17.1 Introduction

Vibro‐acoustography (VA), a new ultrasound‐based imaging modality, has gained much interest in the medical field in recent years. This acoustic imaging modality uses the radiation force of ultrasound to induce low‐frequency vibrations in the tissue and creates images of the acoustic response. This chapter focuses on potential biomedical applications of VA. The purpose is to bring together the results of various studies, ex vivo and in vivo, on breast, thyroid, human arteries, and prostate. Here, after a brief discussion about the general principle of VA, we describe the applications. Future developments and potential impact of VA in breast and thyroid imaging are also discussed.

17.2 Background

New imaging modalities based on radiation force of ultrasound have been developed for characterizing mechanical properties of soft tissues. All of these methods aim to differentiate normal tissue from diseased tissue by exploiting the elasticity as a contrast mechanism. Ultrasound radiation force vibrates and deforms soft tissues noninvasively, and the resulting mechanical response of tissues provides elasticity information useful in detection and differentiation.

17.2.1 General Principles of VA and Method

VA is a noninvasive imaging technique that produces palpation‐like information by measuring the acoustic response of a tissue or object to a vibration induced by the radiation force of ultrasound [1, 2]. The VA technique can be summarized in three steps:

1. applying a localized oscillating force on or inside the tissue to induce vibration,
2. recording the resulting sound arising from the vibrating tissue, and
3. creating an image from the recorded acoustic signal [3].

The basic concept of the VA technique is using the force of ultrasound. Numerous investigators have studied the theory of acoustic radiation force [4–7], and the biomedical applications of acoustic radiation force has been described by Sarvazyan et al. [8].

VA uses two ultrasound beams at slightly different frequencies, f ₁ and f ₂, and these beams focus at a common location to produce a modulated ultrasound radiation force at Δf and creates an acoustic field. The focused US beam is scanned across the tissue. A hydrophone placed nearby obtains acoustic emissions to form an image. The resulting VA images are speckle free. Figure 17.1 shows a simplified VA system [3, 9].

17.3 Application of Vibro‐acoustography for Detection of Calcifications

Ex vivo VA has been used to characterize and image biological tissues [10–14]. VA is capable of detecting macro‐ and micro‐calcifications and delineates these calcifications with high contrast. Microcalcifications are common findings in a wide spectrum of breast lesions, ranging from benign to malignant [15]. The clinical application of VA in detection of microcalcifications in radiologically dense breasts found in younger, pregnant, or lactating women has great potential. The ability of VA to detect calcification has been studied in vitro in a variety of human tissues including breast [16–20], prostate [21, 22], heart valve leaflets [23], and human arteries [24].

We present an example of breast tissue microcalcification detected by VA. A bright spot at the center of X‐ray represents the microcalcification. VA of this tissue clearly shows the microcalcification also as a bright spot. The shape and position of the microcalcification match well with the corresponding spot in the X‐ray. VA also shows the structure of the soft tissue (Figure 17.2).

Figure 17.3 shows VA images of two carotid arteries. The left artery is from a young person and has no calcification. The right artery is from an older person. The arteries were immersed in a water tank for scanning. The Δf in this experiment is 7 kHz. The VA image shows no calcification on the left artery, while some calcium deposit near the bifurcation on the right artery is seen as a bright region.

Figure 17.4 shows VA images of an aortic valve and the corresponding radiography. The VA image resembles the radiography of this heart valve. The arrow in both images points to a small piece of calcification, about 1 mm in diameter, that is visible in both the radiograph and the vibro‐acoustic scans. This image demonstrates that VA may be used to identify early calcification buildup on heart valves.

VA scanning has been conducted on a series of prostate tissues. Imaging results of ex vivo prostate tissues reveals the potency of VA as a promising tool to detect abnormalities, delineate tissue structures and anatomical zones, and locate calcifications. We present the X‐ray, US, and VA images of a prostate tissue in Figure 17.5. Tissue X‐ray shows a cluster of micro and macro‐calcification, but the US image is not informative. The VA image of this prostate tissue clearly demonstrates a group of large calcifications as well as the anatomical zones, peripheral zone (PZ) and central zone (CZ).

17.4 In Vivo Breast Vibro‐acoustography

17.4.2 Method of In Vivo VA and Results

A VA system was integrated into a stereotactic mammography machine (Fischer Imaging Inc., Mammotest^TM system) and has been tested for in vivo breast imaging [18]. This combined system enables the operator to obtain matching VA and mammography images of the human breast. The patient lies down in a prone position while her breast is passed through a hole in the bed. The breast is placed between the back panel, which includes the X‐ray detector, and a sliding compression panel. The compression panel consists of a window covered with a thin latex membrane transparent to US beam. An annular confocal US transducer is located behind the window. VA images were acquired in the cranial‐caudal view at different depths from the skin. The VA image area was 5 × 5 cm. A hydrophone is placed on the side of the breast to receive the acoustic emission generated by the radiation force of US. The simplified diagram of the VA system is shown in Figure 17.6.

In vivo breast VA using the integrated system has been studied on 60 female patients with breast lesions [31]. Benign and malignant breast cases will be discussed as follows.

A female patient in her 40s with a palpable mass in her right breast has been examined. Targeted US examination on palpable site revealed a 29 × 19 ×13 mm lobulated well‐defined, mildly hypoechoic mass. Diagnostic mammography showed heterogeneous, dense parenchyma in both breasts, but did not show the palpable mass. A marker was placed on the skin to identify the location of the palpable mass (Figure 17.7). The result of pathology has proved the mass to be a fibroadenoma. The importance of this case is that VA can identify masses not seen on mammograms.

A case of fibroadenoma is shown in Figure 17.8. The patient is in her 70s. Scattered fibroglandular densities and two masses were identified on both breasts in mammography screening. The diagnostic mammography showed a 2 cm sharply marginated mass with coarse lobulation on the right breast (Figure 17.8a). The VA image of the right breast clearly showed the margins and mass with the gentle coarse lobulation that are classic findings in fibroadenoma. The calcification seen in mammogram is at a different depth and is not visible at the depth of this VA image.

Figure 17.9 shows another case, a woman in her 60s, whose screening and diagnostic mammography identified a small group of suspicious microcalcifications of different sizes and shapes along with minimal architectural distortion and increased soft‐tissue density. Targeted US confirmed a 5 × 7 cm hypoechoic lesion with an irregular border and posterior shadowing. The biopsy revealed an invasive ductal carcinoma, Nottingham grade II/III, in her right breast. The VA image was able to identify the lesion as a small irregular mass with fine spiculation that is characteristic of this type of malignant mass. The characteristic spiculation was difficult to see in the mammogram.

A patient in her 60s with mammographically dense breasts was examined. During mammography, a spiculated mass with no calcification was noted in her left breast (Figure 17.10a). Breast MRI identified a large, enhancing, irregular, spiculated mass measuring 8.5 × 3.3 × 5.4 cm in the left breast (Figure 17.10b). This was associated with left breast shrinkage and nipple inversion. VA of this breast also identified the lesion, which extended beyond the 5 × 5 cm of the imaging window, with remarkable spiculation that is suggestive of malignancy (Figure 17.10c). The pathology revealed the mass as grade I infiltrating lobular carcinoma. This case demonstrates that VA can detect breast cancer.

VA studies using a confocal VA system demonstrate the ability of VA in identifying various breast abnormalities, including microcalcifications as well as benign and malignant masses with relatively high specificity [3, 31]. This system was equipped with a water tank to accommodate acoustic coupling to tissue during scanning. A drawback of this system is limited access to parts of the breast near the chest wall and slower image acquisition.

To overcome the limitations of the annular confocal VA system, to shorten the scanning time, and to provide optimum coverage of the breast for imaging, we have advanced our imaging system by implementing VA on a clinical ultrasound scanner equipped with a “quasi‐2D” array transducer. We call this technique “quasi‐2D vibro‐acoustography” (Q2‐DVA). A clinical ultrasound scanner (GE Vivid 7, GE Healthcare Ultrasound Cardiology, Horten, Norway) was modified to perform both ultrasound imaging and VA. The Q2‐D transducer array is in the form of a matrix with multiple rows and columns of ultrasound elements. This transducer is electronically constructed to generate an ultrasound beam resembling that of the confocal transducer. The newly designed VA system was tested on patients with breast lesions [32]. Our results indicate that our newly modified VA system can identify benign and malignant solid breast lesions and can easily detect microcalcification. Our results suggest that with further development, Q2‐DVA can provide high‐resolution images and has the potential to provide diagnostic information in the clinical setting and may be used as a complementary tool in support of other clinical imaging modalities. Here, we present the preliminary in vivo results of breast VA obtained by the new VA system equipped with the array Q2‐D transducer [33].

First we present a case of invasive ductal carcinoma. The patient is a woman in her 50s with a palpable lump in her right breast. Her mammography demonstrated a heterogeneous dense breast with a central focal asymmetry (dashed yellow contour) and small microcalcifications (red arrows). Targeted clinical US showed a 21 mm × 14 mm irregular hypoechoic mass with an indistinct margin and posterior acoustic shadowing. VA images obtained with the handheld 1.75D probe show the mass and dimensions of the lesions are larger than those of the clinical US image (Figure 17.11). Similar findings have been seen and confirmed in our previous VA study [31] where malignant breast masses appeared lager in VA than in B‐mode US. The pathology of this mass revealed it to be invasive ductal carcinoma, Nottingham grade II.

VA imaging of a benign fibroadenoma is presented here. A woman in her 40s with a palpable lump in her left breast was examined. Diagnostic mammography showed a heterogeneous dense breast with a 15 mm well‐circumscribed solid mass at the anterior depth (yellow arrow), shown in Figure 17.12. Her targeted US demonstrated a corresponding solid round mass with circumscribed margins. VA images were obtained at a depth of 20 mm and revealed a well‐defined mass (yellow arrows). US guided biopsy revealed a benign fibroadenoma.

A diagnostic mammogram in a patient discovered a partially obscured oval mass (yellow arrow in Figure 17.13a). A targeted transverse US image demonstrated an oval hypoechoic mass with posterior shadowing measuring 19 × 10 × 10 mm (Figure 17.13b). The VA image obtained at a depth of 30 mm showed an elongated mass with a well‐defined border, suggesting a benign lesion. The biopsy result revealed the lesion as sclerosing fibroadenoma with densely hyalinized stroma. The sclerosing accounts for the shadowing posterior to the lesion. The mass is well‐visualized (dark) in the VA image. The lesion shown to be at deeper depths by VA than shown in B‐mode imaging, due to more compression applied during the clinical US imaging procedure.

The results of the study using VA implemented on a clinical ultrasound scanner equipped with a Q2‐D US transducer indicate that this new VA has the potential to identify and differentiate breast lesions. The Q2‐DVA system can also overcome the difficulties associated with using confocal VA, such as the inability to image lesions close to the chest wall or the discomfort associated with patient positioning and compression. Our results provide a foundation for further development of clinical VA systems and further investigation in a larger group of patients.

17.5 In Vivo Thyroid Vibro‐acoustography

Ultrasonography of thyroid does not always lead to conclusive results. Furthermore, current ultrasound imaging technology has a poor performance in detecting important microcalcifications and its role in diagnosis of malignant nodules is limited and carries poor specificity [34]. Uncertainties in ultrasound and other thyroid imaging methods lead to a large number of unnecessary biopsies. Fine needle aspiration biopsy (FNAB) is associated with false‐negative rate of up to 11%, a false‐positive rate of up to 8%, with a sensitivity of about 80%, and a specificity of 73% [35–38]. Vibro‐acoustography is sensitive not only to the ultrasound properties of the tissue but also to the dynamic behavior at low frequencies; thus VA offers information that is not available with conventional ultrasound.

We have investigated the feasibility of using VA with a handheld array US transducer for detection and localization of thyroid nodules [39]. The results demonstrate that VA implemented on a clinical ultrasound scanner equipped with a handheld array US transducer can identify and has potential to differentiate thyroid nodules.

A 48‐year‐old female patient with a benign thyroid nodule was examined. B‐mode ultrasound identifies large hypoechoic nodule with small cystic appearance measuring about 47 × 27 mm (x‐z dimensions). The nodule appears on C‐mode US, taken at 2 cm depth, measuring about 44.2 × 30.5 mm (x‐z dimensions). The VA at 2.0 cm depth reveals the large nodule with distinct margin measuring about 30.5 mm in the y direction and more than 47 mm in the x direction, with its side margins extending out of VA image window. Its shape and location corresponds to the C‐scan US at 2 cm depth (Figure 17.14).

US and VA images of the right side thyroid of a 37‐year‐old male with papillary thyroid carcinoma are shown in Figure 17.15. Targeted US shows a cystic nodule measuring about 1.0 × 1.3 × 1.4 cm with peripheral calcifications, one of the characteristics of papillary carcinoma. The VA scan at 2.5 cm depth identifies the nodule with a cystic appearance in slightly larger dimensions as well as some peripheral calcifications with greater clarity than shown in the US image, denoted by arrows.

These results suggest that VA may have a potential as a clinical tool in thyroid imaging; however, VA is not intended to replace B‐mode US or FNAB. Larger studies are needed to determine sensitivity and specificity of this imaging tool in thyroid cancer detection and differentiation.

17.6 Limitations and Further Future Plans

This VA system can overcome the difficulties associated with using confocal VA, such as inability to image the lesions close to the chest wall, and the discomfort associated with patient positioning, breast compression, and longer scanning duration. There were a few problems that were encountered in the in vivo study. First, a system artifact that is associated with steering the VA beams across the aperture, which created streaks in the VA image. We have developed an algorithm to correct for these streaks [40], but this algorithm can diminish image details. Effort is continued to find alternatives to correct this artifact. In addition, motion artifacts are associated with patient breathing occurring during in vivo VA scanning and manifested as jagged image detail. Our results should provide a foundation for further development of clinical VA systems and further investigation in a larger group of patients.

One step in further development of a VA system is using a reconfigurable array (RCA) transducer that would provide another route for clinical implementation of VA imaging. VA using a RCA transducer has important advantages. Using a 2D RCA transducer eliminates the need for mechanical translation as is needed with a confocal transducer [2] or a linear array transducer [40]. The RCA electronic scanning is expected to take about 2 ms per pixel, which is 6‐fold improvement over the confocal transducer [41]. The simulation study performed by our group provides a strong framework for optimization of VA imaging with RCA transducers for different medical applications. Further development and implantation with RCA transducer is in progress to achieve the optimum VA imaging.

Acknowledgments

The work described in this chapter was supported by grants from grant BCTR0504550 from the Susan G. Komen for the cure and National Institutes of Health (NIH) grants R21 CA121579, R01CA127235, R21 EB00535, R33 EB00535, R01EB017213, R01CA148994, R01CA148994‐S1, R01CA168575, and R01CA174723 from the NIH‐National Cancer Institute. The content of this chapter is solely the responsibility of the author and does not necessarily represent the official views of NIH. The authors are very grateful to Dr. James Greenleaf and Dr. Matthew Urban for their collaboration during the study and Ms. Adriana Gregory for providing a VA scheme figure for this chapter.

Disclosure: MF and AA disclose that MF and Mayo Clinic hold patents on VA technology (discussed in this chapter) as a potential financial conflict of interest. MF has received royalties from a company that has licensed the VA technology from Mayo Clinic.

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