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 and MRI has not been clinically useful for characterization of the adnexa. They may be used to locate large solid masses and distinguish benign from frankly malignant ovarian tumors, with overall accuracy of 88% to 93% (1). However, cross sectional imaging appear less accurate for borderline ovarian tumors and small adnexal masses. A recent study using PET/CT showed that detection of the areas of abnormal increased metabolic activity considered highly suspicious for malignant tumors in preoperative discrimination of benign versus malignant ovarian diseases with sensitivity of 100% and specificity of 92.5% (2). However, because of relative expense and limited availability as well as possible delays in referral and surgery, routine use of PET/CT is not recommended in this setting.
Transvaginal sonography (TVS) is the initial diagnostic 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 differential diagnosis of morphologically suspicious adnexal masses, especially in postmenopausal women, typically includes ovarian cancer. Conventional sonographic criteria for diagnosing ovarian cancer, is based on the morphological classification of ovarian masses. Malignancy is unlikely in those simple cysts with smooth walls, but the presence of a solid mass or solid projections into the cyst cavity significantly increases the risk of malignancy.
Sonography often fails to differentiate between benign and malignant lesions (3). 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 (4, 5). As the result of these studies, many morphological sonographic scoring systems have been developed, including features such as the presence of papillary projections or irregular or thick septae (6-7). 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 diagnostic system are significantly better in ovarian lesion characterization than Doppler arterial resistance measurements, color Doppler flow imaging, or gray scale morphologic information alone (8).
Detection of early stage EOC is difficult. In multiple studies, sonography has not been proven to decrease mortality from ovarian cancer (9, 10). The reason for this is likely multifactorial, however, any means of improving visualization of the ovary, may be helpful in the detection of early lesions. The following innovative sonographic techniques are currently used to improve identification of early stage EOC.
Ultrasound Contrast Imaging - Contrast-enhanced sonography is a great tool for detection and characterization of angiogenesis. Ultrasound contrast agents for intravenous use consist of small, stabilized microbubbles usually on the order of 1-10 microns in diameter (11). These bubbles cause increased echogenicity and are thus termed, echoenhancers. The agents create this effect by causing an acoustic impedance mismatch with the adjacent tissues. This, in turn, causes increased scattering and reflection of the sound beam, thereby leading to increased sonographic signal and increased echogenicity. The degree of echo-enhancement depends on a multitude of factors including the size of the microbubble, the concentration of contrast agent, and the compressibility of the bubbles as well as the interrogating ultrasound frequency (11).
Pulse Inversion Harmonic Imaging (PIH) - In Pulse Inversion Harmonic imaging two pulses are transmitted down each ray line. The first is a normal pulse, the second is an inverted replica of the first so that wherever there was a positive pressure on the first pulse there is an equal negative pressure on the second. Any linear target such as soft tissues responds equally to positive and negative pressures will reflect back to the transducer equal but opposite echoes. Microbubbles respond in non-linear fashion and do not reflect identical inverted waveforms. This allows the separation of the fundamental component of the bubble echoes from the background, improving resolution, and increasing sensitivity to contrast agents.
Microvascular Imaging (MVI). Pulse Inversion Harmonic Imaging has led to the ability to image individual bubbles in small vessels within and adjacent to tumors with very low blood flow rates. MicroVascular Imaging allows to capture and track the bubbles as they go around and through these small leaky vessels, providing improved visualization of slowly perfused tumors. The MIP technique involves selection of maximum pixel values throughout consecutive, PIH images as the bubbles enter of replenish replenish the imaging plane. A composite image showing the vascular architecture is constructed and can be used to improve aour abitily to detect areas of abnormal vascularity.
Flash Contrast Imaging While the ability to visualize microvascular blood flow in real-time is a significant advancement, the ability to destroy contrast at will, also has diagnostic potential. By destroying the contrast within the scanplane, a “negative bolus” of contrast is created locally. Then, the time it takes for contrast to refill the scan plane and the amount of the contrast in the ROI may be used for estimation of microvessel cross-sectional area, blood flow velocity and tumor perfusion (12).
Contrast enhanced sonography may significantly improve the diagnostic ability of ultrasound to identify early microvascular changes that are known to be associated with early stage ovarian cancer (11, 13). Currently, contrast agents play a pivotal role in the imaging modalities of computed tomography (CT) and magnetic resonance imaging (MRI) by increasing image conspicuity. By increasing the density or signal intensity of a particular organ and thus, the signal to noise ratio, contrast agents help to detect and characterize parenchymal lesions. Indeed, contrast agents have received such widespread acceptance, that a CT exam performed without intravenous contrast for many indications is now considered limited. Our preclinical studies demonstrated that the intravenous contrast agents in ultrasound holds great promise in a multitude of potential clinical applications, especially in identifying aberrant vascular changes associated with malignancy (11, 14-18).
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. According to Kupesic et al the use of a contrast agent with three-dimensional power Doppler sonography showed diagnostic efficiency (95.6%) that was superior to that of nonenhanced three-dimensional power Doppler sonography (86.7%) (19). 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 enhancement 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. Ordén et al demonstrated that after microbubble contrast agent injection, malignant and benign adnexal lesions behave differently in degree, onset, and duration of Doppler US enhancement. Dopler CEUS perameters in that study had 79-100% sensitivity of 79-100% and 77-92% specificity (20). Marret et al reported that washout times and areas under the curves were significantly greater in ovarian malignancies than in other benign tumors (P < .001), leading to sensitivity estimates between 96% and 100% and specificity estimates between 83 and 98%. They concluded that Doppler CEUS parameters had slightly higher sensitivity and slightly lower specificity when compared with transvaginal sonographic variables of the resistive index and serum cancer antigen 125 levels (21).
Our clinical studies explored differences in enhancement parameters in benign versus malignant ovarian masses using the new method of CEUS using pulse inversion harmonic imaging (21, 22). This method produces more reliable estimates of tumor microvascular perfusion and provides more consistent results compared to Doppler CEUS. We reported that all malignant tumors and 50% of benign ones showed detectable contrast enhancement (image intensity >10% above the baseline) after contrast injection. 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 seconds; 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. Our data suggest that, except for the wash-in time, contrast enhancement parameters are significantly different in benign versus malignant ovarian masses. The wash-in time probably reflects intrinsic circulation depending on cardiac contraction, blood pressure, and overall vascular tone. Once blood circulates through the tumor, however, differences may reflect the unique branching patterns and vessel morphologic characteristics in the microvascularity of the tumors. The area under the enhancement curve 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 a half wash-out time of greater than 41.0 seconds (100.0% sensitivity and 92.3% specificity) proved to be useful. These 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 summary, contrast enhancement patterns significantly differ between benign and malignant ovarian masses. The addition of a vascular ultrasound contrast agent allows a more complete delineation of the vascular anatomy through enhancement of the signal strength from small vessels and provides an entirely new opportunity to time the transit of an injected bolus. Contrast sonography has higher sensitivity and specificity to differentiate between benign and malignant lesions than conventional TV-US and for discriminating between endometriosis and detecting occult Stage I disease.
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