Optical Mammography. Introduction. Sergio Fantini and Paola Taroni

Transcription

1 Ch4.16-P qxd 3/15/07 5:51 PM Page Optical Mammography Sergio Fantini and Paola Taroni Introduction Sources of Intrinsic Optical Contrast in Breast Tissue Principles of Optical Mammography Continuous-wave Approaches: Dynamic Measurements and Spectral Information Time-resolved Approaches Interpretation of Optical Mammograms Prospects of Optical Mammography References Introduction White-light transillumination was introduced into medicine in the early 1800s, but only in the late 1920s was it applied for breast imaging and visualization of breast lesions. In a darkened room, the breast was illuminated with powerful white light, and the transmitted image was observed directly by eye on the other side of the pendant breast, looking for shadows that might reveal the presence of a pathologic condition. The procedure was simple and inexpensive, and it proved useful to identify hematomas and liquid cysts. However, it did not reach wide applicability, because it did not enable discrimination between malignant and benign solid lesions, and some physicians had problems with image interpretation. In the 1980s, new systematic attempts were made to apply optical techniques to breast imaging, and led to a method of transillumination called diaphanography, or lightscanning. A tungsten filament lamp, filtered to select red and near-infrared (NIR) light, was used for illumination, typically through a fiber-optic hand-held illuminator applied to the breast, and the breast shadow was recorded on an infrared-sensitive film or with a video camera connected to a black-and-white monitor and videotape recorder. In a diaphanography examination, light was diffused throughout the breast and randomly scattered. Opaque lesions formed shadows on the surface of the breast that acted as a screen. The deeper is the lesion, the greater the distance from the screen, and the less the contrast. This implies an inherent limitation of the technique, since small lesions will only appear with high contrast if they are not too far from the surface. Typically, high absorption, showing as a dark shadow, was regarded as the most specific sign of abnormality, but also asymmetry between the two breasts and abnormal vasculature (again visualized as dark shadows) were considered in the interpretation of the images. Initial studies, performed on a small series of selected patients, suggested the possibility of successfully detecting solid breast tumors (Ohlsson et al., 1984). Those positive Cancer Imaging Lung and Breast Carcinomas 449 Copyright 2007 by Elsevier, Inc. All rights of reproduction in any form reserved.

2 Ch4.16-P qxd 3/15/07 5:51 PM Page IV Breast Carcinoma outcomes fostered the research on diaphanography: commercial instruments became available and systematic trials were carried out, including blind studies performed prospectively in a screening population to compare diaphanography with X-ray mammography. Contrasting results were obtained. In some cases, optical methods compared favorably with X-rays (Wallberg et al., 1985), while other studies were negative about the diagnostic potential of diaphanography (Monsees et al., 1987). The latter studies highlighted a high number of equivocal or false-positive findings, which could only partially be retrospectively explained with technical limitations such as limited field of view, insufficient illumination level, or inadequate positioning of the light source. The sensitivity was also significantly lower than with mammography (about 60 to 70% versus 90 to 98%), especially when small lesions were considered. Moreover, previous knowledge of the lesion location seemed to be a critical factor, leading to much better results in retrospective analysis of data that were originally acquired and first analyzed prospectively (e.g., an increase in sensitivity from 76 to 94% was achieved by Bartrum and Crow, 1984). Despite the mixed results, even the researchers who would not recommend diaphanography as a screening method stressed its advantages in terms of noninvasiveness, good patient acceptance, quick and easy examination, and cost-effective instrumentation. They also suggested potential adjunct roles for diaphanography, like improving the positive yield of biopsies among patients recommended for surgery or following up equivocal lesions at frequent intervals. However, the negative results in the diagnostic discrimination of solid breast tumors discouraged further development of diaphanography. A first reason for the failures of optical methods in their early application to the detection and classification of breast lesions is the insufficient training and experience of the investigators performing the examination and, more importantly, interpreting the images. But a second and more conceptual limitation of diaphanography was associated with the instrumentation used and the lack of a physical model to quantitatively describe light propagation in breast tissue. As a result, diaphanography could not address crucial challenges in optical imaging associated with the diffusive nature of light propagation in breast tissue, the strong attenuation of light, and the sensitivity to breast boundaries. Furthermore, diaphanography did not take full advantage of the diagnostic value of the spectral information that can be obtained with optical mammography. More recently, starting in the 1990s, technical improvements on both instrumental aspects and theoretical modeling have suggested possibilities to better exploit the optical properties of healthy and diseased breast for diagnostic purposes, and have opened new opportunities to the application of optical methods for breast cancer detection. Sources of Intrinsic Optical Contrast in Breast Tissue A practical problem associated with optical techniques is the strong light attenuation in biological tissues, which prevents whole-body examinations. Even in more favorable cases, dealing with a few centimeters of soft tissue, as in the case of breast imaging, the attenuation of ultraviolet or blue/green light is too strong for any practical application. As a result, red and near-infrared (NIR) light is always used in practice for its relatively low attenuation. The red-nir spectral region, say from 600 to 1000 nm, is sometimes called the optical diagnostic window. As described above, diaphanography relied on the direct visualization of a shadow resulting from a localized increase in light attenuation. Two optical phenomena contribute to the attenuation of light: absorption and scattering. Absorption annihilates the incoming photons, thus reducing the intensity of the transmitted light. Scattering events are essentially changes in the direction of propagation of photons. Even though photons continue to propagate in the medium, their change in direction contributes to the attenuation of the light transmitted through tissue along the original direction of propagation. To fully understand the diagnostic potential of optical data, one needs to consider the origin of both absorption and scattering phenomena. Different substances typically absorb at different wavelengths. Thus, at least in principle, the measurement of the absorption spectrum of a medium allows for identification of its constituents. Moreover, the higher is the amount of a specific constituent, the stronger is its relative contribution to the overall absorption of tissue. Thus, the absorption properties of tissue also provide information on the concentration of its various constituents. Early studies have shown that hemoglobin contributes markedly to breast absorption at red and NIR wavelengths. This can have important diagnostic implications, since areas of high vascularization can be readily identified. Moreover, the two forms of hemoglobin (oxy-hemoglobin and deoxy-hemoglobin) have different absorption spectra. Therefore, changes in oxygen saturation levels can also be optically measured. Water and lipids show characteristic strong absorption peaks in the NIR. The balance of water and lipids in breast tissue depends on factors like age and hormonal status. Furthermore, the water and lipid content of pathologic lesions is likely to differ from that of healthy tissue, making its assessment potentially useful for diagnostic purposes. From an experimental point of view, to derive information on tissue composition, measurements must be performed at several wavelengths. In fact, the absorption coefficient µ a of tissue (which is related to the absorption probability per unit distance) at any wavelength λ is due to the superposition of the contributions from its constituents, where each contribution is given by the product of the specific absorption ε and the concentration c of the constituent. In an equation:

3 Ch4.16-P qxd 3/15/07 5:51 PM Page Optical Mammography 451 na( m) = / fi m c i ^ h i (1) In a simplified description of breast tissue, we can consider four main constituents absorbing significantly in the red and NIR, namely, oxy-hemoglobin (HbO 2 ), deoxyhemoglobin (Hb), water, and lipids. Their specific absorption spectra are known from the literature. Thus, by measuring the absorption of breast tissue at a minimum of four different wavelengths, one can estimate the concentration of each constituent. Scattering is essentially due to the presence of interfaces, or refractive index discontinuities, at a microscopic level. For visible and NIR light, scattering is believed to originate mostly from cell nuclei and subcellular organelles. The scattering properties are affected by both the size and density of these scattering centers. So their assessment can provide information on the microscopic structure of tissue and, in particular, on the local density of cellular nuclei and organelles. The wavelength dependence of the transport scattering coefficient µ s can be expressed as follows using a simple empirical approximation to Mie theory: b nl s ( m) = am - (2) This description is in agreement with the experimental finding that the transport-scattering coefficient decreases progressively upon increasing wavelength, with no characteristic peaks. The scattering amplitude a provides information on the density of the scattering centers (higher values of a correspond to denser tissues), while the scattering power b is related to their size (smaller scattering centers lead to steeper slopes). Because both absorption and scattering contribute to light attenuation, a direct visualization of the transmitted light as performed in diaphanography cannot enable the discrimination between the two optical phenomena, which have independent origins and can even compensate each other. For example, a highly vascularized region of low-density tissue combines a higher absorption associated with a higher blood concentration and a lower scattering associated with a lower density. These two effects tend to balance each other, leading to overall low contrast, if any. Hence, the possibility of discriminating between absorption and scattering is beneficial and, at least in principle, could increase the sensitivity of optical techniques. Providing more information on the nature of the detected abnormality could also aid its identification, thus affecting positively even the specificity to cancer detection. The assessment of the optical properties (i.e., absorption and scattering coefficients) of tissue in vivo in a clinical environment has become technically feasible in the last two decades. This implies the potential to derive noninvasively information on tissue composition and structure that can be profitably used for diagnostic purposes. Consequently, the biomedical community has shown a renewed interest in optical mammography, that is, optical imaging for the detection and characterization of breast lesions. Principles of Optical Mammography Breast imaging approaches can be classified into those based on a direct projection of optical data and those based on solution of the inverse imaging problem of tomography. The latter approaches yield a more rigorous spatial reconstruction of the breast optical properties, but are more complex in terms of data acquisition, analysis, and interpretation. Consequently, instruments for breast optical tomography have been developed only recently, and only initial studies on human subjects have been reported. By contrast, larger human studies based on projection imaging have been performed over the last 20 years. For projection imaging, the breast is typically positioned between plane parallel plates, similar to what is done in conventional X-ray mammography, but with a much milder degree of compression so as not to cause discomfort to the patient even when the full examination requires several minutes to be completed. As already in the case of diaphanography, the light illuminates one side of the breast and the transmitted light is collected on the opposite side. However, discrete wavelengths are typically used, not broad band light. This is done to take advantage of the different absorption properties of tissue constituents at different wavelengths and derive their concentrations, as described earlier. Moreover, the breast is not fully illuminated. The light is generally coupled to an optical fiber that provides a relatively small (1 to 2 mm) illumination spot on the breast, and the light transmitted through the breast is collected with another optical fiber on the opposite side of the breast. Images are built by raster-scanning the two fibers in tandem over the compressed breast and collecting data every 1 to 2 mm. This measurement step determines the pixel size of the images. This may seem to set an undesired technical limit to the spatial resolution of optical images but this is not the case. In fact, at red and NIR wavelengths, the attenuation in breast tissue is dominated by scattering. Contrary to what occurs with X-rays, which mostly propagate straight through tissue, optical photons undergo hundreds of scattering events per centimeter traveled within tissue. So, a collimated light beam injected into tissue rapidly broadens upon propagation. As a consequence, the shadow cast by an optical inhomogeneity (e.g., a region of altered vascularization) is expected to appear bigger than the real size of the inhomogeneity, and the effect is more marked for deeper inhomogeneities. This sets a physical limitation to the spatial resolution that can be achieved by imaging at optical wavelengths. The spatial resolution of optical mammography cannot be easily quantified because it depends on several factors

4 Ch4.16-P qxd 3/15/07 5:51 PM Page IV Breast Carcinoma (optical properties of the inhomogeneity and surrounding tissue, optical contrast, depth of the inhomogeneity). However, as a rule of thumb, we could say that an accurate estimate of the size is possible typically around 1 cm and above. Smaller objects, down to a few millimeters, can still be detected, provided that their optical contrast is large enough, but their image will be significantly bigger than their real size, thus preventing any accurate estimate of their dimensions. Consequently, optical imaging cannot compete with X-ray mammography on the ground of morphologic information. In particular, it will not be possible to visualize small calcifications that are a key element for diagnosing malignant lesions in X-ray images. However, optical data can provide different pieces of information. Specifically, functional information is available through the assessment of total hemoglobin content and oxygen saturation, and potentially of other constituents and related roles. For breast optical tomography, the geometry of illumination and collection is more complex than for projection imaging, with a number of possible arrangements. For a parallel-plate geometry (similar to the case of projection imaging), more illumination and collection points are used at the planes of illumination and collection, whereas for a circular geometry, arrays of illumination and collection optical fibers are arranged around the pendulous breast. The larger number of illumination and collection points yields data that is suitable for tomographic image reconstruction of the breast optical properties. Optical measurements are noninvasive, and safe, and do not cause any discomfort to the patient. The optical instrumentation is relatively simple and cost-effective, as compared to other diagnostic imaging equipment that is routinely in a clinical setting. Consequently, optical imaging could be effectively applied even as a complementary technique. Moreover, promising preliminary results have recently been achieved in monitoring neoadjuvant chemotherapy, where repeated measurements can be performed with no risk for the patient, thus potentially allowing the optimized development of individual therapeutic protocols. Continuous-wave Approaches: Dynamic Measurements and Spectral Information While continuous-wave approaches to optical mammography are conceptually similar to the diaphanography techniques of the 1980s, a number of technical advances in the data collection and data analysis have been introduced since the 1990s to generate much richer functional information with respect to the transillumination images of diaphanography. The term continuous-wave indicates that the light source emission is constant with time. On the one hand, this fact limits the information content of the measured data to the overall attenuation (or optical density) contributed by the combination of absorption and scattering events within breast tissue. On the other hand, continuous-wave methods are technologically straightforward, provide a high signalto-noise ratio, and ideally lend themselves to real-time dynamic measurements and to spectral measurements over a broad, continuous spectrum. The real-time measurement of dynamic processes within the breast has the potential to provide novel functional information that was not previously sensed by other diagnostic imaging modalities. For example, the oscillatory hemodynamics associated with arterial pulsation or respiration may reflect the local vascular impedance and compliance, which can in turn be affected by cancerous modifications. Furthermore, the dynamic features of the return to equilibrium in response to a mechanical perturbation (for example, a transient application of pressure to the breast) may reveal spatial patterns that can be associated with the presence of cancerous lesions. We have already discussed how multiwavelength data can provide functional and metabolic information, which represents the greatest promise of optical mammography for diagnostic imaging and distinguishes it from X-ray mammography and ultrasonography of the breast. The measurement of a continuous optical spectrum, as readily afforded by continuous-wave methods, is a most effective way to identify the relative concentrations of the various absorbing species in breast tissue. Within the spectral region considered in optical mammography, which is typically within the nm wavelength range, the absorption of deoxyhemoglobin decreases with wavelength, with the exception of a peak at ~758 nm; the absorption of oxy-hemoglobin shows a broad valley with a minimum at ~692 nm and a broad peak with a maximum at ~924 nm; the absorption of water shows a relatively strong peak at ~975 nm; and the absorption of lipids shows a peak at ~924 nm. The scattering spectrum of breast tissue is featureless and decreases with wavelength (see Eq. (2)). It has a wavelength power dependence that is typically in the range λ 0.4 λ 1.5 (Shah et al., 2004), which is a weaker wavelength dependence than the Rayleigh limit (~λ 4 ) for particles that are much smaller than the wavelength. Even though single-wavelength, continuous-wave measurements are generally not able to discriminate absorption from scattering contributions, full spectral data can accomplish such a discrimination by taking advantage of the featureless scattering spectrum of breast tissue. It is well-established that cancer is associated with a higher concentration of hemoglobin in breast tissue (Fantini et al., 1998; Tromberg et al., 2000; Grosenick et al., 2003; Dehghani et al., 2003), while it is still unclear whether hemoglobin saturation provides a reliable intrinsic source of contrast for cancer. With regard to water and lipids, case studies have indicated that cancer, relative to healthy breast tissue, typically has a higher water concentration (Tromberg

5 Ch4.16-P qxd 3/15/07 5:51 PM Page Optical Mammography 453 et al., 2000; Jakubowski et al., 2004) and a lower lipids content (Jakubowski et al., 2004). Time-resolved Approaches Continuous-wave measurements of the attenuation of light transmitted through the breast do not allow one to fully exploit the diagnostic potential of optical mammography that is associated with separate measurements of absorption and scattering properties of breast tissue. Time-dependent methods, where the light source emission is not constant with time and the optical detection is time-resolved, afford the measurement of absorption and scattering features of breast tissue. Time-resolved approaches are implemented in the time domain or in the frequency domain. These two implementations differ in the instrumentation used, but the data collected in the time domain and frequency domain are mathematically related by a temporal Fourier transformation. In time-domain measurements, a short light pulse (~100 ps duration) is injected into the tissue. Scattering and absorption events occurring during propagation through tissue cause attenuation, delay, and broadening of the injected pulse. From a qualitative point of view, we can say that the scattering essentially delays the detected pulse, as each scattering event changes the direction of photon propagation. Thus, photons move along zigzag trajectories that are much longer than the distance between the injection and the detection points. So photon detection is delayed: the higher the scattering, the longer the delay. The absorption determines how steep the temporal tail of the detected pulse is. We see the effects of the absorption mostly at long times, on the pulse tail, because the longer the photons stay in the medium, the higher the probability they undergo an absorption event. Thus, strong absorption means that many photons are removed from the temporal tail of the pulse and its slope becomes steeper. This holds qualitatively, but to get a quantitative estimate of the absorption and scattering properties, we need a suitable theoretical model of light propagation that correlates the shape and delay of the transmitted pulse to the absorption and scattering properties of breast tissue. Generally, the diffusion approximation to the radiative transport theory (Patterson et al., 1989) is used, as it provides a simple analytical solution that can be readily applied for the interpretation of clinical data. In its simplest derivation, the model holds only for a homogeneous medium. So it does not allow the estimate of local values of the optical properties. It can only provide average values measured over the light path between the injection and the collection point. More realistic theories that describe the heterogeneity of breast tissue are just starting to be developed, and models that take into account at least the presence of a localized inhomogeneity (i.e., a pathologic lesion) have been applied only recently, and not routinely yet, for the interpretation of patient data (Torricelli et al., 2003; Grosenick et al., 2005). The idea of optical diagnosis of breast lesions relies on optical contrast, on the different optical properties of lesion and surrounding tissue. This clearly violates the hypothesis of homogeneous medium. Moreover, the healthy breast tissue itself is markedly heterogeneous. Even under such conditions, the diffusion approximation still provides effective information on the scattering properties. On the contrary, absorption images are of difficult use because the inadequacy of the model limits the contrast and spatial resolution, thus hindering the detection of lesions, especially small ones. However, the availability of the time distribution of the transmitted photons can have direct applications, as the scattering and absorption events modify the pulse shape in a different way and at different times. Consequently, a convenient temporal selection of the detected photons can yield information on the optical properties. In particular, early arriving photons, on the raising edge of the pulse, are mostly (even though not only) affected by the scattering properties. Conversely, late-arriving photons, on the tail of the detected pulse, are mostly sensitive to the absorption properties. Thus, if only late photons are selected from the transmitted pulse at each measurement position during the breast scan, special intensity images so called delayed gated images can be built. The intensity in each pixel is related to the absorption properties in the corresponding position: high transmitted intensity indicates low absorption. The method is clearly not quantitative, as the absorption coefficient is not assessed. However, it is relatively simple, not requiring data analysis based on a theoretical model, and allows one to compare two locations and determine where the absorption is higher or lower and whether the difference is small or large. Such a procedure is commonly used to detect spatial changes in the absorption properties and to identify areas of abnormal absorption, whereas diffusion theory is used to translate time-domain data into scattering images. Time-domain optical mammography has been applied in clinical trials (Grosenick et al., 2005; Taroni et al., 2005) according to the measurement scheme where the slightly compressed breast is raster-scanned in a transmission geometry, and time-domain data are collected at every measurement position. Spectral information is obtained by injecting picosecond pulses at different wavelengths and collecting independently each of the transmitted pulses. As already described, time-gated intensity images are routinely used to track absorption changes as a function of position. If the imaging wavelengths are chosen so that each wavelength isolates the contribution of a specific constituent, namely, a single constituent absorbs at each wavelength, then each image can be used to investigate the spatial distribution of a different constituent. In practice, it is usually difficult to find wavelengths where just one constituent absorbs. So, it

6 Ch4.16-P qxd 3/15/07 5:51 PM Page IV Breast Carcinoma is not possible to isolate single constituents, but still, with proper choice of the imaging wavelengths, each of them can dominate a different image. In particular, Politecnico di Milano (Milan, Italy) has developed a prototype that operates at 4 to 7 wavelengths between 637 and 985 nm (Taroni et al., 2005). Using that instrument, it was shown that images at wavelengths shorter than 685 nm are dominated by deoxy-hemoglobin, at 916 nm by lipids, and at 975 nm by water, while 785 nm enhances the sensitivity to oxyhemoglobin. An example is shown in Figure 116, which displays images acquired at 683, 785, 916, and 975 nm from a 55-year-old patient with a 1.8 cm invasive ductal carcinoma in her left breast. The cancer is detected because of its marked vascularization that causes strong absorption at the two shorter wavelengths (Figs. 116a and 116b). Moreover, the uniform and dark appearance of the image at 916 nm (Fig. 116c) indicates a high lipid content, revealing the adipose nature of the breast, in agreement with what derived from the X-ray mammogram (Fig. 116e). Further details on [AU1] image interpretation are reported in Section F. The frequency-domain approach is based on modulating the intensity of the light source (at a frequency f that is typically in the order of 100 MHz) and performing phasesensitive detection of the modulated optical signal. One can fully describe the modulated optical signal using three parameters, namely, the average intensity (DC intensity), and the amplitude (AC amplitude) and phase (Φ) of the intensity oscillations. These three parameters can provide sufficient information to characterize both the absorption and scattering properties of tissue. In particular, the phase measurement is directly associated with the time-delay experienced by the probing intensity-wave in tissue, which is also directly measured in the time-domain approach. Frequency-domain instruments have been developed for direct projection imaging of the breast (Fantini et al., 2005), as well as optical tomographic imaging of the breast (Dehghani et al., 2003). A frequency-domain prototype originally developed by Siemens AG, Erlangen, Germany (Götz et al., 1998), has produced a clinical data set of optical mammograms in a planar transmission geometry. Figure 117 shows a picture of this prototype (panel (a)) and two representative optical mammograms (panels (b) and (c)) obtained on a 53-year-old patient with a 3 cm invasive ductal carcinoma in her left breast. The optical mammograms shown in Figure 117 (panels (b) and (c)) are direct projection images of the slightly compressed left breast taken in a craniocaudal (cc) projection. The total time required to scan the breast is 2 to 3 min. The frequencydomain optical data have been initially processed with an algorithm designed to enhance tumor contrast by minimizing the effects of the breast geometry on the optical data. Then a spatial second derivative algorithm is applied to enhance the spatial information content of the image and the visualization of blood vessels (Fig. 117b). Finally, data at four wavelengths (690, 750, 788, and 856 nm) are combined to yield a measure of tissue saturation (StO2) that results in an oxygenation image (Fig. 117c) The optical mammograms in Figure 117 illustrate the potential of this imaging technique to detect angiogenic signatures and oxygenation data associated with breast tumors. In particular, the invasive ductal carcinoma of Figure 117 (indicated by the arrow in panels (b) and (c)) is associated with a high density of blood vessels (Fig. 117b) and low levels of oxygenation (Fig. 117c). (a) 683 nm (b) 785 nm (c) 916 nm (d) 975 nm (e) X-ray image Figure 116 Late-gated intensity images at 683 nm (a), 785 nm (b), 916 nm (c) and 975 nm (d), and X-ray mammogram (e) of the left breast (oblique view) of a 55-year-old patient bearing an invasive ductal carcinoma (max. diameter = 1.8 cm), indicated by the red arrow. The images were acquired with the time-resolved multiwavelength optical mammograph developed by Politecnico di Milano (Milan, Italy).

7 Ch4.16-P qxd 3/15/07 5:52 PM Page Optical Mammography 455 (a) lcc (b) lcc (c) low StO2 high Figure 117 (a) Photograph of a prototype for frequency-domain (70 MHz) optical mammography developed by Siemens AG, Medical Engineering (Erlangen, Germany). The slightly compressed breast is optically scanned to obtain 2D projection images at four wavelengths (690, 750, 788, and 856 nm). The scanning time is about 2 min per image. (b) Second-derivative image at 690 nm, and (c) oxygenation image from data at all four wavelengths of the left (l) breast in craniocaudal (cc) view of a 53-year-old patient affected by invasive ductal carcinoma (indicated by the arrow in panels (b) and (c)). Cancer size is 3 cm. Interpretation of Optical Mammograms A number of structures of the healthy breast can be identified in optical images. First, blood vessels and highly vascularized regions, like those surrounding the lactiferous ducts in the nipple area, are detected due to the strong hemoglobin absorption at short wavelengths (below 800 nm). The mammary gland is characterized by marked absorption at 975 nm, possibly due to its high water content as compared to the surrounding more adipose breast tissue, even though a contribution could also come from collagen, which shows significant absorption at 975 nm. Moreover, lipids have a characteristic absorption peak around 924 nm. Thus, optical images collected around this wavelength of 924 nm provide information on lipid distribution, and regions that appear dark in those images, due to strong absorption, show good correspondence with areas that are relatively transparent to X-rays. The scattering images of healthy breasts are generally uniform, except for the mammary gland that in some cases reveals slightly lower scattering, especially at the longest wavelengths. Concerning breast lesions, cancers are usually identified through the detection of associated neovascularization. Thus, they appear as strongly absorbing areas at short wavelengths. The contrast is often higher at nm than at nm, suggesting the presence of deoxygenated blood. However, low oxygenation has not yet been proven to be a reliable index for identifying malignant lesions. These qualitative observations are based on the visual inspection of images acquired at different wavelengths. However, they are confirmed by the quantitative estimate of blood content and oxygenation in the lesion and surrounding tissue. Such estimates are obtained applying inhomogeneous models of breast tissue that account for the presence of a localized lesion and allow one to quantify its optical properties and estimate its composition. These models indicate that the blood content in the tumor area is typically two to five times higher than in the surrounding tissue. However, such values are often exceeded. On the contrary, no systematic and reliable findings have yet been reported for the oxygenation level of breast cancer with respect to the oxygenation level of healthy tissue or benign breast lesions. At least in principle, the scattering images could provide diagnostically useful information. Actually, the neoplastic transformation affects the entire tissue architecture, altering cell density and nuclear volume, degrading the extracellular matrix upon invasion, and forming a complex network of

8 Ch4.16-P qxd 3/15/07 5:52 PM Page IV Breast Carcinoma new blood vessels. All these processes may modify the scattering properties of tissues, especially when poorly differentiated invasive lesions develop. Experimentally, changes in scattering are often observed, especially when the lesion involves a significant volume. The detection and identification of cysts are performed relying on their liquid nature that leads to low scattering. Cysts may be of several types, containing a clear fluid, a turbid liquid, or even big floating particles. The effect of these various structures on the slope of the scattering spectrum is different. Consequently, the higher or lower contrast at different wavelengths provides information on the nature of the cyst. For example, a marked increase in contrast at long wavelengths, corresponding to a very steep scattering spectrum, will suggest the presence of a clear fluid. In some cases, specific absorption features may also identify fluid-filled cysts, as a result of their relatively high water concentration, low lipid concentration, and high concentration of deoxygenated blood. The detection of fibroadenomas is often more challenging for optical mammography. When identified, fibroadenomas are generally characterized by high absorption around 975 nm and sometimes even in the red spectral region ( nm). The marked absorption at 975 nm is likely related to their high water content, but it might also be due, at least in part, to collagen. In the early stages of a clinical test of the only time-domain instrument currently featuring wavelengths longer than 900 nm (Taroni et al., 2005), data acquisition was characterized by limited signal levels at wavelengths longer than 900 nm. Such technical limitation has likely reduced the potential for detecting fibroadenomas in that clinical test. However, instrumental upgrade is ongoing and is expected to improve the diagnostic potential for fibroadenomas in the near future. Optical images are routinely acquired in two views: craniocaudal and either mediolateral (90 ) or oblique (45 ). If localization of the lesion is required in both views, the detection rate (sensitivity) of optical mammography is around 80% for both cancers and cysts. As already observed, the detection of fibroadenomas is often difficult, with only 39% of fibroadenomas identified in both views. If the criterion for positive classification is relaxed to lesion localization in just one view, the sensitivity increases significantly, reaching 92 to 96% for cancers and 90% for cysts. On average, the optical contrast of detected cancers increases progressively with their size, but no such correlation with size has been reported for other lesion types. This different trend observed for malignant and benign lesions is likely due to the fact that cancers are detected in intensity images at short wavelengths, where all blood-reach structures, not only the neovascularization associated with tumor development, are highlighted and can hamper the detection of the lesion. Thus, a bigger lesion size can significantly increase the optical contrast. On the contrary, cysts are detected in scattering images, which are rather uniform for healthy breasts. Thus, no main dependence on the lesion size and generally higher contrast can be expected. Demographic parameters, such as age and body mass index (BMI), seem to have no influence on lesion detection or on the contrast for detected lesions, either malignant or benign ones of any kind. Prospects of Optical Mammography X-ray mammography, the current gold standard for breast cancer screening, is less effective in women younger than 50, who have radiographically dense breasts, leading to high rates of both false-negative and false-positive cases. By contrast, no clear dependence on age was observed for optical imaging in terms of cancer detection rate or image contrast. The possible effect of breast density was also investigated. Five mammographic parenchymal patterns were identified following Tabàr s classification (Gram et al., 1997). Dense breasts (type IV and V) were compared with adipose breasts, more transparent to X-rays (type II and III). The detection rate is a few percent points higher for dense breasts, with slightly lower average value of the detection contrast. However, the difference between the two categories is not significant (Taroni et al., 2005). Because most findings are based on retrospective studies, involving patients with lesions previously identified in X-ray mammograms, there is no information on how optical mammography performs in patients with false-negative X-ray results. Consequently, the results might be somehow biased. Nevertheless, there are strong indications that optical imaging is not negatively affected by the radiological density of breast. For this reason, optical mammography may find a niche of clinical applicability in a population of younger women, where X- ray mammography is not applicable or suffers from degraded performance. It is also envisioned that optical mammography may effectively complement X-ray mammography. First, the information about hemodynamic, oxygenation, and water/lipids composition provided by optical mammography is complementary to the fine structural information provided by X-ray mammography. The combination of these complementary pieces of diagnostic information has the potential to result in a more effective breast imaging modality than X-ray mammography alone. Second, the optical scattering spectrum correlates with breast density. Consequently, a prescreening optical mammogram may identify breasts at high risk for cancer and indicate cases in which X-ray exposure should be avoided if conventional mammography is not expected to be effective. There is also promise in the combination of ultrasound and optical techniques. On the one hand, it is possible to complement the information content of optical mammography

9 Ch4.16-P qxd 3/15/07 5:52 PM Page Optical Mammography 457 and ultrasound imaging, similarly to the way that it is envisioned to complement the information content of optical and X-ray mammography. On the other hand, ultrasound and light may be combined into a truly hybrid diagnostic tool either by using a focused ultrasound beam to label or tag optical photons that have traveled through the ultrasound focal volume (ultrasonic tagging of light), or by using photoacoustics to generate high-frequency pressure waves (ultrasound) as a result of localized areas of increased optical absorbance. It has also been suggested that the rich spatial information provided by magnetic resonance imaging (MRI) can provide crucial a priori information for the implementation of optical tomographic reconstruction algorithms. In this sense, MRI and optical mammography can also be combined into a hybrid imaging tool. Another potential clinical role of optical mammography is in the area of monitoring the effectiveness of therapeutic procedures and performing post-treatment follow-up. This potential results from features of optical mammography such as its safety, lack of discomfort, noninvasiveness, realtime capability, implementation in portable instrumental units, and cost-effectiveness. While there is an obvious emphasis on basing optical mammography on the intrinsic optical contrast provided by the human breast (mostly from oxy-hemoglobin, deoxyhemoglobin, water, and lipids), research efforts are also being aimed at assessing the potential offered by extrinsic optical contrast agents. Although extrinsic contrast agents introduce the need for an intravenous injection, thus making the procedure invasive, they can offer unprecedented opportunities and possibly lead to a more powerful approach (in terms of both sensitivity and specificity) to the optical detection of breast cancer. For example, it is possible to detect specific enzyme activity by using auto-quenched near-infrared fluorescence probes, whose fluorescence emission is restored in the presence of enzymes that are overexpressed by tumors. Other approaches use nearinfrared fluorescent dyes (typically, the clinically approved indocyanine green or structurally related dyes) that exhibit preferential accumulation in cancerous tissue. Some animal studies have shown promising results of cancer detection based on extrinsic contrast agents, but more research is needed to fully appreciate the potential of this approach in humans. In conclusion, optical mammography is a potentially powerful imaging modality for the human breast, which provides diagnostic information that is not available from other current imaging tools. Optical mammography may play an important clinical role as a stand-alone technique for breast cancer detection (especially in younger women) or for follow-up to treatment, and can effectively complement other diagnostic imaging modalities such as X-ray mammography, ultrasound imaging, and magnetic resonance imaging. The potential of combining multiple imaging tools for the detection and diagnosis of cancer is enormous, and optical methods can play an important role in developing such synergistic combinations of imaging tools. Acknowledgments We acknowledge support from the National Institutes of Health (Grant CA95885) and the National Science Foundation (Award BES ). References Bartrum, R.J., and Crow, H.C Transillumination lightscanning to diagnose breast cancer: a feasibility study. 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10 Ch4.16-P qxd 3/15/07 5:52 PM Page IV Breast Carcinoma Tromberg, B.J., Shah, N., Lanning, R., Cerussi, A., Espinoza, J., Pham, T., Svaasand, L., and Butler, J Non-invasive in vivo characterization of breast tumors using photon migration spectroscopy. Neoplasia 2: Wallberg, H., Alveryd, A., Bergvall, U., Nasiell, K., Sundelin, P., and Troell, S Diaphanography in breast carcinoma: correlation with clinical examination, mammography, cytology and histology. Acta Radiol. Diagn. 26: AU1: What is Sention F?