Many breast cancer patients receive neoadjuvant treatment to reduce tumor size and enable breast conserving therapy. Most imaging methods used to monitor response to neoadjuvant chemotherapy or hormone therapy depend on overall gross tumor morphology and size measurements, which may not be sensitive or specific, despite tumor response on a cellular level. A more sensitive and specific method of detecting response to therapy might allow earlier adjustments in treatment, and thus result in better outcomes while avoiding unnecessary morbidity. We developed an imaging system that combines spectral photoacoustic tomography and ultrasonography to predict breast neoadjuvant therapeutic response based on blood volume and blood oxygenation contrast. The system consists of a tunable dye laser pumped by a Nd:YAG laser, a commercial ultrasound imaging system (Philips iU22), and a multichannel data acquisition system which displays co-registered photoacoustic and ultrasound images in real time. Early studies demonstrate functional imaging capabilities, such as oxygen saturation and total concentration of hemoglobin, in addition to ultrasonography of tumor morphology. Further study is needed to determine if the co-registered photoacoustic tomography and ultrasonography system may provide an accurate tool to assess treatment efficacy by monitoring tumor response in vivo

Erpelding, Todd N.

Garcia-Uribe, Alejandro

Holley, Susan

Jacobs, Eileen

Ke, Haixin

Monsees, Barbara

Wang, Lihong V.

Caltech Authors - Main

PROCEEDINGS OF SPIE
SPIEDigitalLibrary.org/conference-proceedings-of-spie
Co-registered spectral photoacoustic
tomography and ultrasonography of
breast cancer
Haixin  Ke, Todd N. Erpelding, Alejandro  Garcia-Uribe,
Eileen  Jacobs, Susan  Holley, et al.
Haixin  Ke, Todd N. Erpelding, Alejandro  Garcia-Uribe, Eileen  Jacobs, Susan
Holley, Barbara  Monsees, Lihong V. Wang, "Co-registered spectral
photoacoustic tomography and ultrasonography of breast cancer," Proc. SPIE
8943, Photons Plus Ultrasound: Imaging and Sensing 2014, 89434G (3 March
2014); doi: 10.1117/12.2040591
Event: SPIE BiOS, 2014, San Francisco, California, United States
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Co-registered spectral photoacoustic tomography and 
ultrasonography of breast cancer 
 
Haixin Ke1, Todd N. Erpelding2, Alejandro Garcia-Uribe1, Eileen Jacobs3, Susan Holley3,  
Barbara Monsees3, and Lihong V. Wang1 
 
1Department of Biomedical Engineering, Washington University in St. Louis, MO, USA 
2Philips Research North America, Briarcliff Manor, NY, USA 
3Washington University School of Medicine, St. Louis, MO, USA 
 
 
ABSTRACT 
 
Many breast cancer patients receive neoadjuvant treatment to reduce tumor size and enable 
breast conserving therapy. Most imaging methods used to monitor response to neoadjuvant 
chemotherapy or hormone therapy depend on overall gross tumor morphology and size 
measurements, which may not be sensitive or specific, despite tumor response on a cellular level. 
A more sensitive and specific method of detecting response to therapy might allow earlier 
adjustments in treatment, and thus result in better outcomes while avoiding unnecessary 
morbidity. We developed an imaging system that combines spectral photoacoustic tomography 
and ultrasonography to predict breast neoadjuvant therapeutic response based on blood volume 
and blood oxygenation contrast. The system consists of a tunable dye laser pumped by a 
Nd:YAG laser, a commercial ultrasound imaging system (Philips iU22), and a multichannel data 
acquisition system which displays co-registered photoacoustic and ultrasound images in real time. 
Early studies demonstrate functional imaging capabilities, such as oxygen saturation and total 
concentration of hemoglobin, in addition to ultrasonography of tumor morphology. Further study 
is needed to determine if the co-registered photoacoustic tomography and ultrasonography 
system may provide an accurate tool to assess treatment efficacy by monitoring tumor response 
in vivo. 
 
Keywords: Neoadjuvant chemotherapy, photoacoustic tomography, ultrasonography, breast 
cancer. 
 
1. INTRODUCTION 
 
Some breast cancer patients receive neoadjuvant treatment with chemotherapy or endocrine 
therapy before definitive surgery. The treatment aims to reduce tumor size in patients for whom 
breast conserving therapy would otherwise not be possible. Although it is hoped that neoadjuvant 
therapy would improve patient survival outcomes, data from clinical trials have not shown this 
benefit [1]. A sensitive method of detecting the primary tumor’s response to a given therapy 
might allow earlier adjustment in treatment and result in better outcomes. Effective methods to 
monitor the early tumor response would also help limit unnecessary morbidity associated with 
patients not responding to therapy. Previous studies showed the feasibility of using optical 
tomography in monitoring tumor vascular changes and assessing tumor pathological response 
Photons Plus Ultrasound: Imaging and Sensing 2014, edited by Alexander A. Oraevsky, Lihong V. Wang, 
Proc. of SPIE Vol. 8943, 89434G · © 2014 SPIE · CCC code: 1605-7422/14/$18 · doi: 10.1117/12.2040591
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during neoadjuvant chemotherapy. Various predictors such as concentration (ct) of deoxy-
hemoglobin (ctHHb), oxy-hemoglobin, water (ctH2O), and bulk lipid, were assessed [2]-[4].  
Photoacoustic Tomography (PAT) is a non-ionizing and noninvasive hybrid imaging 
technique that can measure strong optical absorption contrasts with high ultrasonic spatial 
resolution at depths beyond the optical diffusion limit [5] [6]. Both image resolution and depth 
are highly scalable with the ultrasonic frequency. Photoacoustic imaging relies on the 
photoacoustic effect to generate pressure waves that can be detected by conventional ultrasound 
array transducers. Therefore, it is highly compatible with ultrasound imaging. The same 
detection mechanism greatly simplifies spatial registration between photoacoustic and ultrasound 
images. Photoacoustic imaging is an emerging modality that could expand the scope of 
diagnostic ultrasonography into new clinical applications, such as image-guided sentinel lymph 
node biopsy, breast cancer diagnosis, and therapy monitoring.  
We developed a dual-modality system that combines PAT and ultrasonography. The system 
can provide co-registered PAT and ultrasound images that reveal both morphological and 
functional information. Therefore, the technology described represents a potential new way to 
evaluate response to therapy, and may be capable of detecting response earlier than conventional 
imaging techniques, such as mammography and ultrasound (US), that can detect a change in 
tumor morphology. 
With the help of ultrasonography for identifying the tumor region, we demonstrated the 
capability of the PA technique to monitor in vivo blood oxygen saturation in breast tumors. 
Repeated imaging of the same patient was performed to evaluate the possibility of monitoring 
the treatment progress. Further study is needed to determine if the combination of the functional 
as well as morphological information obtained by both modalities can provide more accurate 
evaluation of the treatment progress and efficiency. 
 
 
2. MATERIALS AND METHODS 
 
2.1 Imaging system 
The dual-modality imaging system integrates a laser system into a clinical US imaging 
scanner. A system diagram is shown in Fig. 1(a). The commercial US scanner was modified to 
allow access to raw per-channel RF acoustic data, while all imaging capabilities of the 
commercial US scanner were retained [7]. The laser system consists of a tunable dye laser 
(PrecisionScan-P, Sirah) pumped by a Q-switched Nd:YAG laser (PRO-350-10, Newport). We 
designed a photoacoustic transducer that integrates the fiber output into a commercial ultrasound 
linear array transducer (L8-4, Phillips), as shown in Fig. 1(b). The optical fiber bundles flank 
both sides of the ultrasound array transducer. Photoacoustic waves are received by the ultrasound 
transducer in the same geometry as pulse-echo ultrasound. The custom-made data acquisition 
system controls the triggering of both modalities and collects raw data for image display and 
post-processing. PA images are reconstructed using a  delay-and-sum beam-forming algorithm 
implemented in FPGA firmware, generating cross-sectional PA B-mode images that can be fused 
into corresponding US images displayed in real-time at 5 frames per second [8].  
 
The oxygen saturation was calculated using the method described in [9]. To calculate the 
oxygen saturation, we need to acquire PA images at multiple wavelengths. The system can 
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(a)
Nd:YAG
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system 4-
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operate in two different modes to acquire and display spectroscopic PA/US images. First, the 
system can tune the dye laser to multiple, user-defined preset wavelengths while PA images are 
acquired. Second, we modified the pump Nd:YAG laser to get access to the fundamental laser 
(1064 nm). A mechanical shutter is synchronized to the laser trigger and alternatively blocks the 
dye output or the fundamental output on consecutive laser shots. Therefore, the PA imaging can 
also operate in a fast-switching, dual-wavelength mode with one wavelength from the dye laser 
and the other wavelength at 1064 nm. Based on the spectra of oxy- and deoxy-hemoglobin [10], 
we chose 782 nm from the dye laser and 1064 nm from the Nd:YAG laser for the dual-
wavelength mode. The two wavelengths are routed to the same path by a dichroic mirror before 
they enter the fiber bundle. A beam sampler is placed just before the fiber so that a small amount 
of the laser is reflected to a photodiode to measure the pulse-to-pulse laser power fluctuations for 
subsequent compensation. 
 
 
 
 
Fig.1. (a) Schematics of the dual-modality imaging system. (b) A photograph of the integrated transducer. 
 
 
 
2.2 Clinical study 
Patients enrolled in this study must be newly diagnosed with clinical stage II or III biopsy-
proven breast cancer (initial diagnosis), or have relapsed/recurrent stage II or III biopsy-proven 
breast cancer, and be considered eligible for breast surgery. They must be preparing to undergo 
neoadjuvant therapy (chemotherapy or endocrine/hormone therapy) prior to definitive surgical 
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interventions. Each participant will undergo imaging at three separate times: 1) prior to initiation 
of neoadjuvant therapy; 2) during neoadjuvant therapy, probably at two weeks after initiation of 
therapy; and 3) at a later point in time to be determined from the results of Phase I (and possibly 
Phase II), but prior to definitive surgery.  
During each visit, the total imaging procedure included three steps. First, standard ultrasound 
measurements of the tumor were made by the operator to locate the tumor and record the tumor 
dimensions. Second, we scanned across the tumor region with interleaving US and PA imaging 
in both longitudinal and transverse directions. This scanning measurement gave us a full view of 
the tumor area, and at the same time allowed us to identify critical features on the co-registered 
US and PA images. These features were not only the targets for oxygen saturation measurements, 
but also for monitoring longitudinal changes. Third, after we found good targets, we did spectral 
PA measurements over these targets, during which the transducer position was fixed. 
 
 
3. RESULTS AND DISCUSSION 
 
Each patient was imaged before her neoadjuvant treatment started, and then during her 
treatment (17 days after the first visit), following the same imaging procedure. Given the 
stronger laser power and lesser melanin absorption from the skin at 1064 nm, the PA images at 
1064 nm were used to find critical features and select the targets for oxygen saturation 
measurements.  
The imaging results of one patient’s first visit are shown in Fig. 2. During the scanning 
measurement, PA and US data were collected alternatively. At the same time, they were 
processed to overlay PA and US images so that we could better interpret the images. The PA, US 
and fused images could be shown in real time at 5 frames/s.  Fig. 2(a) shows one frame during 
the scan in the longitudinal direction. The tumor boundary was identified by US imaging. A 
vessel-like structure was clearly shown in the US image, which also generated a strong PA signal 
on the corresponding PA image, suggesting a large blood vessel lying near the tumor. The 
transducer was then fixed at roughly the same position at which this frame was collected, and the 
PA spectral measurement was performed. Fig. 2(b) shows a PA image when the laser wavelength 
was 1064 nm. Comparing this image to the fused PA/US image helped identify a couple of other 
blood spots on the boundary of and inside the tumor. We chose three regions to calculate the 
oxygen saturation, with the data collected in dual-wavelength mode. PA signals in these regions 
were thresholded and spatially averaged over neighboring pixels.  
The imaging results of the patient’s second visit are shown in Fig. 3. The same blood vessel 
and similar tumor shape as in Fig. 2 were found in the PA/US image in Fig. 3(a). Similar features 
on the boundary of and inside the tumor can be found on the thresholded PA image in Fig. 3(b), 
although the positions were slightly changed. The same three regions were chosen to calculate 
the oxygen saturation, and they had similar values to those from the first visit.  
 
 
4. CONCLUSIONS 
 
We developed a dual-modality imaging system that integrates PAT and ultrasonography, and 
applied it to study patients undergoing neoadjuvant therapy for breast cancer. We demonstrated 
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that the system provides the functional imaging capabilities provided by PAT, such as oxygen 
saturation, in addition to ultrasonography of tumor morphology. Our initial results also showed 
the importance of combining functional PA and morphological US images to identify critical 
features in tumors. Further study is needed to determine if co-registered photoacoustic 
tomography and ultrasonography system can provide an accurate tool to assess treatment 
efficacy by monitoring tumor response in vivo. 
 
 
 
 
 
 
Fig.2. The imaging results of the first visit.  (a) The PA and US images acquired during the scan in the 
longitudinal direction, as well as the overlay of the two images. (b) The threshold PA image at 1064 nm. 
The dashed the boxes show the three regions over which the averaged oxygen saturation were calculated. 
The values (mean ± standard derivation) are shown in the figure. 
 
 
 
 
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(a) PA imaap
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Fig.3. The imaging results of the second visit. (a) The PA and US images acquired during the scan in the 
longitudinal direction, as well as the overlay of the two images. (b) The threshold PA image at 1064 nm. 
The dashed the boxes show the three regions over which the averaged oxygen saturation were calculated. 
The values (mean ± standard derivation) are shown in the figure. 
 
 
ACKNOWLEDGEMENTS 
 
This work was sponsored by NIH grants R01 CA134539, DP1 EB016986 (NIH Director’s 
Pioneer Award), R01 EB016963, and U54 CA136398. L. V. Wang has a financial interest in 
Endra, Inc., and Microphotoacoustics, Inc., which, however, did not support this work. 
 
 
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Co-registered spectral photoacoustic tomography and ultrasonography of breast cancer

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Co-registered spectral photoacoustic tomography and ultrasonography of breast cancer

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