Michelle Heijblom

Visualizing breast cancer using the Twente photoacoustic mammoscope: what do we learn from twelve new patient measurements?

We acquired images of breast malignancies using the Twente photoacoustic mammoscope (PAM), to obtain more information about the clinical feasibility and limitations of photoacoustic mammography. Results were compared with conventional imaging and histopathology. Ten technically acceptable measurements on patients with malignancies and two measurements on patients with cysts were performed. In the reconstructed volumes of all ten malignant lesions, a confined region with high contrast with respect to the background could be seen. In all malignant cases, the PA contrast of the abnormality was higher than the contrast on x-ray mammography. The PA contrast appeared to be independent of the mammographically estimated breast density and was absent in the case of cysts. Technological improvements to the instrument and further studies on less suspicious lesions are planned to further investigate the potential of PAM.

Photoacoustic image patterns of breast carcinoma and comparisons with Magnetic Resonance Imaging and vascular stained histopathology

Photoacoustic (optoacoustic) imaging can visualize vasculature deep in tissue using the high contrast of hemoglobin to light, with the high-resolution possible with ultrasound detection. Since angiogenesis, one of the hallmarks of cancer, leads to increased vascularity, photoacoustics holds promise in imaging breast cancer as shown in proof-of-principle studies. Here for the first time, we investigate if there are specific photoacoustic appearances of breast malignancies which can be related to the tumor vascularity, using an upgraded research imaging system, the Twente Photoacoustic Mammoscope. In addition to comparisons with x-ray and ultrasound images, in subsets of cases the photoacoustic images were compared with MR images, and with vascular staining in histopathology. We were able to identify lesions in suspect breasts at the expected locations in 28 of 29 cases. We discovered generally three types of photoacoustic appearances reminiscent of contrast enhancement types reported in MR imaging of breast malignancies, and first insights were gained into the relationship with tumor vascularity.

Poly(vinyl alcohol) gels as photoacoustic breast phantoms revisited.

A popular phantom in photoacoustic imaging is poly(vinyl alcohol) (PVA) hydrogel fabricated by freezing and thawing (F-T) aqueous solutions of PVA. The material possesses acoustic and optical properties similar to those of tissue. Earlier work characterized PVA gels in small test specimens where temperature distributions during F-T are relatively homogeneous. In this work, in breast-sized samples we observed substantial temperature differences between the shallow regions and the interior during the F-T procedure. We investigated whether spatial variations were also present in the acoustic and optical properties. The speed of sound, acoustic attenuation, and optical reduced scattering coefficients were measured on specimens sampled at various locations in a large phantom. In general, the properties matched values quoted for breast tissue. But while acoustic properties were relatively homogeneous, the reduced scattering was substantially different at the surface compared with the interior. We correlated these variations with gel microstructure inspected using scanning electron microscopy. Interestingly, the phantoms reduced scattering spatial distribution matches the optical properties of the standard two-layer breast model used in x ray dosimetry. We conclude that large PVA samples prepared using the standard recipe make excellent breast tissue phantoms.

Imaging Tumor Vascularization for Detection and Diagnosis of Breast Cancer

Breast cancer is one of the major causes of morbidity and mortality in western women. Current screening and diagnostic imaging modalities, like x-ray mammography and ultrasonography, focus on morphological changes of breast tissue. However, these techniques still miss some cancers and often falsely detect cancer. The sensitivity and specificity for detecting the disease can probably be improved by focusing on the consequences of tumor angiogenesis: the increased microvessel density with altered vascular characteristics. In this review, various techniques for imaging breast tumor vasculature are discussed. Dynamic contrast enhanced magnetic resonance imaging is the most-used imaging modality in this field. It has a proven high sensitivity, but a low specificity and cannot be applied in all women. Moreover, it has problems with detecting ductal carcinoma in situ (DCIS). On the contrary, contrast enhanced digital mammography can detect DCIS, but requires the use of ionizing radiation. Contrast enhanced ultrasound provides real-time information about true intravascular blood volume and flow. However, this technique still has difficulties with discriminating benign from malignant tissue. Moreover, these three imaging modalities all require the injection of contrast agents. Two relatively new techniques that do not use external contrast agents are diffuse optical imaging and photoacoustic imaging. Both visualize the increased concentration of hemoglobin in malignant tissue and thereby provide a high intrinsic contrast.

Clinical Photoacoustic Breast Imaging: The Twente experience.

Globally, breast cancer is the most frequently occurring malignancy in women and the leading cause of cancer deaths, with up to half a million women dying of the disease in 2008. Early detection and accurate diagnosis of breast cancer is crucial for optimizing survival chances, with imaging technologies playing a major role. X-ray mammography (XRM) and ultrasound (US) imaging, however, suffer from nonoptimal sensitivity and specificity. Furthermore, X-ray mammography uses ionizing radiation and painful breast compression and has poor performance in dense breasts. For US imaging, interoperator dependence and poor soft tissue contrast are drawbacks.

Appearance of breast cysts in planar geometry photoacoustic mammography using 1064-nm excitation

Abstract. In the search for improved imaging modalities for detection and diagnosis of breast cancer, a high negative prediction value is also important. Photoacoustic (optoacoustic) imaging is a relatively new technique that has high potential for visualizing breast malignancies, but little is known about the photoacoustic appearance of benign lesions. In this work, we investigate the visibility of benign breast cysts in forward-mode photoacoustic mammography using 1064-nm light, as currently applied in the Twente photoacoustic mammoscope. Results from (Monte Carlo and k-wave) simulations and phantom measurements were used to interpret results from patient measurements. There was a strong agreement among the results from simulations, phantom, and patient measurements. Depending on the absorption contrast between cyst and breast tissue, cysts were visible as either one or two confined high-contrast areas representing the front and the back of the cyst, respectively. This edge enhancement is most likely the consequence of the local sudden change in the absorbed energy density and Grüneisen coefficients. Although the current forward-mode single-wavelength photoacoustic mammoscope cannot always unambiguously discriminate cysts from malignancies, this study reveals specific features of cysts compared to malignancies, which can be exploited for discrimination of the two abnormalities in future modifications of the imager.

Photoacoustic imaging of breast tumor vascularization: a comparison with MRI and histopathology

Breast cancer is the most common form of cancer and the leading cause of cancer death among females. Early diagnosis improves the survival chances for the disease and that is why there is an ongoing search for improved methods for visualizing breast cancer. One of the hallmarks of breast cancer is the increase in tumor vascularization that is associated with angiogenesis: a crucial factor for survival of malignancies. Photoacoustic imaging can visualize the malignancyassociated increased hemoglobin concentration with optical contrast and ultrasound resolution, without the use of ionizing radiation or contrast agents and is therefore theoretically an ideal method for breast imaging. Previous clinical studies using the Twente Photoacoustic Mammoscope (PAM), which works in forward mode using a single wavelength (1064 nm), showed that malignancies can indeed be identified in the photoacoustic imaging volume as high contrast areas. However, the specific appearance of the malignancies led to questions about the contrast mechanism in relation to tumor vascularization. In this study, the photoacoustic lesion appearance obtained with an updated version of PAM is compared with the lesion appearance on Magnetic Resonance Imaging (MRI), both in general (19 patients) and on an individual basis (7 patients). Further, in 3 patients an extended histopathology protocol is being performed in which malignancies are stained for vascularity using an endothelial antibody: CD31. The correspondence between PAM and MRI and between PAM and histopathology makes it likely that the high photoacoustic contrast at 1064 nm is indeed largely the consequence of the increased tumor vascularization.

In vivo determination of scattering properties of healthy and malignant breast tissue by use of multi-diameter-single fiber reflectance spectroscopy (MDSFR)

Elastic scattering of light in tissue offers a natural biologic contrast that can be used to classify tissue for diagnostic purposes. For a single fiber reflectance spectroscopy setup, which uses a single multimode optical fiber with diameter dfib for both illumination and detection, our group has previously reported a relationship between the single fiber reflectance (SFR) signal and the dimensionless scattering (μ′sdfib). Based on this relationship, the multi-diameter single fiber reflectance method (MDSFR), was developed. This method allows the extraction of μ′S and a phase function dependent parameter γ=(1-g2) / (1-g1) from tissue by taking multiple SFR measurements with different fiber diameters. Limitations and the sensitivity of the MDSFR method have been discussed previously based on an in silico analysis and the feasibility of the method has been proven experimentally during measurements in scattering phantoms containing polystyrene spheres. In the current study we will present data from an in-vivo clinical study utilizing MDSFR to determine tissue scattering properties of healthy and malignant breast tissue, on patients undergoing biopsy of a suspicious lesion found during mammographic breast imaging. Here MDSFR measurements are performed with a custom made disposable probe, incorporating two fiber diameters (0.4 and 0.8 mm), which is inserted through the biopsy needle before the biopsy is taken, allowing in vivo spectroscopic measurements of tumor center and healthy tissue.

Imaging breast lesions using the Twente Photoacoustic Mammoscope: ongoing clinical experience

Current imaging modalities are often not able to detect early stages of breast cancer with high imaging contrast. Visualizing malignancy-associated increased hemoglobin concentrations might improve breast cancer diagnosis. Photoacoustic imaging can visualize hemoglobin in tissue with optical contrast and ultrasound resolution, which makes it potentially ideal for breast imaging. The Twente Photoacoustic Mammoscope (PAM) has been designed specifically for this purpose. Based on a successful pilot study in 2007, a large clinical study using PAM has been started in December 2010. PAM uses a pulsed Q-switched Nd:YAG laser at 1064 nm to illuminate a region of interest on the breast. Photoacoustic signals are detected with a 1MHz, unfocused ultrasound detector array. Three dimensional data are reconstructed using an acoustic backprojection algorithm. Those reconstructed images are compared with conventional imaging and histopathology. In the first phase of the study, the goal was to optimize the visualization of malignancies. We performed sixteen technically acceptable measurements on confined breast malignancies. In the reconstructed volumes of all malignancies, a confined high contrast region could be identified at the expected lesion depth. After ten successful measurements, the illumination area was increased and the fluence was substantially decreased. This caused a further significant increase in PAM lesion contrast.

A custom-made linear array transducer for photoacoustic breast imaging

A custom-made first prototype of a linear array ultrasound transducer for breast imaging is presented. Large active area transducer elements (5 mm × 5 mm) with 1 MHz resonance frequency are chosen to obtain a relatively high sensitivity. Acoustic lenses are used to enlarge the narrow acceptance angle of such transducer elements. The minimum detectable pressure, frequency bandwidth and electrical impedance of the transducer elements are characterized. The results show the transducer has a minimum detectable pressure of 0.8 Pa, which is superior than the transducers used in the Twente Photoacoustic Mammoscope system previously developed in our group. The bandwidth of the transducer is relative small, however it can be improved when using optimized matching layer thickness in future. We also observed a strong lateral resonance at 330 kHz, which may cause problems in various aspects for a photoacoustic imaging system. We discuss the future improvement and plans for the transducer optimizations.