A Coregistered Ultrasound and Photoacoustic Imaging Protocol for the Transvaginal Imaging of Ovarian Lesions

As we all know that ovarian cancer is the deadliest of all the gynecology malignancies, when ovarian cancer detected at earlier and localized stage, surgery and chemotherapy can cure about 70 to 90%of patients compared with only 20%or fewer when it's diagnosed at the later stages. And current standard of care methods are known to have a lower sensitivity for early ovarian cancer detection. Furthermore, standard of care methods have very low specificity for accurate risk assessment of ovarian adnexal lesions, leading to unnecessary surgeries so with potential surgical complications and the significant healthcare cost.

Therefore, our technology sensitive to early stage ovarian cancer detection and specific for accurate diagnosis of ovarian adnexal lesions is needed. Photoacoustic tomography or PAT illuminates with near-infrared lights at specific wavelengths and is selectively absorbed by oxygenated and deoxygenated hemoglobin. The photoacoustic wave generated from the light absorption can map out hemoglobin contrast, and this can be coregistered to anatomical structures imaged by coregistered ultrasound.

The total hemoglobin concentration and oxygen saturation provide functional information on tissue vascularity and oxygen consumption. Since malignant lesions generally have higher total hemoglobin and lower oxygen saturation, these two independent variables may help detect ovarian cancers earlier and differentiates malignant from benign ovarian adnexal lesions accurately to improve surgical management recommendations. And we have obtained the pilot of patient data and result have demonstrated that coregistered photoacoustic imaging combined with transvaginal ultrasound and ovarian cancer blood biomarker CA 125 can actually diagnose ovarian adnexal lesions.

Our pilot data also show evidence that coregistered photoacoustic imaging can detect early stage ovarian and fallopian tube cancers. And coregistered photoacoustic and ultrasound has been applied to detection and the diagnosis of breast cancer, skin cancer, thyroid cancer, cervical cancer, prostate cancer, and the colorectal cancer. However, the imaging probes vary depending on the imaging window of different organs.

The first commercial coregistered photoacoustic and ultrasound breast imaging system is available from Sino Medical Instrument. We expect that more commercial coregistered photoacoustic ultrasound system will be available on the market. However, the transvaginal photoacoustic and ultrasound imaging probes will need to be specially designed for imaging patients.

To begin, expand the laser beam by first diverging the beam with a plano concave lens and then collimating the beam with a plano convex lens. Use two mirrors to direct the beam onto a beam splitter. Split the original beam into two with a polarizing beam splitter and then split the two beams with two more second stage beam splitters.

This way, the expanded laser beam will split into four beams with equal energy. Mount four multi-mode optical fibers with fiber chucks, and use four plano convex lenses to focus the four laser beams into the four fibers. Cover all the optical components under a metal box to ensure that the optical path is not exposed.

Connect an additional monitor to the programmable clinical ultrasound or ultrasound system to run the PATUS display software for the realtime visualization of the relative total hemoglobin, the blood oxygen saturation maps, and other functional parameters. Then connect the internal trigger of the laser to the external trigger of the ultrasound system and sequentially acquire five consecutive PAT frames and one coregistered ultrasound frame. To calibrate the system, set the laser pump energy to a fixed level.

And for each wavelength, check the per pulse energy output at each fiber tip to ensure the calculated energy density at each selected wavelength is at the expected value. To prepare the PATUS imaging system, turn on the clinical ultrasound system and start the ultrasound system software. Press the transducer button on the ultrasound machine control panel to open the transducer selection screen.

Then select the correct ultrasound transducer. Calibrate the laser system and enter the total pulse energy for each wavelength into the PATUS display software. Assemble the PATUS probe by enclosing the fibers and the probe inside the probe sheath.

For imaging, adjust the position of the PATUS transducer. A hypoechoic target slowly shows up at the center of the B-scan. Then select the desired depth in the PATUS control software and click scan in the control software to start the coregistered PATUS B-mode data acquisition.

Watch the PATUS image display software to review the coregistered ultrasound and PAT B-mode images in real time. The single wavelength PA data is displayed on top of the ultrasound as they are acquired. Repeat the steps to acquire more images, and if necessary, image the second lesion.

Once the data acquisition is complete, the PATUS display software receives a trigger to reconstruct the functional maps. Here, the left panel shows the ultrasound B-scan, while the right panel shows relative total hemoglobin overlaid with coregistered ultrasound. Select a region of interest or ROI, here the target ovary, to compute the SO2 map within the ROI.

This image shows a 50-year-old premenopausal woman with bilateral multicystic adnexal masses revealed by contrast enhanced CT.The ultrasound image of the left adnexa with the region of interest or ROI marking the suspicious solid nodule inside the cystic lesion is shown here. The PAT relative total hemoglobin map was superimposed onto the ultrasound. The relative total hemoglobin displayed an extensive diffused vascular distribution in the depth range of one centimeter to five centimeters and the level was high at 17.1.

The blood oxygen saturation distribution was superimposed onto the ultrasound and the level was low at a mean value of 46.4%Surgical pathology revealed the well-differentiated endometrioid adenocarcinoma of both the right and left ovaries. The depth was marked on the right side of the B-scan images. This figure shows a 46-year-old woman with bilateral cystic lesions.

The ultrasound of the right ovary with a simple cyst measuring 4.2 centimeters in maximum diameter is shown here. The PAT relative total hemoglobin map superimposed onto the coregistered ultrasound shows scattering signals on the left side of the lesion with a low average level of 4.8. The blood oxygen saturation map revealed higher oxygen saturation content of 67.5%The surgical pathology revealed a normal right ovary with follicular cysts.

For each wavelength, measure the total energy output at the four fiber tips and compare them to a previous record. If the measurement is more than one millijoule less than the record, adjust the optics to maximize energy coupling. In vivo PAT using FDA approved clinical ultrasound system is an important step in the clinical translation of PAT.

Compared to ex vivo imaging, in vivo human imaging presents novel challenges in data acquisition. Clinical PAT data can be further used for computer aided diagnosis research. Our technology development and the promising pilot patient study result inspire researchers and companies to explore the full capacity of coregistered photoacoustic and ultrasound for early ovarian cancer detection and for surgical risk management.