In 2000, more than 1 million women were diagnosed with breast cancer worldwide (Ferlay et al. 2001). Early detection decreases mortality (Tabar et al. 2003), so many countries routinely screen for breast cancer. X-ray mammography is the screening method of choice (Fletcher and Elmore 2003) but its effectiveness may depend on issues such as the age of the woman, family history of cancer, body mass index, the use of hormone replacement therapy, the use of computer aided detection, and the availability of additional clinical or imaging information (Blarney et al. 2000, Warren 2001, Houssami et al. 2004, Banks et al. 2004). It requires ionizing radiation and its benefits for younger women are unclear (Lucassen et al. 2004). Other imaging modalities such as MRI and ultrasound may be useful in certain circumstances but neither is suitable for screening of asymptomatic women (Morris et al. 2003, Warner et al. 2004).
It is well known that tumours are associated with increased vascularisation (Rice and Quinn 2002) so optical methods provide a natural method for both interrogating tissue to identify disease and for spectroscopically determining the blood volume and oxgenation of a suspicious lesion seen on x-ray mammography to improve specificity. A major disadvantage of optical mammography is the inherently poor spatial resolution. A successful screening tool must be able to identify tumours smaller than 1 cm, as mortality increases rapidly for tumours which exceed this size (Webb et al. 2004). Because of this, optimizing spatial resolution is an important concern in optical mammography. Researchers are also exploring other uses of optical mammography which are less dependent on resolution, such as staging previously identified suspicious lesions, and monitoring the response to new and existing forms of therapy. One of the attractions of the technique is its suitability for repeated investigations on the same subject.
Despite many previous efforts to determine them, the in vivo optical properties of healthy breast tissues and common lesions are not fully known. Most early work (e.g. Peters et al. (1990)) concentrated on measuring the properties of breast tissue in vitro and, as blood and water are the primary chromophores, it is not clear how in vitro values relate to the intact breast. Even optical properties measured in vivo will depend on the geometry of the measurement (particularly if the breast is compressed) and the model used to derive the optical properties from the measurements. Measurement at a single location can give information only about the local average properties. Even so, such measurements have been shown to correlate with age, body mass index and menstrual state (Shah et al. 2001, Cerussi et al. 2001). Perhaps the most reliable measurements of breast optical properties to date are those of Durduran et al. (2002), who obtained frequency-domain measurements at 750, 786 and 830 nm in 52 women using a parallel plate geometry with gentle compression. The average optical properties (± standard deviation) were µa = 0.0041 ± 0.0025 mm-1, µ's = 0.85 ±0.21 mm-1 (at 780 nm), blood volume = 34 ± 9 µM and oxygen saturation = 68 ± 8%. These values agree with other published in vivo values (e.g. Suzuki et al. (1996)), but the µa is approximately double that of corresponding in vitro measurements, possibly because of the lower blood volume in excised breast tissue. Grosenick et al. (2004b) measured the optical properties of tissue and tumour in 50 women at 680 and 785 nm by assuming a spherical tumour in an infinite, homogeneous slab. They found that µa in the tumour was between two and four times that of surrounding tissue due to the increased blood volume, and µ's was slightly elevated. These results agree with similar measurements made by Fantini et al. (1998) and Chernomordik et al. (2002). Holboke et al. (2000) report a similar increase in µa but a 50% reduction in µ's.
A number of alternative approaches to optical mammography have been evaluated. Most clinical studies have been performed using instruments which compress the breast, though generally more gently than in x-ray mammography. This reduces the attenuation of the transmitted light and ensures that the geometry of the problem is well-known. The breast is compressed between either two parallel arrays of sources and detectors, or between plates over which individual sources and detectors are scanned in a rectilinear manner. However, the latter method is only suitable for generating projection images (analogous to x-ray mammograms) since it does not yield sufficient depth information for a 3D reconstruction.
Groups based in Berlin and Milan have between them performed more than 300 clinical studies as part of Optimamm, a consortium funded by the European Union (see www.optimamm.de and a forthcoming special issue of Physics in Medicine and Biology). Both systems acquire time-domain measurements at multiple wavelengths by scanning a single source and detector in tandem across a gently compressed breast. The Milan group have explored the effect of using a wide range of wavelengths (Pifferi et al. 2003, Taroni et al. 2004a), and the Berlin group have investigated the benefits of acquiring additional off axis measurements (Grosenick et al. 1999). Figure 5 shows an optical mammogram recorded by Grosenick et al. (2003) with two views of a tumour in the left breast of a patient, and the corresponding images of the healthy right breast. Both groups report that they can successfully identify around 80-85% of radiologically identified tumours (Grosenick et al. 2004a, Taroni et al. 2004b), and it is likely that second generation systems which incorporate improved spatial and spectral discrimination will yield improved detection rates.
Compressed breast geometries have also been evaluated for imaging by Pera et al. (2003) using a frequency-domain instrument built by Siemens Medical Engineering, and by Culver et al. (2003) using a hybrid system which determines the bulk optical properties using frequency-domain measurements and spatial information from up to 105 continuous wave measurements (see section 2.4).
One of the potential disadvantages of breast compression is the corresponding reduction in the blood volume. Although this improves overall transmission, blood represents the principal source of contrast between tissues, and the most likely means by which tumours may be identified and characterised. Several groups avoid compression by surrounding the breast with rings of sources and detectors. This arrangement is also ideal for generating 3D images. The main disadvantage of this approach is that a much greater volume of tissue is sampled, and therefore the detected light intensities are much lower and have a greater dynamic range than for the compressed breast geometry.
The 3D breast imaging approach has been pioneered by the group at Dartmouth College. They are exploring optical mammography as part of a larger study involving four different breast imaging modalities (optical, impedance, microwave and MR elastography (Poplack et al. 2004)). They use a frequency-domain optical tomography system (McBride et al. 2001) with 6 laser diodes operating at wavelengths from 660-836 nm multiplexed to 16 source positions, and 16 detectors, located around the circumference of a 2D ring whose diameter can be varied to fit the breast. 3D images are reconstructed from three 2D datasets, each consisting of amplitude and phase measurements (Dehghani et al. 2003). Recently, the group has successfully extended their technique to reconstruct directly for haemoglobin and water concentrations, blood oxygenation, and scattering parameters (Pogue et al. 2004). A similar approach has been investigated by Jiang et al. (2002) using a single-wavelength CW system.
The 32-channel time-resolved system at UCL has also been used to generate 3D images of the uncompressed breast, either by using a 2D ring of connectors or a 3D hemispherical tank filled with a tissue matching fluid (Yates et al. 2004), an approach originally employed for the prototype developed by Phillips Medical Systems (Colak et al. 1999).
A sophisticated CW system for imaging both breasts simultaneously has recently been presented by (Barbour et al. 2004). It is designed to acquire images which reveal haemodynamic phenomena within the breast.
Because the prognosis for breast cancer depends largely on the size of the tumour, the relatively poor spatial resolution of optical mammography may limit its use in routine screening. However, the technique may provide a powerful method for the examination of suspicious lesions previously identified by other means. With this in mind, attempts have been made to use the prior information from other medical imaging techniques to condition the optical image reconstruction. In principle, this will allow images with the excellent physiological information content of optical imaging to be reconstructed with the high spatial resolution provided by MRI, ultrasound or x-ray mammography. Ntziachristos et al. (1998) built and tested a combined MR/optical imaging system and successfully used it to record optical and MR images from volunteers with a range of benign and malignant lesions (Ntziachristos et al. 2000, 2002). Li et al. (2003) built an optical imaging probe which was interchangeable with a standard film cassette in an x-ray mammography tomosynthesis instrument. They used this combined system to generate 3D x-ray images of the compressed breast which they segmented into suspicious and background regions, which were then used as anatomical prior information in the optical tomography image reconstruction. The spatial resolution of the optical image was enhanced such that the reconstructed absorber was confined to a volume even smaller than the suspicious region identified in the x-ray images (see Figure 6).
Exogenous contrast media can also be used to improve the sensitivity to small lesions. The most widely used contrast agent is indocyanine green (ICG), which has been approved for use on human subjects by the US Food and Drug Administration as an NIR absorbing and fluorescing dye, and has been used for breast imaging by Ntziachristos et al. (2000) and Intes et al. (2003). When injected intravenously, ICG binds immediately and totally to blood proteins, primarily albumin. This ensures that ICG is confined almost entirely to the vascular compartment except for incidences of abnormal blood capillaries with high permeability, as in the case of tumours with high vascularity. Thus ICG is primarily an indicator of blood volume, although it provides a certain degree of specificity for some types of tumour. Other, more selective contrast agents and fluorescent dyes for breast cancer detection are currently being evaluated in animal models (Ntziachristos and Chance 2001) (see section 4.5 below).
One of the attractive benefits of using contrast agents for optical tomography is that the imaging process involves reconstructing a change in optical properties, which is generally more tolerant of experimental and modelling errors. Therefore the use of contrast agents could lead to significant improvements in image quality, albeit at the expense of a more invasive investigation.
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