Contrast-enhanced three-dimensional subharmonic ultrasound imaging

Breast cancer is the most frequent type of cancer among women, and accounts for 25% of all cancers across both sexes. There are various markers of malignancy. The angiogenic process that fuels the growth of tumors is one of the potential early indicators for differentiating between malignant and benign tumors. Recently, the use of microbubble based contrast agents in combination with ultrasound imaging has allowed for the development of contrast agent specific imaging modes that provide visualization of tumor neovascularity.;This thesis evaluates the feasibility of using contrast-enhanced ultrasound imaging to generate quantifiable parameters of vascularity in breast lesions in a clinical population. This work is divided into two parts, the pre-clinical and clinical work. The pre-clinical work consisted of developing and implementing three-dimensional (3D) harmonic (HI) and subharmonic (SHI) imaging modes on a commercial ultrasound scanner. The ability to visualize and quantify blood perfusion using these modes is investigated in an in vivo canine model. The clinical study involved imaging women (n=237) identified with breast lesions using 3D HI and 3D SHI. The ultrasound contrast agent (UCA) used for this study was Definity (Lantheus Medical Imaging, N Billerica, MA). All lesions were biopsied after imaging and pathology was used as the reference standard. Time-intensity curves were generated based on UCA flow within the lesions and were used to evaluate vascular heterogeneity and develop parametric maps of blood perfusion and area under the curve.;In terms of pre-clinical work, both 3D HI and 3D SHI were able to provide visualization of flow and, thus generate estimates of perfusion. However, 3D SHI provided near complete tissue suppression and improved visualization of UCA flow compared to 3D HI. Microsphere perfusion data (reference standard) showed an average perfusion of 9.30 +/- 6.60 and 5.15 +/- 3.42 mL/min/g pre and post ligation, respectively. The reference standard showed significant correlation with overall 3D HI perfusion estimates (r=0.38; P=0.007), but correlated better with 3D SHI (r=0.62; P<0.001). For the clinical study, biopsies resulted in 164 (75%) benign and 55 (25%) malignant lesions. Benign lesions primarily consisted of fibroadenomas (31%) while invasive ductal carcinomas (76%) made up the majority of malignant cases. For contrast-enhanced ultrasound, 3D SHI showed UCA flow in 83 (58 benign and 25 malignant) lesions while 3D HI only detected flow in 8 (5 benign and 3 malignant) lesions. Vascularity was observed with PDI in 95 lesions (69 benign and 26 malignant). Comparison of UCA flow parameters between malignant and benign lesions resulted in significantly longer transit times for invasive ductal carcinomas compared to fibroadenomas (28.97+/-3.21 vs. 20.95+/-2.22 seconds, p=0.0398). Overall, malignant lesions had a longer transit time compared to benign lesions, but this was not a statistically significant finding. Analysis of vascular heterogeneity using 3D SHI time-intensity curve volumes showed a significant difference in vascularity between central and peripheral sections (1.83+/-0.16 vs. 1.15+/-0.09, p=0.0003) for the benign cases, whereas malignant lesions showed no significant difference (1.72+/-0.33 vs. 1.26+/-0.21, p=0.23), indicative of more vascular coverage. Parametric maps of PER and AUC were able to highlight the variations in the vascularity for individual pixels in the lesion volume. It was observed that for malignant cases, specifically for IDC's the vascularity was dispersed throughout the lesion volume with feeding vessels being present around the lesion. Benign cases exhibited a more structured vasculature, usually with a single large vessel within the lesion volume. "Heat-maps" of the varying levels of PER and AUC across the lesion were generated in order visualize the localized variations in the behavior of vascularity. Malignant lesions had a significantly (p=0.032) higher number of perfused pixels/slice within the lesion volume compared to benign lesions. For specific lesion types, IDC's were significantly higher perfused (p=0.048) compared to the fibroadenomas. This thesis presents findings that show contrast-enhanced ultrasound imaging of breast lesions is feasible, specifically using a new contrast imaging mode; subharmonic imaging and capable of providing supplementary information to mammography for characterization of lesions.