US is frequently used as an adjunct to conventional mammography in differentiating simple cysts from solid lesions. US also plays an important role in guiding interventional procedures, such as needle aspiration, core-needle biopsy, and prebiopsy needle localization (24
). Previously, screening US has also been recommended for patients with dense breasts (25
). We believe that our technique, which incorporates optical tomography and US localization, has demonstrated great potential to noninvasively distinguish malignant from benign breast masses and thereby potentially reduce the number of benign biopsy results. In a previous study (19
), results obtained from two invasive early stage cancers and 17 benign lesions demonstrated that malignant cancers measuring 1 cm in diameter have an average maximum total hemoglobin concentration of 119 μmol/L, whereas benign lesions have an average maximum total hemoglobin concentration of 67 μmol/L. Thus, a nearly twofold greater total hemoglobin concentration was observed. Our study of eight early stage cancers and 73 benign lesions obtained at different clinical sites further demonstrates the diagnostic potential of this technique. In our current study, invasive cancers revealed a more than twofold greater total hemoglobin concentration. No false-negative results were found. Because our samples were limited, a larger prospective clinical trial is needed to validate these results.
In addition to the elevated hemoglobin concentration, information on the distribution of hemoglobin—that is, on the morphologic features of the lesion—is important in reaching an appropriate diagnosis. In general, the hemoglobin distribution of early stage invasive cancers appears isolated, and the lesion is well resolved; the hemoglobin distribution of solid benign lesions, however, appears more diffused. For larger complex cysts, a ring-shaped structure is sometimes observed around the lesions because of the substantial water content. Thus, cross-referencing the hemoglobin level and distribution with the results of standard imaging techniques will likely yield the most accurate diagnosis.
One potential limitation of optical tomography is the difficulty of imaging of lesions that are located close to dark nipple-areolar tissue. Because the light absorption of dark skin is high, the light perturbations that are attributed to the lesions may be secondary to the perturbations that are caused by the nipple-areolar complex. Therefore, the optical imaging algorithm may not reconstruct these lesions correctly. In our study, two cases were excluded from analysis because of this problem. A lighter-colored nipple-areolar complex did not appear to cause a problem. Also, lesions that were located more than 2 cm away from a dark nipple did not cause artifacts.
Another potential problem is the poor probe-to-tissue contact that is made while examining small dense breasts. Three cases were excluded from analysis because of this problem. Good probe-to-tissue contact could be achieved by developing probes of different sizes that are suitable for smaller breasts. Currently, we have designed an optical switch that allows the selection of different probes that are suitable for the size of the examined breast.
Three benign lesions, including two fibroadenomas, one case of minimal nonatypical duct hyperplasia, and one case of fibrosis, showed a high total hemoglobin concentration that suggested high microvessel density. The high total hemoglobin concentration of fibroadenomas may be explained by the results of a pilot study on vascular features of fibroadenoma (27
). In this study (27
), two different groups of fibroadenomas were recognized. The first group showed low microvascular permeability and a high extracellular volume fraction. At histopathologic analysis, lesions with low vascular permeability had a lower density of small vessels. The second group showed higher microvascular permeability and a lower extracellular volume fraction. Lesions with higher microvascular permeability had a higher density of small vessels than lesions in the first group. In our study, the patient with minimal nonatypical duct hyperplasia and fibrosis showed significant enhancement at MR imaging, suggesting increased vascularity in the area of the lesion. This patient had undergone excisional biopsy at the same location 2 years earlier, with similar pathologic findings. It was therefore unlikely that a clinically important lesion was missed during the recent core biopsy. The residual angiogenesis resulting from changes associated with the normal healing process may be a possible reason for the enhanced vascularity.
We do not envision that our technique will be used as a screening tool because lesions must be visible at US to map the lesion and background regions for dual-mesh optical imaging reconstruction. If lesion locations can be accurately estimated by using other imaging modalities, such as MR imaging, our technique could be expanded for lesion characterization by using those modalities, as well. More precise depth information, however, is required if data obtained with other modalities are not coregistered with the near-infrared data. The three reported cases of lesions seen at MR imaging or conventional mammography were reconstructed with accurate a priori knowledge of lesion location.
Because of intense light scattering, optical tomography alone has not been widely used in clinical studies. The data in the published literature have been limited to feasibility studies or case reports. In addition, the systems that are used to acquire optical tomographic data vary considerably. Most of the optical systems use transmission geometry, in which either the light sources and detectors are deployed around the examined breast in single or multiple rings (13
) or the light sources are deployed on one side of the breast and the detectors are deployed on the opposite side with the breast compressed in between (17
). It is clear that without a priori knowledge of lesion locations from other imaging modalities, no one has achieved significant and consistent improvements in accurate light quantification and, therefore, in the differentiation of benign from malignant processes. Only two examples that were related to our study were found in the literature (15
). In one of the studies (15
), the authors reported an average total hemoglobin concentration of 35 μmol/L in a 2-cm ductal carcinoma in situ by using near-infrared measurements alone. After reprocessing the same near-infrared data with an approximate lesion depth obtained from a separate US image, the average total hemoglobin concentration was increased to 67 μmol/L (28
). This value was closer to the average of 88 μmol/L, which was obtained in eight malignant lesions in our study.
In principle, deoxygenated and oxygenated hemoglobin distributions can be estimated from absorption distributions obtained at wavelengths of 780 nm and 830 nm. The estimated deoxygenated and oxygenated hemoglobin distributions, however, were not robust because the negative coefficients in the computation formulas (see Appendix
) could lead to negative deoxygenated and/or oxygenated hemoglobin values in some imaging voxels. The total hemoglobin distribution is more robust because of the positive coefficients in the computation formula. Therefore, no deoxygenated or oxygenated hemoglobin distribution was computed alone.
In principle, the distribution of oxygen saturation can be estimated from two wavelengths (29
). For the two wavelengths (780 nm and 830 nm) that were used in this study, the estimated oxygen saturation in normal background tissue was not robust and could exceed the physiologic range. Recently, we added a 660-nm wavelength to the near-infrared system and found that the background tissue oxygen saturation can be estimated more reliably from measurements of 660 nm and 830 nm.
The reported malignant lesions were generally early stage cancers that were approximately 1 cm in diameter (except for one that measured 2.2 cm in diameter). For larger cancers, the angiogenesis distributions are complex and heterogeneous (29
). This heterogeneous distribution is dependent on angiogenic factors (9
) and is related to the incorporation of existing host blood vessels into tumor and the creation of tumor microvessels. Blood flow through these tumor vessels is heterogeneous. Some areas may have high flow, whereas others may have slower flow and develop necrosis (30
). Tumors with relatively poor blood perfusion may not receive adequate delivery of systemic therapy. This lack of perfusion may be a factor in some patients who have poor response to chemotherapy treatment (31
). Optical tomography for the imaging of larger tumors may be a valuable technique for mapping tumor angiogenesis and evaluating vascular changes, as well as tumor hypoxia, during chemotherapy (29
). This type of information could also prove invaluable in monitoring chemotherapy responses to breast cancer treatment and assessing treatment efficacy.