BackgroundIn addition to breast imaging, ultrasound offers the potential for characterizing and distinguishing between benign and malignant breast tissues due to their different microstructures and material properties. The aim of this study was to determine if high-frequency ultrasound (20-80 MHz) can provide pathology sensitive measurements for the ex vivo detection of cancer in margins during breast conservation surgery.MethodsUltrasonic tests were performed on resected margins and other tissues obtained from 17 patients, resulting in 34 specimens that were classified into 15 pathology categories. Pulse-echo and through-transmission measurements were acquired from a total of 57 sites on the specimens using two single-element 50-MHz transducers. Ultrasonic attenuation and sound speed were obtained from time-domain waveforms. The waveforms were further processed with fast Fourier transforms to provide ultrasonic spectra and cepstra. The ultrasonic measurements and pathology types were analyzed for correlations. The specimens were additionally re-classified into five pathology types to determine specificity and sensitivity values.ResultsThe density of peaks in the ultrasonic spectra, a measure of spectral structure, showed significantly higher values for carcinomas and precancerous pathologies such as atypical ductal hyperplasia than for normal tissue. The slopes of the cepstra for non-malignant pathologies displayed significantly greater values that differentiated them from the normal and malignant tissues. The attenuation coefficients were sensitive to fat necrosis, fibroadenoma, and invasive lobular carcinoma. Specificities and sensitivities for differentiating pathologies from normal tissue were 100% and 86% for lobular carcinomas, 100% and 74% for ductal carcinomas, 80% and 82% for benign pathologies, and 80% and 100% for fat necrosis and adenomas. Specificities and sensitivities were also determined for differentiating each pathology type from the other four using a multivariate analysis. The results yielded specificities and sensitivities of 85% and 86% for lobular carcinomas, 85% and 74% for ductal carcinomas, 100% and 61% for benign pathologies, 84% and 100% for fat necrosis and adenomas, and 98% and 80% for normal tissue.ConclusionsResults from high-frequency ultrasonic measurements of human breast tissue specimens indicate that characteristics in the ultrasonic attenuation, spectra, and cepstra can be used to differentiate between normal, benign, and malignant breast pathologies.

Normal and malignant mammary epithelial cells were studied using laboratory measurements, wavelet analysis, and numerical simulations of monolayer cell cultures to determine whether microscopic breast cancer can be detected in vitro with high-frequency ultrasound. Pulse-echo waveforms were acquired by immersing a broadband, unfocused 50-MHz transducer in the growth media of cell culture well plates and collecting the first reflection from the well bottoms. The simulations included a multilayer pulse-reflection model and a model of two-dimensional arrays of spherical cells and nuclei. The results show that normal and malignant cells produce time-domain signals and spectral features that are significantly different.

Developing an in vivo ultrasonic detection method for cancer would be valuable for applications such as the real-time assessment of surgical margins during breast conservation surgery. To study the spectral signatures of normal and malignant mammary epithelial cells, computer simulations and laboratory measurements were performed on 2-D cell cultures. The simulations modeled the cell monolayers as arrays of spherical cells containing spherical nuclei. Multipole expansions and boundary conditions were used to solve for the acoustic scattering from each cell. Backscattered wave fields were summed at the transducer face to calculate the measured ultrasonic amplitude. The measurements used a high-frequency NDT pulser-receiver with a broadband, unfocused 50-MHz immersion transducer. Waveforms were acquired by immersing the transducer in the growth media of cell culture well plates and collecting the first reflection from the well bottoms. Simulated spectra and preliminary data indicated that a confluent cell monolayer was detectable at 75–100 MHz. To reduce variability in test results, an in situ monitoring system was designed to periodically collect ultrasonic waveforms inside a tissue culture incubator over several days without moving the well plate or transducer during monolayer growth. Results from these and other tests will be presented. [Work supported by NIH 5R21CA131798-02.]

High-frequency ultrasonic spectroscopy is a promising approach for the in vivo detection of cancer in applications such as margin assessments during breast cancer surgery. To advance this approach, a multiple scattering model was developed to more fully understand and analyze ultrasonic backscatter data in the 10–100-MHz region from breast tissues in various stages of tumor progression. The model uses an iterative multipole approach to simulate the multiple scattering of shear and longitudinal waves between nucleated cells in a histologically accurate tissue representation. Previously, concentric spheres were used to model the nucleus and cytoplasm of cells organized in complex, hierarchical tissue structures consisting of alveolar cavities and up to 2075 cells [Doyle et al., J. Acoust. Soc. Am. 125, 1751–1767 (2009)]. The simulations used addition theorems to model multiple scattering and showed significant spectral changes that correlated with tumorigenesis. To increase the fidelity of the simulations, the scattering model has been expanded to incorporate spheroidal and cuboidal cells, non-centered nuclei, mixed tissue types, and duct-like channels representing the three-dimensional luminal structure in breast tissue. Theory, simulation results, and experimental data will be presented. [Work supported by NIH 1R21CA131798-01A1.]