Dual Scan Mammoscope has the potential to help detect breast cancer earlier


A new, portable breast imaging system under development in Buffalo has the potential to better identify breast cancer in women with dense breast tissue.

That is among the findings of a study published in the journal IEEE Transactions on Biomedical Engineering in August.

The study was led by University at Buffalo researchers in collaboration with Roswell Park Comprehensive Cancer Center and Windsong Radiology.

“We’re developing a new imaging system – it’s called a Dual Scan Mammoscope – that combines light and ultrasound technology. We believe it has the potential to help detect breast cancer earlier, thereby increasing survival rates,” says UB researcher and the study’s lead author, Jun Xia.

Xia, Ph.D., is an assistant professor in the Department of Biomedical Engineering, a joint program of the School of Engineering and Applied Sciences and the Jacobs School of Medicine and Biomedical Sciences at UB.

The images above show 3D vasculature of breast tissue acquired by the Dual Scan Mammoscope. The vessels in blue are closest to the breast surface, while the ones in red are located deeper in the tissue. Credit: Jun Xia, University at Buffalo.

Regular mammograms are the best tests doctors have to find breast cancer early, according to the Centers for Disease Control and Prevention.

However, they are less effective for women with dense breast tissue.

There are alternatives methods in such cases, including MRI. But MRI tests are costly, they require intravenous contrast agents that can cause allergic reactions, and they’re not easily portable.

The Dual Scan Mammoscope, or DSM, is similar to a mammogram, in that patients stand upright to have their breast compressed for imaging.

Unlike mammograms, however, the DSM requires only mild compression of the breast, likely reducing the severity of pain that women can experience pain during the procedure.

Unlike a mammogram, the DSM is a radiation free-test. It uses a laser to illuminate breast tissue.

In turn, this generates acoustic waves that are measured by ultrasound technology. T

he combination of lasers and ultrasound is an imaging technique called photoacoustic tomography.

While MRI requires a contrast agent, the DSM test uses hemoglobin, a protein in red blood cells that carries oxygen throughout the body.

The technology Xia and his colleagues are developing features two simultaneous scans, one working from the bottom of the breast while the other works from the top.

The design, Xia says, ensures optimal light delivery and acoustic detection, enabling imaging deep into breast tissue.

It’s also portable; for example, it could easily fit into mobile mammogram units.

In initial laboratory tests, the research team imaged breast sizes B, D and DD. The study highlights the D breast test, which shows imaging through 7 centimeters – the first time a photoacoustic system produced imaging that deep, the research team believes.

Xia says the DSM method shows promise in detecting tumors in the sub-millimeter range, provided they exhibit sufficiently developed blood vessels.

The team plans additional studies, including the imaging of more patients with different breast sizes and tumor characteristics, to ensure the DSM machine’s effectiveness.

In recent years, molecular imaging techniques have rapidly been translated and integrated into mainstream clinical practice and standard of care [2].

Such techniques improve understanding, characterization, and monitoring of pathologies, thus enabling earlier detection, more accurate diagnosis, and improved disease management. While magnetic resonance imaging (MRI) and radionuclide imaging methods have offered fertile ground for developing a huge variety of novel contrast agents and mechanisms, the relatively high costs and logistical restrictions of such modalities (such as magnetically shielded rooms or radiation safety equipment) limit their cost-effectiveness [[4][5][6]].

By comparison, the increased affordability and portability of ultrasound instruments, as well as the advent of contrast-based methods such as elastography and microbubble-based ultrasound molecular imaging, have made clinical ultrasound an invaluable tool for clinical imaging, both anatomy, and molecular content [7].

Photoacoustic imaging (PAI), which is also referred to as optoacoustic imaging, is an emerging technique that has immense potential for augmenting ultrasound with rich optical contrast and can serve as a portable and (relatively) low-cost standalone modality for regional imaging of blood vessels and other optical contrast agents [9,10].

The core strengths of PAI are its potential for high spatial/temporal resolution, clinically relevant imaging depth [11], ability to image both endogenous [12] and exogenous [13] chromophores, and the absence of ionizing radiation.

Common endogenous chromophores include water (both free and bound), oxyhemoglobin (HbO2), deoxyhemoglobin (Hb) melanin and lipids.

Exogenous agents are mostly small molecule dyes such as Indocyanine green (ICG), Methylene Blue Dye (MBD), nanoparticles or even reporter gene agents. Unlike current microbubble-based ultrasound contrast agents, PAI can image small molecules that can readily extravasate, target cell membrane molecules, or even enter cells of interest to target intracellular molecules, and thus provides the clinician with potentially valuable molecular data [[14][15][16]].

The photoacoustic effect was first described by Alexander Graham Bell [17] over a century ago as a conversion of optical energy to audible pressure waves.

However, little progress was made until the invention of the laser allowed for a much-improved signal generation. Subsequently, the use of photoacoustics grew in popularity, first in the field of gas spectroscopy and later for biomedical applications [18].

Over the past 20 years, PAI has rapidly evolved from the concept phase [19] to a tomographic modality for small animal imaging [14] to clinical devices [20].

The effect itself is based on pressure transients generated by absorption of pulsed or modulated light [9].

Such acoustic transients experience far less scattering and absorption than visible or near infrared (NIR) light as they propagate through the tissue.

Measuring those transients by an acoustic transducer at tissue boundaries allows faithful reconstruction of the absorption sites.

Owing to its inherent scalability, PAI can be performed over a wide range of depths and resolutions (Fig. 1) [11]. Acoustic-resolution photoacoustic tomography (PAT) can achieve sub-millimeter resolution at depths up to several centimeters [21], while optical-resolution photoacoustic microscopy (PAM) can achieve even sub-micron resolution but is restricted to a few hundred microns of depth penetration [22] with a typical depth-to-resolution ratio of about 200. The field of view (FOV) usually also scales with depth as well as with the scanning time.

Fig. 1
Fig. 1
various configurations for PAI.
(a) Optical resolution photoacoustic microscopy. Here the optical excitation is focused and co-aligned with the acoustic transducer. While many configurations exist to maintain alignment, a simple but effective one was devised by Wang et al. [1]. Here two prisms are joined together with a thin layer of silicone oil between them. This layer transmits light interruptedly but reflects the acoustic waves and thus acts as an optical/acoustic splitter. A rhomboid prism is required for the acoustic side to ascertain that a longitudinal wave (rather than sheer) reaches the transducer. Penetration depth is very shallow in order to maintain the optical focusing. The optical focal region (mm scale) is much smaller than the acoustic one and thus determines the (lateral) resolution which can be sub-cellular. (b) Acoustic resolution photoacoustic microscopy. Here the light is delivered around the transducer to create uniform illumination. The unfocused light allows for greater penetration. Both the lateral and axial resolutions are determined by the acoustic focal region. See for example Kim et al. [3] (c) Acoustic resolution photoacoustic tomography/macroscopy. Here neither the light nor the sound are focused which allows several cm of imaging depth. Imaging is based on multiple transducers which views each point in the region of interest (ROI) from a different angle and thus able to resolve it. See for example Witte et al [8].
US- Ultrasound, MO – Microscope objective, UST – Ultrasound transducer

In recent years, advanced light sources technologies allow for mobility, tunability, compactness, and affordability [10]. Novel algorithms allow for real-time, high-resolution and accurate reconstruction of the initial pressure distribution even under non-ideal conditions [23].

Such non-ideal conditions often include a limited viewing angle, in which the sample is not fully enclosed with acoustic detectors. Other common conditions are finite sized and limited bandwidth detectors.

The use of multiple wavelengths can, in principle, allow the concentrations of distinct chromophores to be simultaneously quantified, thus providing molecular-specific contrast [24]. Accurate spectral separation has been a long-standing challenge in PAI, mostly due to the effect of spectral coloring [25].

Here we review the recent advances in the clinical translation of PAI. This paper builds on our previous review from 2014 [26]. The goals of this review are to show the current progress in PAI toward clinical imaging, point out the remaining hurdles and finally discuss possible future directions to make PAI a truly clinically relevant modality.

Thus, we have emphasized on published scientific literature which both reports of human imaging in that have been achieved in clinical settings and those that are close to being achieved. For the reader’s convenience, this review is organized according to the anatomic location from top to bottom of the human body. Afterward, we will briefly discuss the outstanding challenges of PAI clinical translation as well as prospects.

Breast imaging

Breast imaging is a promising area for PAI. Breast cancer is the most common cancer in women and a leading cause of cancer-related death worldwide.

Current screening methods include X-Ray mammography (XRM) and ultrasound imaging. XRM suffers from a low positive predictive value, exposure to ionizing radiation, and reduced sensitivity in women with dense breast tissue a well as causing extreme discomfort [57].

Ultrasonography results are strongly dependent on the examiner’s interpretation and suffer from a high false-positive rate.

MRI of the breast has high sensitivity, but low specificity and high cost [58,59]. As a result, there is a strong need for improved breast cancer imaging techniques that can reduce false-positive rates and improve sensitivity [[60][61][62]].

PAI is particularly well suited to improve diagnostic imaging of the breast. The tissue of interest is superficially located and mostly within the maximum achievable imaging depth of PAI.

Healthy breast tissue has low optical absorption and ultrasound scattering, allowing for highly efficient PAI. In addition, angiogenesis is an important diagnostic and prognostic factor in breast cancer. Since abnormally increased vasculature and hemoglobin at tumor sites produces strong intrinsic photoacoustic contrast, PAI is ideally suited for visualizing angiogenesis [63].

The use of PAI for breast imaging was first proposed in 1994 [19,64]. One of the first instruments used to image patients was the Twente Photoacoustic Mammoscope [65], wherein the patient lies prone with the breast suspended and lightly compressed between a glass plate and a planar US detector array.

Using a 1064 nm laser, the PA Mammoscope has been used to image over 100 patients, and initial results demonstrate that it can identify malignancies with no difference in the average PA contrast between patients with high- and low-density breast tissue [66,67].

Similarly, Ermilov et al. showed promising results, with the Laser-based Optoacoustic Imaging system (LOIS-64) [68]. For imaging, the patient lies prone with the breast suspended into a hemispherical cup with a 64-element detector.

An initial study using a 755 nm laser and 27 patients showed a promising ability to detect malignant and benign lesions. A similar setup was used by Kruger et al. based on a Nexus 128 preclinical PAT system by Endra Life Sciences Inc. to demonstrate imaging feasibility; a single healthy volunteer was imaged with scan times and resolution of 12 s to 3.2 min for scans of 24 mm to 96 mm radius, respectively [69].

A second generation design of this device reduced the center frequency of the ultrasound transducer from 5 to 2 MHz in order to improve depth penetration (trading off spatial resolution) and introduced a spiral detector scan protocol that improved the field of view [70] It was used to image 4 human volunteers and able to visualize the vasculature throughout a breast volume as large as 1335 mL. Kitai et al. developed a photoacoustic system wherein the patients again lie in a prone position with the breast suspended and compressed between two plates and imaged using four different wavelengths: 756 nm, 797 nm, 825 nm, and 1064 nm.

A unique feature of this system is the dual-illumination through both plates. Analyzing images from 26 patients, lesions were correctly identified in 74% of the cases (20 of 27) [20]. Taking advantage of the multispectral images, the mean oxygen saturation (SO2) was also calculated, and all detected lesions showed lower SO2 levels as compared to the surrounding and contralateral breast tissues.

More recently, Toi e.t al. used a modified version of the PA mammoscope called PAM-03, (Fig. 4) which uses a hemispherical detector array with two laser wavelengths of 755 nm and 795 nm.

In this study of 30 patients, their optimized system was able to resolve very fine vascular structures in the breast, even compared with MRI imaging of the same patient [71]. Additionally, the system can characterize cancer treatment-driven changes in vascular morphology and hemoglobin saturation.This is described in Fig. 5.

A recent study tested the capabilities of MSOT breast imaging on six patients using five wavelengths: 700 nm, 730 nm, 760 nm, 800 nm, and 850 nm. A handheld version of a commercial MOST system called MSOT Acuity Echo was used for this study.

This system is marketed by iThera Medical and utilizes a tunable laser, allowing multiple illumination wavelengths in the 680–980 nm range.

The study demonstrated reproducible data on tissue composition and physiological properties, potentially enabling differentiation of solid malignant tissue from healthy tissue [72].

Another handheld system utilizing two wavelengths (1064 nm and 757 nm) is the Imagio by Seno Medical Instruments, which integrates a linear ultrasound array.

Recently, a large multicenter prospective clinical trial of over two thousand women was completed comparing Breast Imaging Reporting and Data System (BI-RADS) categories assigned using combined PAI and ultrasonography (Imagio) versus ultrasound alone. Using combined PAI and ultrasonography exceeded US specificity by 14.9% with similar sensitivity (US: 96% vs. 98.6%) [73]. Further details of PA breast imaging may be found in a separate article by A. Oraevsky et al. in this same journal issue.

Fig. 4
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Fig. 4
An example of PA mass appearance seen in a 63-year-old patient (P55) with infiltrating ductal carcinoma (IDC).
The breast lesion was highly suspicious on XRM (not shown) by the presence of an irregularly shaped, unsharply delineated, 20-mm mass. (a) The average intensity projection (AIP) PA image is shown tilted due to the breast being tilted during the PA measurement to position the lesion favorably in front of the detector. In the PA image, the lesion is clearly visible as an irregular, high-contrast, 29-mm mass. The lesion colocalized perfectly with the lesion on XRM (not shown). The lesion also colocalized well with (b) the AIP MR image after tilting the PA image. The dashed box in the MR image indicates the area from which the PA image is acquired. The MR appearance is described as an irregularly shaped mass. (c) A histopathological assessment of the tissue specimen post-surgery revealed the presence of a 34-mm IDC, grade 2. (d) The CD31-stained tumor section shows the microvascularity spread over the entire lesion supporting the mass appearance observed in PA and MR images. It is intriguing that the patterns in ‘a’–‘d’ appear roughly similar in appearance.
© 2015 IEEE. Reprinted, with permission, from Michelle Heijblom, Wiendelt Steenbergen, Srirang Manohar, “Clinical Photoacoustic Breast Imaging: The Twente experience,” IEEE Pulse Volume 6, Issue 3, Pages 42-26; DOI: 10.1109/MPUL.2015.2409102.
Fig. 5
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Fig. 5
Comparison of visibilities of blood vessels between PAI and MRI using maximum intensity projection (MIP) images on the healthy breast.
Case 1(a–c): (a) PA image, (b) MR image deformed to correspond to the PA image, and (c) fusion image of PA (cyan) and MR (red). Case 2 (d–f): (d) PA image, (e) MR image deformed to correspond to the PA image, and (f) fusion image of PA (cyan) and MR (red). All images are coronal views. We colored the signals according to the depth using the color chart shown in (g). Images were taken at 755 nm and 795 nm.
From: Toi, M. et al. Visualization of tumor-related blood vessels in human breast by photoacoustic imaging system with a hemispherical detector array. Sci. Rep. 7, 41970; doi: 10.1038/srep41970 (2017). http://creativecommons.org/licenses/by/4.0/

Thus, PAI for breast imaging is quite advanced with a handful of clinical systems developed by multiple groups. As most of the technological barriers have been overcome, we can see a multitude of commercial companies aiming at developing a fully capable clinical system. While light penetration still poses some limitations (especially for larger breast tissue) The challenges now are shifting toward the clinical side – to prove the added clinical value and reduced costs / increased patient compliance over the current standard of care mammography.

More information: Nikhila Nyayapathi et al. Dual Scan Mammoscope (DSM)—A New Portable Photoacoustic Breast Imaging System with Scanning in Craniocaudal Plane, IEEE Transactions on Biomedical Engineering (2019). DOI: 10.1109/TBME.2019.2936088

ournal information: IEEE Transactions on Biomedical Engineering
Provided by University at Buffalo


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