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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 seconds 1 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.

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

T 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; 28:1273–1280 • 0278-4297/09/$3.50

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-

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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 8–5 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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was assigned on the basis of the gray scale and color Doppler sonographic findings, a contrast- enhanced study of the area was performed using low–mechanical index (0.06) harmonics with pulse inversion to optimize depiction of intra- venous contrast. A 3-µL/kg dose of a perflutren microbubble contrast agent (Definity; Lantheus Medical

Imaging, North Billerica, MA) was injected intra- venously as a bolus. Subsequently, a bolus of 10

mL of 0.9% sodium chloride solution was given

to flush the vessel. The patient’s blood pressure, respiration, heart rate, and oxygen saturation were monitored during and for 15 to 20 minutes after the procedure as per the manufacturer’s recommendation for Definity. A 3-minute cine loop recording in the PIH mode was started at

the time of the intravenous injection. The sonog-

rapher was instructed not to move the transduc- er during the 3-minute recording. The acquired 3-minute cine loops were stored on the scanner’s internal hard drive and exported to a computer workstation for later analysis. After that, the injection was repeated (up to 2 injections of the contrast agent per examined tumor). Both cine loops were analyzed, and the one that showed the most prominent enhancement for each tumor was chosen for further evaluation. Each 3-minute video clip was then analyzed offline. Late-phase microvascular imaging pro- jections were reconstructed with QLAB software (Philips Healthcare) and analyzed to improve lesion detectability. These maximum-intensity 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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Fleischer et al

time between the peak intensity and the point corresponding to the return to the baseline. The half wash-out time (in seconds) was defined as the time between the peak enhancement and the time when half of the enhancement had disap-

peared. The AUC (in seconds 1 ) was calculated from the arrival of the contrast agent, defined as the point of the increase in image intensity greater than 10% above the baseline to the end of the wash-out period. This parameter correlates with the vascular volume of the mass. Statistical analysis was performed with means and 95% confidence intervals (CIs). The analysis

of variance test was used to compare the contrast

parameters of enhancing benign versus malig- nant ovarian masses. The results were consid- ered significant at P < .05.

Results

A total of 36 masses in 33 consecutive patients

were studied. Of them, 10 were malignant and 26 benign. The histologic types of the ovarian masses are listed in Table 1. Of 8 primary ovari- an neoplasms, 6 were classified as stage I or II and 2 as stage III. Two tumors were breast can- cer metastases.

Figure 1. Contrast enhancement quantification parameters. The time to peak is the time from injection to the peak intensity. The wash-out time is the time between the peak intensity and the point corresponding to the return to the baseline. The half wash-out time is the time between the peak enhancement and the time when half of the enhancement had disappeared. The AUC (in seconds 1 ) is calculated from the arrival of the contrast agent to the end of the wash-out period.

seconds – 1 ) is calculated from the arrival of the contrast agent to the end

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Differentiating Benign From Malignant Ovarian Masses

Table 1. Histologic Types of Ovarian Masses

Type

n

Benign (n = 26) Endometrioma Corpus luteum cyst Serous cystadenofibroma Paraovarian/paratubal cyst Mucinous cystadenoma Teratoma Serous cystadenoma Fibroma Malignant (n = 10) Serous adenocarcinoma Endometrioid adenocarcinoma Breast cancer metastasis Borderline mucinous cystadenocarcinoma

10

4

3

2

2

2

2

1

5

2

2

1

All malignant tumors (100%) and 13 benign lesions (50%) showed detectable contrast enhancement (image intensity >10% above the baseline) after Definity injection. Enhancing benign lesions included 4 endometriomas, 2 mucinous cystadenomas, 2 corpus luteum cysts, 2 teratomas, 1 serous cystadenofibroma, 1 para- ovarian cyst, and 1 fibroma.

Figure 2. Ovarian fibroma (benign). Top right, Gray scale image showing a well- circumscribed hypoechoic lesion within the left adnexa (ROI shown). Top left, Peak enhancement PIH image showing severely diminished vascularity within the tumor. Bottom, Pulse inversion harmonic time-intensity curve showing a time to peak of 31 seconds, very low peak intensity (0.41 dB), a short half wash-out time (6 seconds), and a low AUC (15.3 seconds 1 ).

time (6 seconds), and a low AUC (15.3 seconds – 1 ). 1 2 7 6

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When contrast enhancement dynamics were assessed, we found that malignant lesions had a similar time to peak (26.2 ± 5.9 versus 29.8 ± 13.4 seconds; P = .4), greater peak enhancement (21.3 ± 4.7 versus 8.3 ± 5.7 dB; P < .001 ), a longer half wash-out time (104.2 ± 48.1 versus 32.2 ± 18.9 sec- onds; P < .001), and a greater AUC (1807.2 ± 588.3 versus 413.8 ± 294.8 seconds 1 ; P < .001) when compared with enhancing benign lesions. Examples of contrast enhancement and enhance- ment kinetics in both malignant and benign tumors are presented in Figures 2 and 3. The diagnostic accuracy of all examined criteria was evaluated by ROC analysis and is presented in Table 2 and Figure 4. An AUC of greater than 787 seconds 1 was the most accurate diagnostic criterion for ovarian cancer, with 100.0% sensi- tivity and 96.2 specificity. Additionally, peak contrast enhancement of greater than 17.2 dB (90.0% sensitivity and 98.3% specificity) and a half wash-out time of greater than 41.0 seconds (100.0% sensitivity and 92.3% specificity) proved to be useful. The criterion of peak enhancement of greater 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 greater than 41.0 seconds showed 2 false-positive results in a teratoma (half wash-out time, 64.2 seconds) and a corpus luteum cyst (75.8 sec- onds). An AUC of greater than 787 seconds 1 showed 1 false-positive result in a patient with an endometrioma (AUC, 1085.2 seconds 1 ).

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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however, differences may reflect the unique branching patterns and vessel morphologic characteristics in the microvascularity of the tumors. However, additional studies will be nec- essary to determine whether the parameters are indeed unique to most ovarian malignancies. The lack of screening tests for diagnosis of early- stage ovarian cancer is an important determinant of the mortality rate for this disease. 10 Because of the absence or subtlety of early symptoms, more than 70% of patients have a diagnosis of advanced stage ovarian cancer. 11 If diagnosed early, the 5- year survival rate for stage I disease is approxi- mately 89.6%; for stage II disease, it is 70.7%; for stage IIIC disease, it is 32.5%; and for stage IV dis- ease, it is 18.6%. 12 The main goal of imaging tech- niques in this setting is to identify tumors that are likely to be malignant during early stages. Preoperative evaluation of adnexal masses has been performed by several methods. Notable among these are the noninvasive diagnostic radiologic modalities such as transabdominal and transvaginal gray scale sonography, 3-dimensional sonography, color and power Doppler sonography, computed tomography (CT), magnetic resonance imaging, and positron emission tomography (PET). Computed tomography has not been clinically useful for characterization of the adnexa. However, the recent advances in CT technology and the availability of multidetector CT allowed better detection and improved characterization 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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A recent study using PET and CT that showed areas of abnormal increased metabolic activity considered highly suspicious for malignant tumors in preoperative discrimination of benign versus malignant ovarian diseases found sensitiv- ity of 100% and specificity of 92.5%. 15 However, because of relative expense and limited availabili- ty as well as possible delays in referral and surgery that can result, routine use of fluorodeoxyglucose PET and CT is not recommended. Proteomic technologies have identified hun- dreds of proteins that may have value for the detection of ovarian cancer, but none as yet have achieved clinical validation. Although this promising technology has reported impressive results, with sensitivities and specificities of up to 93% and 97%, respectively, it has varying repro- ducibility, and results may be biased by the model of overfitting and artifacts in the sample preparation, processing and, patient selection. 16 Transvaginal and transabdominal sonography is the most commonly used imaging technique for assessing the characteristics of various pelvic masses. Sonography often fails to differ- entiate between benign and malignant lesions,

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 interest traced). Top left, Peak enhancement PIH image showing markedly increased vascularity within the tumor. Bottom, Pulse inversion harmonic time-intensity curve showing a time to peak of 27 seconds, very high peak intensity (28 dB), a long half wash-out time (83 seconds), and a long AUC (1859 seconds 1 ).

high peak intensity (28 dB), a long half wash-out time (83 seconds), and a long AUC

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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

69.0–100.0

57.7

36.9–76.6

Maximum enhancement >17.2 dB

90.0

55.5–98.3

100.0

86.7–100.0

Half wash-out time >41.0 s

100.0

69.0–100.0

92.3

74.8–98.8

AUC >787 s 1

100.0

69.0–100.0

96.2

80.3–99.4

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.

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A

C

the curves indicate the points of greatest diagnostic accuracy. 1 2 7 8 A C B
the curves indicate the points of greatest diagnostic accuracy. 1 2 7 8 A C B

B

D

the curves indicate the points of greatest diagnostic accuracy. 1 2 7 8 A C B
the curves indicate the points of greatest diagnostic accuracy. 1 2 7 8 A C B

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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

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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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