystic lesion within an isoechoic lesion in the right adnexa (area of
useful for characterization of the adnexa.
interest traced). Top left, Peak enhancement PIH image showing markedly increased
However, the recent advances in CT technology vascularity within the tumor. Bottom, Pulse inversion harmonic time-intensity curve
and the availability of multidetector CT allowed showing a time to peak of 27 seconds, very high peak intensity (28 dB), a long half
better detection and improved characterization wash-out time (83 seconds), and a long AUC (1859 seconds1).
of adnexal masses. In a recent study, CT was able
to show 90% of adnexal masses.13 Lesions that
were not detected were either less than 5 mm in
diameter or were perceived as a single lesion
when in fact the patient had more than 1 adja-
cent lesion. Computed tomography is particu-
larly helpful in identification of fat components
in mature cystic teratomas. The authors of that
study reported that multidetector CT had sensi-
tivity of 90%, specificity of 88.76%, a positive
predictive value of 78.26%, a negative predictive
value of 95.18%, and overall diagnostic accuracy
of 89.15% in diagnosing malignancy.13
Magnetic resonance imaging helps locate large
solid masses and distinguish benign from frankly
malignant ovarian tumors, with overall accuracy
of 88% to 93%, but it is less accurate for border-
line ovarian tumors and small adnexal masses.14

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Differentiating Benign From Malignant Ovarian Masses

Table 2. Diagnostic Accuracy of Contrast-Enhanced Sonographic Criteria for Ovarian Cancer

Criterion Sensitivity, % 95% CI, % Specificity, % 95% CI, %

Time from bolus Injection to maximum >14.1 s 100.0 69.0100.0 57.7 36.976.6
Maximum enhancement >17.2 dB 90.0 55.598.3 100.0 86.7100.0
Half wash-out time >41.0 s 100.0 69.0100.0 92.3 74.898.8
AUC >787 s1 100.0 69.0100.0 96.2 80.399.4

and any small decrease in the false-positive rate
over gray scale sonography is at the cost of a
large drop in sensitivity.17,18 The accuracies of
gray scale sonography and color Doppler
imaging for distinguishing malignant from
benign tumors are 80% to 83% and 35% to
88%, respectively.1922 However, results of a
meta-analysis provide scientific evidence that
sonographic techniques that combine gray
scale morphologic assessment with tumor
vascularity imaging information in a diagnos-
tic system are significantly better in ovarian
lesion characterization than Doppler arterial
resistance measurements, color Doppler flow
imaging, or gray scale morphologic informa-
tion alone.23

Figure 4. Receiver operating characteristic curves of examined contrast-enhanced sonographic criteria for ovarian cancer. A, Time
from bolus injection to maximum enhancement. B, Maximum enhancement. C, Half wash-out time. D, Area under the enhancement
curve. The dots on the curves indicate the points of greatest diagnostic accuracy.

A B

C D

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Several previous studies have addressed the
use of contrast-enhanced sonography for benign
and malignant tumors by showing greater
enhancement of malignant tumors on Doppler
imaging.24 However, simple documentation of
tumor enhancement may not be sufficient
because some benign tumors show detectable
contrast enhancement. This limitation can be
addressed by assessment of the contrast enhance-
ment kinetics. Only 2 studies have been published
that used kinetic parameters of the contrast agent
to compare benign with malignant tumors in the
power Doppler mode. In the first study, enhance-
ment ratio, uptake time, and wash-out parame-
ters were excellent for discriminating benign
from malignant ovarian tumors in women.6 In
the second study, the wash-out time and AUC
were shown to be more accurate than Doppler
sonography for discrimination of ovarian cancer
from benign tumors.7
Characterization of ovarian lesions may be
improved with new imaging modalities such as
PIH sonography. In PIH sonography, multiple
identical pulses with reversed polarity are trans-
mitted down each ray line instead of only a sin-
gle pulse, as is done with conventional imaging.
When the resultant returned waveforms are
added, the harmonic component gives the mul-
tiplied harmonic level of a single waveform,
whereas all linear fundamental components are
canceled out more effectively. This technique,
instead of using a narrow receive filter tuned
around harmonic frequency components,
allows the use of broader transmit and receive
bandwidths for improved resolution.
Our results show that contrast-enhanced PIH
sonography is a more appropriate method for
characterizing blood flow dynamics in ovarian
tumors, and it can provide an important tool to
aid differential diagnoses between benign and
malignant ovarian tumors. In our group, ovarian
tumors were characterized by higher peak con-
trast enhancement, a longer half wash-out time,
and a greater AUC when compared with benign
disease.
Our data indicate that peak enhancement and
wash-out parameters had the best sensitivity
and specificity for ovarian cancer diagnosis. On
the other hand, the wash-in parameter was not
as predictive, possibly related to its variability
J Ultrasound Med 2009; 28:12731280
Fleischer et al
based on circulation times and injection rates. It
is thought that these data should be helpful in
the prospective evaluation of ovarian masses.
Larger studies are needed to evaluate the effica-
cy of including contrast-enhanced TVS as a
means to improve early detection of early-stage
ovarian cancer.
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