Breast cancer detection using optical imaging methods alone is hampered by a lack of specificity of the intrinsic optical properties and chromophore concentrations in breast tissue [1
]. Indeed, the endogenous contrast from angiogenesis in tumors is nonspecific to cancer. Therefore, in case of small tumors or tumors in dense breast tissue this contrast is expected to be low. Furthermore, diffuse optical imaging has relatively low spatial resolution (on the order of 5-10 mm). This combination of low contrast and low spatial resolution of the diffuse optical methods results in limited sensitivity and specificity for lesion detection and characterization, especially in case of small lesions and lesions located in dense breast tissue. The use of fluorescent contrast agents may increase the sensitivity and specificity of lesion detection and subsequently could provide a better and earlier diagnosis [4
]. In the case of blood-pool contrast agent, the intravenously injected fluorescent molecules may preferentially accumulate in diseased tissue, because of firstly, an increased blood content due to tumor angiogenesis and secondly, leaky blood vessels in tumors due to damaged endothelial lining. In addition, the agent may have different decay properties in diseased tissue compared to normal tissue. This pharmacokinetic behavior could be used to localize tumors independently of the concentration of the fluorescent molecule [9
In a clinical trial performed in 2007, a cyanine-based fluorescent dye (Omocianine) using the Philips Diffuse Optical Tomography (DOT) system dedicated for breast imaging has been evaluated [10
]. The fluorescent contrast agent, Omocianine, circulates in the blood stream. Thus, the concentration of the contrast agent in normal tissue can be assumed proportional to the blood concentration. Further, the absorptions of the four wavelengths that were used by the DOT system (690 nm, 730 nm, 780 nm and 850 nm) are sensitive to blood content. Hence, the more blood in breast tissue, the higher the absorption and the more fluorescence is emitted. Since malignant tumors have a higher permeability of their blood vessel walls compared to healthy tissue, the contrast agent tends to accumulate at the tumor location. Therefore, at equal amounts of blood, and hence equal absorption by blood, the fluorescence is higher in tumors than in healthy tissue. The study showed that DOT was feasible and safe for breast cancer visualization in patients, using low doses of Omocianine [10
]. However, a serious limitation was the fact that the contrast agent Omocianine is a non-targeted fluorescent dye, causing fluorescent enhancement of normal tissues. In addition, the reconstruction algorithms produced artifacts in the fluorescence and absorption data, which might lead to clinical misinterpretation of the DOT images.
In this study, the goal is to increase the lesion visibility in DOT by combining fluorescence and optical absorption data at the voxel level in one single graph, a scatterplot. This concept was introduced by Chance et al. in optical imaging of breast cancer [11
]. They plotted the mean percentage of oxygen desaturation of blood versus the mean blood volume of their patients into a graph. Due to angiogenesis and high metabolism of cancers, data from breasts with cancer were found at high blood volume and high percentage of oxygen desaturation of blood, corresponding to the upper right portion of the graph. Data from cancer free breasts accumulated in the lower left portion of the graph. Using this concept, we hypothesize that a scatterplot of the fluorescence versus the absorption will improve the separation between malignant and normal tissue within one breast. In this scatterplot, a parameter space is shown in which each dot corresponds to a single voxel in the breast. It should be emphasized that the parameter space does not show an image of the breast. Instead, the dimensions of the space correspond to physical parameters, fluorescence and absorption at a given wavelength. Then, the “grey level” of a voxel in the fluorescence image and the “grey level” of the same voxel in the absorption image together are the coordinates of the corresponding dot in the scatterplot.
In addition, we aim to improve the specificity and sensitivity of the DOT procedure even further by adding a third dimension to the scatterplot, such as the absorption image of another specific wavelength or total hemoglobin concentration. The fluorescence and absorption datasets are reconstructed with 2 different algorithms. Therefore, the reconstruction artifacts in the absorption and fluorescence images are unrelated. Thus, in the fluorescence-absorption scatterplot, we hypothesize that the signal from cancerous tissue will be enhanced, while the signals from artifacts will remain unchanged.
The aim of this paper is to validate a method for breast cancer imaging using fluorescence and optical absorption tomography combined in a scatterplot. The article is organized as follows: the DOT system, the phantom experiments and clinical measurements, and the scatterplot are described first. In the Results section, phantom measurements are used to validate the method under controlled circumstances. Phantom-lesions with a volume down to 0.9 ml and a dye concentration ratio between lesion and background down to 2 are studied. Next, the increase of lesion visibility and the discrimination of structures from tumors in 5 patients, 6 lesions, are investigated. Due to the physiology of breasts, more anatomical structures are visible than in the phantoms. The pharmacokinetics of the cancerous and healthy tissues are compared in scatterplots. Artifacts are discriminated from the lesions in the scatterplots. In conclusion, scatterplots provide a better way to combine fluorescence and absorption data, leading to improved lesion detection and better discrimination between malignant and other structures.