Contrast-enhanced ultrasound-guided Sentinel lymph node biopsy of the ocular conjunctiva.

OBJECTIVES/HYPOTHESIS: Sentinel lymph node biopsy (SLNB) has been utilized for cutaneous melanoma and other malignancies arising from the eye and ocular adnexa. Currently, SLNB requires blue dyes and/or radiopharmaceuticals; both of which have significant shortcomings. This study sought to evaluate the feasibility of SLNB with the use of real-time, contrast-enhanced ultrasound (CEUS) as an alternative technique for tumors arising in the conjunctiva. STUDY DESIGN: Prospective feasibility study in a porcine model. METHODS: Twelve experiments were performed on six non-tumor-bearing Yorkshire swine. An ultrasound contrast agent, Sonazoid (GE Healthcare, Oslo, Norway), (99m) technetium ((99m) Tc), and methylene blue (MB) (Covidien, Mansfield, MA) were injected in the ocular conjunctiva. Sentinel lymph nodes (SLNs) were localized with CEUS and findings were compared to that of MB and (99m) Tc. Fisher exact test was used. RESULTS: Contrast-enhanced SLNs were identified within an average of 6.2 minutes from time of injection of Sonazoid. A total of 17 SLNs were identified by at least one of the three techniques. Correlation between Sonazoid and (99m) Tc was 94.1% (16/17 SLNs). Correlation between (99m) Tc and MB was 88.2% (15/17). One SLN that was positive for (99m) Tc but negative for Sonazoid and was considered to be a false positive (1/17); findings were similar for MB (1/17). Differences between the three techniques were not significant (P = .886). CONCLUSIONS: CEUS-guided injection of conjunctiva for SLNB is technically feasible and correlates well with standard detection techniques. This technique shows promise for rapid, real-time, intraoperative imaging for SLNB, using a widely available imaging modality and avoiding the need for radiopharmaceuticals. LEVEL OF EVIDENCE: NA

Contrast-enhanced sonography for detection of secondary lymph nodes in a melanoma tumor animal model.

OBJECTIVES: To investigate the use of contrast-enhanced ultrasound imaging (US) for detection of secondary lymph nodes (LNs) in a naturally occurring melanoma swine model compared to surgery and pathologic assessment. METHODS: Twenty-seven Sinclair swine were studied. The perfluorobutane microbubble contrast agent Sonazoid (GE Healthcare, Oslo, Norway) was administered (1.0 mL total dose) around the melanoma, and contrast-enhanced US was used to localize contrast-enhanced sentinel lymph nodes (SLNs). Then Sonazoid (dose, 0.25-1.0 mL) was injected into the SLNs to detect contrast-enhanced efferent lymphatic channels and secondary LNs. After peritumoral injection of blue dye, a surgeon (blinded to the contrast-enhanced US results) performed a radical LN dissection. Contrast-enhanced US was used to guide removal of any enhanced secondary LNs left after radical LN dissection. Clustered conditional logistic regression analyzed the benefit of contrast-enhanced US-directed secondary LN dissection over radical LN dissection using pathologic findings as the reference standard. RESULTS: A total of 268 secondary LNs were resected, with 59 (22%) containing metastases. Contrast-enhanced US detected 92 secondary LNs; 248 were identified by radical LN dissection; and 68 were identified by both methods. Metastases were detected in 20% (51 of 248) and 40% (37 of 92) of the secondary LNs identified by radical LN dissection and contrast-enhanced US, respectively. Thus, secondary LNs detected by contrast-enhanced US were nearly 5 times more likely to contain metastases than secondary LNs removed by radical LN dissection (odds ratio, 4.8; P < .0001). Twenty-two of the 180 secondary LNs (12%) identified only by radical LN dissection contained metastases, whereas contrast-enhanced US identified 20 secondary LNs after the surgeon completed the radical LN dissection, of which 8 (40%) contained metastases. CONCLUSIONS: Secondary LNs can be detected by using contrast-enhanced US after injection of Sonazoid into SLNs. Secondary LNs detected with contrast-enhanced US are significantly more likely to contain metastases than those removed by radical LN dissection.

Guidelines and good clinical practice recommendations for Contrast Enhanced Ultrasound (CEUS) in the liver - update 2012: A WFUMB-EFSUMB initiative in cooperation with representatives of AFSUMB, AIUM, ASUM, FLAUS and ICUS.

Initially, a set of guidelines for the use of ultrasound contrast agents was published in 2004 dealing only with liver applications. A second edition of the guidelines in 2008 reflected changes in the available contrast agents and updated the guidelines for the liver, as well as implementing some non-liver applications. Time has moved on, and the need for international guidelines on the use of CEUS in the liver has become apparent. The present document describes the third iteration of recommendations for the hepatic use of contrast enhanced ultrasound (CEUS) using contrast specific imaging techniques. This joint WFUMB-EFSUMB initiative has implicated experts from major leading ultrasound societies worldwide. These liver CEUS guidelines are simultaneously published in the official journals of both organizing federations (i.e., Ultrasound in Medicine and Biology for WFUMB and Ultraschall in der Medizin/European Journal of Ultrasound for EFSUMB). These guidelines and recommendations provide general advice on the use of all currently clinically available ultrasound contrast agents (UCA). They are intended to create standard protocols for the use and administration of UCA in liver applications on an international basis and improve the management of patients worldwide.

Contrast-enhanced ultrasound imaging of sentinel lymph nodes after peritumoral administration of Sonazoid in a melanoma tumor animal model.

OBJECTIVES: The purpose of this study was to compare lymphosonography (ie, contrast-enhanced ultrasound imaging [US] after interstitial injection of a US contrast agent) for the detection of sentinel lymph nodes (SLNs) in swine with naturally occurring melanoma tumors to lymphoscintigraphy using blue dye-guided surgical dissection as the reference standard. Also, we sought to determine if lymphosonography can be used to characterize SLNs. METHODS: Sixty-three swine with 104 melanomas were evaluated. Contrast-specific US was performed after peritumoral injection (1 mL dose) of Sonazoid (GE Healthcare, Oslo, Norway). Lymphoscintigraphy was performed after peritumoral injections of technetium Tc 99m sulfur colloid. Peritumoral injection of 1% Lymphazurin (Ben Venue Labs, Inc, Bedford, OH) was used to guide SLN resection. The accuracy of SLN detection with the two imaging modalities was compared using the McNemar test. The SLNs were qualitatively and quantitatively characterized as benign or malignant based on the lymphosonography results with histopathology and RNA analyses used as the reference standards. RESULTS: Blue dye-guided surgery identified 351 SLNs. Lymphosonography detected 293 SLNs and 11 false-positives, while lymphoscintigraphy detected 231 SLNs and 20 false-positives. The accuracy of SLN detection was 81.8% for lymphosonography, which was significantly higher than the 63.2% achieved with lymphoscintigraphy (P < .0001). The accuracy of lymphosonography for SLN characterization was 80%. When the size of the enhanced SLN was taken into consideration to characterize SLNs, the accuracy was 86%. CONCLUSIONS: Lymphosonography is statistically better than lymphoscintigraphy for the detection of SLNs in this animal model. The ability to use lymphosonography as a means to characterize SLNs as benign or malignant is limited.

Contrast enhanced maximum intensity projection ultrasound imaging for assessing angiogenesis in murine glioma and breast tumor models: A comparative study.

The purpose of this study was to prospectively compare noninvasive, quantitative measures of vascularity obtained from four contrast enhanced ultrasound (US) techniques to four invasive immunohistochemical markers of tumor angiogenesis in a large group of murine xenografts. Glioma (C6) or breast cancer (NMU) cells were implanted in 144 rats. The contrast agent Optison (GE Healthcare, Princeton, NJ) was injected in a tail vein (dose: 0.4ml/kg). Power Doppler imaging (PDI), pulse-subtraction harmonic imaging (PSHI), flash-echo imaging (FEI), and Microflow imaging (MFI; a technique creating maximum intensity projection images over time) was performed with an Aplio scanner (Toshiba America Medical Systems, Tustin, CA) and a 7.5MHz linear array. Fractional tumor neovascularity was calculated from digital clips of contrast US, while the relative area stained was calculated from specimens. Results were compared using a factorial, repeated measures ANOVA, linear regression and z-tests. The tortuous morphology of tumor neovessels was visualized better with MFI than with the other US modes. Cell line, implantation method and contrast US imaging technique were significant parameters in the ANOVA model (p<0.05). The strongest correlation determined by linear regression in the C6 model was between PSHI and percent area stained with CD31 (r=0.37, p<0.0001). In the NMU model the strongest correlation was between FEI and COX-2 (r=0.46, p<0.0001). There were no statistically significant differences between correlations obtained with the various US methods (p>0.05). In conclusion, the largest study of contrast US of murine xenografts to date has been conducted and quantitative contrast enhanced US measures of tumor neovascularity in glioma and breast cancer xenograft models appear to provide a noninvasive marker for angiogenesis; although the best method for monitoring angiogenesis was not conclusively established.

Thyroid lymphosonography: a novel method for evaluating lymphatic drainage.

OBJECTIVES: We evaluated lymphosonography, or contrast-enhanced, ultrasonography (US)-guided sentinel lymph node (SLN) detection, as a technique for demonstrating the lymphatic drainage of the thyroid gland. METHODS: In this prospective animal study, four 50-kg Yorkshire swine underwent transcutaneous injection of a US contrast agent and methylene blue dye into the thyroid gland. Contrast-enhanced US was used to identify draining lymphatic channels and SLNs. Sentinel node biopsy was conducted. Subsequently, bilateral neck and upper mediastinal dissection was carried out. RESULTS: In 3 of 4 cases, a blue dye-positive and US contrast-positive SLN was identified. We identified SLNs in level IV in 2 cases. One case revealed 2 adjacent nodes in the superior mediastinum. In 1 case, a lymphatic channel was identified traveling into the mediastinum, but exposure of the SLN could not be obtained. No residual blue dye-positive or US contrast-positive nodes were identified on subsequent dissection. CONCLUSIONS: Lymphosonography of the thyroid gland in a porcine model correlates well with blue dye-guided sentinel node biopsy and is technically feasible, although in some cases access to the SLN may be difficult. This technique could potentially enable a detailed analysis of thyroidal lymphatic drainage if applied to humans.

Contrast-enhanced ultrasound: what is the evidence and what are the obstacles?

OBJECTIVE: Although ultrasound contrast agents (UCAs) are popular and widely used in Europe and Asia, the U.S. Food and Drug Administration (FDA) has not approved a microbubble agent for radiology imaging in the United States. Herein, we discuss the evidence for and the obstacles to using UCAs for contrast-enhanced ultrasound (CEUS). CONCLUSION: Despite the obstacles to the use of UCAs for CEUS including regulatory and practice patterns, the evidence indicates that radiologists and patients will be missing an effectual imaging option if we do not encourage the use of CEUS and strongly support the approval of UCAs by the FDA. The evidence outweighs the obstacles: CEUS is cost-effective; can be performed at the bedside; uses no ionizing radiation; has no nephrotoxicity; and, most importantly, can provide accurate diagnostic information comparable to CT and MRI.

Lymphosonographic sentinel node biopsy of the supraglottis in a swine model.

OBJECTIVE: To test the feasibility of a novel contrast-enhanced ultrasound (CEUS) technique, or lymphosonography, for sentinel node biopsy (SNB) of the supraglottis in a porcine model. STUDY DESIGN AND SETTING: In this prospective, nonrandomized animal study, blue dye and ultrasound contrast agent were injected into the supraglottis in seven 50-kg Yorkshire swine. Transcutaneous CEUS was used to identify real-time lymphatic flow of contrast through lymph channels (LC) to the sentinel lymph node (SLN). SNB was carried out, visually identifying a blue node, with the assistance of intraoperative CEUS. Bilateral modified radical neck dissections were performed to search for any residual contrast-positive or blue SLNs. RESULTS: In each case, at least one SLN was identified by preoperative CEUS. A total of 12 nodes were identified on preoperative CEUS, and 11 of 12 nodes were stained with blue dye (91.7%). No residual blue or contrast-positive nodes were identified on neck dissection. CONCLUSIONS: Lymphosonographic SNB of the supraglottis in a porcine model is technically feasible, and yields results comparable to traditional blue dye-guided techniques. No "shine-through" effect or nonsequential nodal enhancement occurred. This technique holds promise for sentinel node biopsy and allows a novel method for in vivo investigation of the lymphatic system.

Comparing contrast-enhanced color flow imaging and pathological measures of breast lesion vascularity.

This study was conducted to compare quantifiable measures of vascularity obtained from contrast-enhanced color flow images of breast lesions to pathologic vascularity measurements. Nineteen patients with solid breast masses received Levovist Injection (10 mL at 300 mg/mL; Berlex Laboratories, Montville, NJ, USA). Color flow images of the mass pre and post contrast were obtained using an HDI 3000 scanner (Philips Medical Systems, Bothell, WA, USA) optimized for clinical scanning on an individual basis. After surgical removal, specimens were sectioned in the same planes as the ultrasound images and stained with an endothelial cell marker (CD31). Microvessel area (MVA) and intratumoral microvessel density (MVD) were determined for vessels 10-19 microm, 20-29 microm, 30-39 microm, 40-49 microm and > or =50 microm in diameter using a microscope and image processing software. From the ultrasound images, the number of color pixels before and after contrast administration relative to the total area of the breast mass was calculated as a first-order measure of fractional tumor vascularity. Vascularity measures were compared using reverse stepwise multiple linear regression analysis. In total, 58 pathology slides (with 8,106 frames) and 185 ultrasound images were analyzed. There was a significant increase in flow visualization pre to post Levovist injection (p = 0.001), but no differences were found between the 11 benign and the eight malignant lesions (p > 0.35). Ultrasound vascularity measurements post contrast correlated significantly with pathology (0.15 < or = r2 < or = 0.46; p < 0.03). The 30-39 microm vessel range contributed most significantly to the MVD relationship (p < 0.001), whereas the MVA was mainly influenced by vessels 20-29 microm (p < 0.004). Precontrast ultrasound only correlated with pathology for relative MVA (r2 = 0.16; p = 0.01). In conclusion, contrast-enhanced color flow imaging provides a noninvasive measure of breast tumor neovascularity, corresponding mainly to vessels 20-39 microm in diameter, when used in a typical clinical setting.

Ultrasound-guided contrast-enhanced sentinel node biopsy of the head and neck in a porcine model.

OBJECTIVE: To test the feasibility of contrast-enhanced ultrasound (CEUS)-guided sentinel lymph node biopsy (SNB) of the head and neck in a porcine model. STUDY DESIGN AND SETTING: In this prospective, nonrandomized study, methylene blue and Sonazoid were injected into the lateral tongue or floor of mouth (FOM) of four swine. Real-time CEUS was used to identify contrast in the lymphatic channels flowing to the sentinel lymph node (SLN). Endoscopic or open SNB was performed. Neck dissection was then performed, and the residual nodal packet was examined for remaining contrast-enhancing or blue dye-stained nodes. RESULTS: In all eight procedures, the SLN was visualized with ultrasound and blue dye. Seven procedures identified a single SLN, and one identified two SLNs. Subsequent neck dissections revealed no other nodes containing methylene blue or contrast in the nodal specimen or operative bed. CONCLUSION/SIGNIFICANCE: CEUS-guided SNB of the head and neck in swine is feasible, with success comparable to blue dye-guided SNB. This technique may offer several advantages over traditional techniques, and warrants further study.

Contrast enhanced ultrasound for radio frequency ablation of canine prostates: initial results.

PURPOSE: We determined the feasibility of contrast enhanced ultrasound for radio frequency ablation of the entire prostate as a method of minimally invasive treatment for prostate cancer in a canine model. MATERIALS AND METHODS: Approval of the Institutional Animal Use and Care committee was obtained. Initially 5 dogs (group 1) were tested using variable power (5 to 30 W), time (4 to 12 minutes), bolus (0.01 to 0.04 ml/kg) and infusion (3 to 11 ml per minute at 0.015 microl/kg) injections of an ultrasound contrast agent with conventional grayscale power Doppler and pulse inversion harmonic imaging to establish optimal parameters. Subsequently 4 dogs (group 2) underwent entire prostate ablation using parameters based on group 1. The size of the thermal lesions and residual viable tissue was measured with ImageJ software (National Institutes of Health, Bethesda, Maryland) on ultrasound and pathological study. Linear regression and Student's t test were used for statistical analysis. RESULTS: A bolus of 0.04 ml/kg, an infusion of 11 ml per minute at 0.015 microl/kg and the contrast enhanced pulse inversion harmonic imaging mode were ranked best for guiding ablation. Thermal lesion volume was proportional to ablation power and time. There was no significant difference in measured thermal lesion size in group 1 between ultrasound and pathological findings (mean +/- SD 1.51 +/- 0.74 and 1.46 +/- 0.74 cm3, p = 0.56) or in residual viable tissue in group 2 (0.43 +/- 0.043 and 0.41 +/- 0.291 cm3, p = 0.21). The average volume of prostate ablation achieved in group 2 was 96.3%. CONCLUSIONS: Contrast enhanced pulse inversion harmonic imaging is able to guide, monitor and control radio frequency ablation of the entire prostate.

Contrast-enhanced sonographic imaging of lymphatic channels and sentinel lymph nodes.

OBJECTIVE: The purpose of this study was to determine whether lymphatic channels (LCs) and sentinel lymph nodes (SLNs) could be detected on sonographic imaging after subcutaneous, submucosal, or parenchymal injections of a sonographic contrast agent (ie, lymphosonography) in a variety of anatomic locations in several animal models. METHODS: Eight swine, 7 canines, 4 rabbits, and a monkey were used for these evaluations. Gray scale pulse inversion harmonic imaging of the LCs and the SLNs was performed after subcutaneous (n = 58), submucosal (n = 14), or parenchymal (n = 8) injections of a tissue-specific sonographic contrast agent (Sonazoid; GE Healthcare, Oslo, Norway). In many instances, blue dye was injected into the same locations as Sonazoid, and surgical dissection of the SLNs and LCs was performed for comparison. Scanning electron microscopy (SEM) of contrast-enhanced and control lymph nodes from 2 rabbits was performed to determine the mechanism of contrast agent uptake and retention within SLNs. RESULTS: After subcutaneous, submucosal, or parenchymal contrast agent injections, gray scale pulse inversion harmonic imaging could be used to identify the number and location(s) of LCs and SLNs. After subcutaneous, submucosal, or parenchymal contrast agent injections, Sonazoid was confined to the SLNs (ie, contrast enhancement was not detected in the second-echelon nodes). There was good agreement between the results of lymphosonography and blue dye with surgical dissection in identifying the regional LCs and SLNs. Scanning electron microscopy identified vacuoles representing intact contrast microbubbles within contrast-enhanced SLN macrophages, which were not present in the control lymph nodes. CONCLUSIONS: Lymphosonography can be used to detect lymphatic drainage pathways and SLNs in a variety of animal models.

Sentinel lymph nodes in a swine model with melanoma: contrast-enhanced lymphatic US.

PURPOSE: To determine if lymphatic channels and sentinel lymph nodes (SLNs) with and without metastases can be detected with lymphatic ultrasonography (US) after peritumoral injection of a US contrast agent and to determine if lymphatic US can be used to assess SLNs for the presence of metastatic infiltration. MATERIALS AND METHODS: Six swine with 17 melanomas were evaluated. Conventional gray-scale, color flow, and gray-scale phase-inversion harmonic US examinations were performed. A US contrast agent was administered in four sites around each melanoma (1-mL total dose). Lymphoscintigraphy was followed by injection of a blue dye and then dissection. SLNs identified at lymphatic US were characterized by two readers in consensus as normal or as having metastases; results were compared with histologic findings. Statistical analyses included the sign test and the kappa statistic. RESULTS: Lymphatic US depicted 28 SLNs, while lymphoscintigraphy depicted 27 "hot spots" suspected of representing SLNs (including two false-positive findings). Dissection after blue dye injection helped identify 31 SLNs. There were no false-positive US findings for SLN detection. Five of six nodes not seen with lymphoscintigraphy were detected with lymphatic US. The accuracy of SLN detection was 90% (28 of 31) for lymphatic US and 81% (25 of 31) for lymphoscintigraphy (P =.29). Lymphatic US correctly depicted metastases in 19 of 20 SLNs, and five of the eight normal SLNs were correctly characterized, with an accuracy of 86% (kappa = 0.62). CONCLUSION: Detection of SLNs with lymphatic US compared favorably with that at lymphoscintigraphy. Lymphatic US can depict metastases within the SLN, which was not possible with lymphoscintigraphy.

Diagnosing breast lesions with contrast-enhanced 3-dimensional power Doppler imaging.

OBJECTIVE: To compare mammography with contrast-enhanced 2- and 3-dimensional power Doppler imaging for the diagnosis of breast cancer. METHODS: Fifty-five patients, who underwent breast biopsies with histopathologic assessment, participated in a study of mammography and contrast-enhanced sonography. Levovist (Berlex Laboratories, Montville, NJ) and Optison (Mallinckrodt, St Louis, MO) were administrated to 22 and 33 patients, respectively. Precontrast and postcontrast 2-dimensional power Doppler data of the lesion were obtained with an HDI 3000 system (Philips Medical Systems, Bothell, WA), and 3-dimensional data were acquired with an LIS 6000A system (Life Imaging Systems Inc, London, Ontario, Canada). Two independent and blinded readers assessed diagnosis. Receiver operating characteristic curves were computed individually and in combination for mammography and 2- and 3-dimensional sonography (before and after contrast). Histopathologic and imaging parameters were compared by Mann-Whitney statistics. RESULTS: Mammographic findings were available for 50 patients, biopsy for 54, and 2- and 3-dimensional sonographic images for 53 and 52, respectively. Of the 50 patients who had all 4 measures, 15 (30%) had malignancies. The areas under the receiver operating characteristic curve for the diagnosis of breast cancer were 0.51 for 2-dimensional contrast-enhanced imaging, 0.60 for 3-dimensional power Doppler imaging, and 0.76 for 3-dimensional contrast-enhanced imaging (P < .01). Mammography produced an area of 0.86, which increased when combined with 3-dimensional contrast-enhanced imaging to 0.90 and with all sonographic modalities to 0.96 (P < .001). The histopathologic diagnosis of benign or malignant correlated with the presence or absence of anastomoses and with the degree of vascularity assessed with contrast-enhanced 3-dimensional power Doppler imaging (P = .007 and .02). CONCLUSIONS: Contrast-enhanced 3-dimensional power Doppler imaging increases the ability to diagnose breast cancer relative to conventional 2- and 3-dimensional sonographic imaging.

Computer-aided classification of breast masses in ultrasonic B-scans using a multiparameter approach.

Classification of breast masses in ultrasonic B-scan images is undertaken using a multiparameter approach. The parameters are generated on the basis of a non-Rayleigh statistic model of the backscattered envelope from the breast tissue. They can be computed automatically with minimal clinical intervention once the location of the mass is known. A new discriminant is developed that combines these parameters linearly. It is seen that this new discriminant performs classification of masses into benign or malignant better than the classification by any one of the individual parameters. The data set studied consisted of 99 cases (70 patients with benign masses and 29 patients with malignant masses). The areas under the receiver operating characteristic (ROC) curves (Az) and statistical attributes of the areas were studied to establish the enhancement in performance. The Az value after combining all the parameters was found to be 0.8701. Upon combining this parameter with the level of suspicion (LOS) scores of a radiologist, the performance is further enhanced with an area under the (empirical) ROC of 0.94 having an operating point at a sensitivity of 0.965 and specificity of 0.87. It is suggested that this automated approach may hold promise as a means of classifying breast masses.

Classification of breast masses in ultrasonic B scans using Nakagami and K distributions.

Classification of breast masses in greyscale ultrasound images is undertaken using a multiparameter approach. Five parameters reflecting the non-Rayleigh nature of the backscattered echo were used. These parameters, based mostly on the Nakagami and K distributions, were extracted from the envelope of the echoes at the site, boundary, spiculated region and shadow of the mass. They were combined to create a linear discriminant. The performance of this discriminant for the classification of breast masses was studied using a data set consisting of 70 benign and 29 malignant cases. The Az value for the discriminant was 0.96 +/- 0.02, showing great promise in the classification of masses into benign and malignant ones. The discriminant was combined with the level of suspicion values of the radiologist leading to an Az value of 0.97 +/- 0.014. The parameters used here can be calculated with minimal clinical intervention, so the method proposed here may therefore be easily implemented in an automated fashion. These results also support the recent reports suggesting that ultrasound may help as an adjunct to mammography in breast cancer diagnostics to enhance the classification of breast masses.

ROC analysis of ultrasound tissue characterization classifiers for breast cancer diagnosis.

Breast cancer diagnosis through ultrasound tissue characterization was studied using receiver operating characteristic (ROC) analysis of combinations of acoustic features, patient age, and radiological findings. A feature fusion method was devised that operates even if only partial diagnostic data are available. The ROC methodology uses ordinal dominance theory and bootstrap resampling to evaluate A(z) and confidence intervals in simple as well as paired data analyses. The combined diagnostic feature had an A(z) of 0.96 with a confidence interval of at a significance level of 0.05. The combined features show statistically significant improvement over prebiopsy radiological findings. These results indicate that ultrasound tissue characterization, in combination with patient record and clinical findings, may greatly reduce the need to perform biopsies of benign breast lesions.