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2
Breast Imaging and Related Technologies

Medical imaging is central to breast cancer screening, diagnosis, and staging. Mammography is the most sensitive technique available for the detection of nonpalpable breast lesions, and thus, screening mammography has secured a routine place in health maintenance for women in the United States. Although it is less than perfect, screening mammography can reduce breast cancer mortality when combined with appropriate interventions (see Chapter 1).

Conventional X-ray mammography is a mature technology that provides high-quality images at low radiation doses in the majority of patients. However, conventional film-based mammography may not provide adequate diagnostic information for some women with radiodense breast tissue. It has been estimated that this technology misses about 15 percent of breast cancer lesions (Mushlin et al., 1998). In addition, studies have reported that the positive predictive value1 of conventional mammography ranges only from 15 to 40 percent (Kerlikowske et al., 1993; Kopans, 1992; Kopans et al., 1996). Consequently, 60 to 85 percent of lesions detected by mammography are benign, and thus, many biopsies could potentially be avoided. This situation creates an important incentive for the development of novel technologies to improve detection, diagnosis, and staging and monitoring of treatment for breast cancer.

Accordingly, other imaging technologies, particularly nonionizing



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Page 55 2 Breast Imaging and Related Technologies Medical imaging is central to breast cancer screening, diagnosis, and staging. Mammography is the most sensitive technique available for the detection of nonpalpable breast lesions, and thus, screening mammography has secured a routine place in health maintenance for women in the United States. Although it is less than perfect, screening mammography can reduce breast cancer mortality when combined with appropriate interventions (see Chapter 1). Conventional X-ray mammography is a mature technology that provides high-quality images at low radiation doses in the majority of patients. However, conventional film-based mammography may not provide adequate diagnostic information for some women with radiodense breast tissue. It has been estimated that this technology misses about 15 percent of breast cancer lesions (Mushlin et al., 1998). In addition, studies have reported that the positive predictive value1 of conventional mammography ranges only from 15 to 40 percent (Kerlikowske et al., 1993; Kopans, 1992; Kopans et al., 1996). Consequently, 60 to 85 percent of lesions detected by mammography are benign, and thus, many biopsies could potentially be avoided. This situation creates an important incentive for the development of novel technologies to improve detection, diagnosis, and staging and monitoring of treatment for breast cancer. Accordingly, other imaging technologies, particularly nonionizing

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Page 56 modalities such as magnetic resonance imaging and ultrasound, are being tested for application to breast cancer, with promising results. At present, these methods may provide additional diagnostic specificity over X-ray mammography alone. Additional tools such as scintimammography, positron emission tomography, magnetic resonance spectroscopy, and optical imaging are under investigation as well. To date, no single imaging method appears to offer both high sensitivity and high specificity for the detection and diagnosis of breast cancer. The previous chapter summarized the main technologies in current use for breast cancer detection, whereas this chapter looks more closely at imaging modalities under development (Tables 2-1 and 2-2). The various technologies can roughly be divided into three categories: (1) those that are currently in use, such as X-ray mammography and ultrasound, but that are being further refined; (2) those that are commonly used for medical imaging, such as magnetic resonance imaging (MRI), but that are still experimental with regard to breast cancer detection; and (3) and novel imaging modalities that may be used in the future. A 1996 report, The Mathematics and Physics of Emerging Biomedical Imaging, explains the technical background of many of these promising new technologies in greater detail than is possible here (Institute of Medicine, 1996). The chapter describes the current state of the art as well as technological roadblocks associated with promising near-term imaging technologies. Potential longer-term solutions using alternative modalities, such as optical or microwave imaging, are also briefly addressed. In addition, this chapter describes how novel technologies may affect breast cancer detection in ways beyond image acquisition, including image processing, display, management, storage, and transmission. Common to all imaging systems is the increasing use of digital methods for signal processing, which also offers the possibility of computer-aided detection by texture analysis and pattern recognition. FUNDAMENTALS OF IMAGING ANALYSIS Breast imaging technologies are being developed with three distinct goals in mind: (1) to identify abnormal tissues, (2) to localize the abnormalities within the breast to facilitate further examination or treatment, and (3) to characterize the abnormalities and aid the decision-making process following identification. An ideal imaging modality would accomplish all three goals in a single use, but in reality, most current technologies cannot achieve this, so developers tend to focus on optimizing one goal at a time. In addition to these technical goals, developers hope to generate detection methods that are more practical, inexpensive, harmless, and appealing to the patient than current methods. Many of the current medical imaging methods are used to map struc-

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Page 57 TABLE 2-1 Current Status of Imaging and Related Technologies Under Development for Breast Cancer Detection Current Status Technology Screening Diagnosis FDA approved for breast imaging/detection Film-screen mammography (FSM) +++ +++ Yes Full-field digital mammography (FFDM) ++ ++ Yes Computer-assisted detection (CAD) ++ o Yes Ultrasound (US) + +++ Yes Novel US methods (compound, three-dimensional, Doppler, harmonic) o o No Elastography (MR and US) o o No Magnetic resonance imaging (MRI) + ++ Yes Magnetic resonance spectroscopy (MRS) −/o a +/o a No Scintimammography o + Yes Positron emission tomography (PET) o o Yes Optical imaging o + No Optical spectroscopy − o No Thermography o + Yes Electrical potential measurements o + No Electrical impedance imaging o + Yes Electronic palpation o NA No Thermoacoustic computed tomography, microwave imaging, Hall effect imaging, magnetomammography NA NA No NOTE: This table is an attempt to classify a very diverse set of technologies in a rapidly changing field and thus is subject to change in the near future. aEx vivo analysis of biopsy material/in vivo MRS. Current Status Explanation of Scale — Technology is not useful for the given application NA Data are not available regarding use of the technology for given application o Preclinical data are suggestive that the technology might be useful for breast cancer detection, but clinical data are absent or very sparse for the given application. + Clinical data suggest the technology could play a role in breast cancer detection, but more study is needed to define a role in relation to existing technologies ++ Data suggest that technology could be useful in selected situations because it adds (or is equivalent) to existing technologies, but not currently recommended for routine use +++ Technology is routinely used to make clinical decisions for the given application tural or morphological differences in tumors, such as microcalcifications, tissue masses, angiogenesis, asymmetry, and architectural distortion. Some of the more recently developed techniques can provide information about the biological or functional differences between tumors and normal tissues (Glasspool and Evans, 2000; Hoffman and Menkens, 2000). Such information is critical for making the “quantum leap” in fully achieving

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Page 58 TABLE 2-2 Imaging Technologies Being Developed for Detection of Breast Cancer Technology Description, Mechanism Full Field Digital Mammography (FFDM) Detector responds to X-ray exposure, sends electronic signal to computer to be digitized and processed. Separates detector and image display. Computer-Aided Detection and Diagnosis (CAD) Computer programs to aid in identification of suspicious mammograms and classification as benign or malignant. Serves as a second opinion to radiologists. Ultrasound Use of high-frequency sound waves to generate an image. [New ultrasound technologies, in early stages of development] Compound imaging: uses several ultrasound beams that strike the tissue from different angles. Significantly reduces speckle and improves contrast and definition of small masses and microcalcifications. May cause reduction in display of some masses. Three-dimensional ultrasound imaging: permits display of a volume of tissue rather than a single slice. Examination of tumor volume and changes in tumor size over time.

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Page 59 Stage of Development Potential Strengths Current Limitations General Electric's Senographe 2000 D has FDA approval for use as both hard-copy and soft-copy displays. Studies are under way to compare FFDM with FSM. Ability to manipulate contrast and magnification with one exposure. Ease of image storage and retrieval. Facilitates CAD, digital tomo-synthesis, and telemammography. Spatial resolution and luminance of digital display are lower than those for FSM. Old film screens difficult to digitize for comparisons. Cost may be prohibitive. R2 Technology, Inc. has a program on the market. General Electric has agreement with R2 Technologies to use GE FFDM machine with R2's CAD system. Retrospective studies show that CAD can improve radiologists' readings and improve rate of false-negative results. CAD used alone has very low specificity. Sensitivity and specificity are undetermined for general screening population. Currently used as follow-up to mammography, to determine if lesion is a cyst or solid mass, or to characterize or localize a mass Studies suggest potential for increased use in diagnosis and perhaps even screening, especially for women with dense breasts. Poor ability to detect microcalcifications due to speckle. Compound imaging may help reduce speckle. Three-dimensional and power Doppler imaging: use of Doppler technology may allow assessment of tumor vascularity; it is potentially useful for predicting biological activity and predicting responses to treatment. Can be coupled with contrast agents. Ultrasound elastography: uses information from ultrasound signal to generate images showing elastic properties of tissue. Detects differences in tissue stiffness and may detect features not visible with mammography or conventional ultrasound.

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Page 60 Technology Description, Mechanism Magnetic Resonance Imaging (MRI) Image generated by signals from excitation of nuclear particles in a magnetic field. Breast tumors show increased uptake of contrast agent. [Other MRI technologies under development.] Minimally invasive prognosis and therapy monitoring: different cancer types that display distinct MRI enhancement characteristics may be important as prognostic indicators. MR Spectroscopy (MRS) Use of magnetic resonance spectra and “functional” molecular markers to measure biochemical components of cells and tissues. Scintimammography Image created with radioactive tracers, which concentrate more in cancer tissues than in normal tissues. Measures spatial concentration of radio-pharmaceuticals to generate planar or three-dimensional images by SPECT.

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Page 61 Stage of Development Potential Strengths Current Limitations National Cancer Institute trials are under way to study three-dimensional high-resolution and dynamic contrast MRI in conjunction with mammography. Completion by 2001. Benefits in detection: • detection of multiple malignancies • detection of invasive lobular carcinoma • screening for high-risk women with dense breasts • detection of recurrent cancers Lack of uniform interpretation criteria. Cannot reliably detect microcalcifications and small tumors, especially if they do not pick up the contrast agent. Overlap in uptake time course of benign and malignant tumors. “Smart” MRI contrast agents: agents “activated” by biochemical processes are then detected by MRI; can correlate cell functions with disease state, and can track cell growth and behavior. Limited by identification of appropriate markers and lack of clinical data. Pursued commercially by Metaprobe in Pasadena, CA. MR Elastography: image elastic properties of tissue. Studied as potential adjunct to mammography, fine needle aspirates, and assessment of lesions in vivo. MRS spectra of samples mayincrease accuracy of FNA analysis. Potential noninvasive method of characterizing lesions. High cost and low sensitivity and specificity for detection of small lesions. MIBI approved by FDA. Other radioactive compounds being studied. Used as adjunct to mammography to localize tumors, distinguish malignancies versus benign lesions, and identify metastatic cells in distal regions of the body. MIBI scans unaffected by dense tissue, implants, or scarring. Used when mammograms are indeterminate; can avoid the need for follow-up mammograms. High-resolution scinti-mammography uses a gamma camera and may improve resolution. Potential for SPECT monitoring of multidrug resistance. Radiation health risks similar to those from X rays, although small doses generally considered safe except for pregnant women. MIBI more expensive than ultrasound or mammography, but less expensive than MRI. MIBI unable to detect cancers smaller than 1 cm and less accurate for nonpalpable masses.

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Page 62 Technology Description, Mechanism Positron emission tomography (PET) Uses tracers such as labeled glucose to identify regions in the body with altered metabolic activity, which is common in malignant tumors. Radioactive antibodies Target antigens specific to breast cancer, include carcinoembryonic antigen and certain growth factor receptors. Optical imaging Elastic scattering spectroscopy (ESS), “Optical Biopsy” Use of fiber-optic probes to obtain spectral measurements of elastically scattered light from tissue. Generates spectral signatures that reflect architectural changes at cellular and subcellular levels. Optical tomography Use of light to image the breast. Infrared thermography Measures heat emitted by the body. Tumors can raise skin surface temperature by 2 to 3 degrees C, with heat detected by infrared cameras. Dynamic Area Telethermometry detects changes in blood flow. Electrical potential measurements Measurement of electrical potential at the skin surface. Proliferation of epithelial tissue disrupts normal polarization.

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Page 63 Stage of Development Potential Strengths Current Limitations More studies needed to determine clinical utility. In theory, could be useful in women with dense breasts, implants, or scars. Currently no technique to target biopsy specimens that are identified by PET but not visible on mammograms. PET scanners expensive and not readily available. Only small studies to date; need more clinical studies to determine role in breast cancer diagnosis. Some agents show promising sensitivity and specificity for breast cancer. Scans can be difficult to interpret. Need to identify optimal markers for imaging. Early clinical studies on transdermal needle diagnostic. Portable, designed for convenient clinical use. Instant diagnosis would reduce patient anxiety and allow immediate treatment. Currently depends on endoscopic approach, which may not be relevant to breast tissue. Systems being developed by Imaging Diagnostic Systems Inc., Dynamics Optical Breast Imaging Medical Systems, and Advanced Research Technologies, Inc. Low cost, speed, comfort, and noninvasiveness. Optical scans can be digitized for image manipulation and serial studies. Must optimize accuracy and resolution and improve target-to-background ratios. Variations in breast tissues due to age, hormone status, and genetic makeup. FDA approval in December 1999 to OmniCorder for its BioScan System, based on Dynamic Area Tele-thermometry. Computerized Thermal Imaging, Inc., is testing its system in clinical trials. Noninvasive, does not require compression or radiation exposure. New cameras offer improved spatial and thermal resolutions. Results of numerous studies have been inconsistent. Old technology, especially infrared cameras, has hindered development. Biofield Breast Exam (BBE) has received CE Mark Certification that allows the company to sell in Europe. FDA approval pending. BBE gives a single, numerical result that objectively determines malignancy. Inexpensive, does not require an expert reader, no discomfort, and speedy procedure. Two large clinical studies demonstrated specificity of 55 to 60%.

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Page 64 Technology Description, Mechanism Electrical impedance imaging Measures voltage at skin surface while passing small current through breast. Cytological and histological changes in cancerous tissue decrease impedance of tissue. Electronic palpation Quantitative palpation of breast using pressure sensors. Thermoacoustic Computed Tomography (TCT) Breast is irradiated with radio waves, causing different thermal expansion of tissue and generating sound waves, from which a three-dimensional image is constructed. Microwave imaging Transmits low-power microwaves into tissue and collects backscattered energy to create three-dimensional image. Higher water content in malignant tissues causes more scatter. Hall Effect Imaging (HEI) Induces vibrations by passing electric pulse through tissue while exposed to a magnetic field. Magnetomammography (MMG) Tags cancerous tissue with magnetic agents that are imaged with SQUID magnetometers.

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Page 65 Stage of Development Potential Strengths Current Limitations FDA approval in 1999 to TransScan Medical (Ramsey, NJ) for use of T-Scan 2000 device as an adjunct to mammography for women with lesions in BIRADS a 3/4. Potential as adjunct to mammography for women with certain indeterminate lesions. Painless, no breast compression or ionizing radiation. Not to be used for women with clear indications for biopsy. Currently conducting more trials to validate technology. Assurance Medical (Hopkinton, MA) is seeking FDA approval and is testing 400 women with suspicious lesions. Ultratouch (Paoli, PA) is developing robotic device (Palpagraph) and starting clinical studies for FDA approval. Potential to standardize performance and documentation and serially monitor physical breast exams. Preliminary studies suggest use for general screening. Limited sensitivity for small lesions. Clinical utility unproven. Development in early stages. To date, no large published clinical trials. Optosonics plans to initiate a study of 80 women this year. Does not use ionizing radiation and does not compress the breast. Retains three-dimensional structural information and images are highly consistent. Three-dimensional images difficult to display or analyze; more time-consuming and costly than mammography. To date, research focused on theoretical validation through computer modeling and studies with excised breast tissue. Does not require compression or use ionizing radiation. In theory, should produce high-contrast image, regardless of tissue density. Technology has been constrained by poor resolution, poor depth penetration, excessive power requirements, unsafe microwave levels, and intensive image reconstruction programs. Early stages of development; first published account of HEI in 1998. To date, HEI tested only with excised and simulated tissue. May be useful for a limited population of women. Prohibitive cost; requires an expensive, super-conducting magnet. Still untested; looking for an agent that is both magnetic and specific to cancerous tissue. Would not require compression or ionizing radiation. Should be equally effective with dense breasts. Poor spatial resolution, expensive to fabricate and operate.

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Page 94 palms. Following an equilibration period, average voltages are recorded for each of the electrical potential sensors. Differences in electrical potential can be calculated both between sensors on the symptomatic breast and between sensors on the symptomatic breast and the contralateral breast. One unique feature of BBE is that it gives a single, numerical result that objectively determines whether the lesion is considered malignant or benign. Conversely, tests such as mammography rely on the subjective interpretation of the data by a trained reader. BBE is also relatively inexpensive because it uses very basic equipment and does not require an expert reader. It is noninvasive and not uncomfortable to women, and the procedure can be performed in less than 15 minutes (Faupel et al., 1997). BBE has been tested primarily as a diagnostic tool for women with palpable breast lesions or nonpalpable lesions identified by mammography or ultrasonography. Two clinical studies of diagnostic BBE have been conducted. All of the women in the studies received a BBE followed by a biopsy. The electrical potential differences between sensors were retrospectively analyzed in light of the biopsy outcomes to determine which weighted sum of measurements best predicted the biopsy outcome. In the first study, which included 101 women, BBE was found to have a sensitivity of 90 percent and a specificity of 60 percent. It was also observed that for cancers measuring less than 2.5 cm, the sensitivity of BBE was 95 percent. The investigators speculated that the test's reduced sensitivity to larger tumors could be associated with the tissue necrosis seen in larger tumors. There were, however, only 19 tumors less than 2.5 cm, so this preliminary calculation of sensitivity for patients with small tumors must be validated (Fukuda et al., 1996). In a second study, which included 661 women at eight different centers, BBE was found to have a sensitivity of 90 percent and a specificity of 55 percent for women with palpable lesions (Cuzick et al., 1998). Although Biofield has submitted a premarket approval (PMA) application, BBE has not yet been approved by the FDA and so is not used clinically in the United States. However, Biofield has received CE Mark Certification15 for its diagnostic system, which allows the company to sell 15Since 1992, the European Parliament has enacted a series of directives intended to provide controls on product design, with the principal objective being to provide a “level playing field” for product safety requirements across the European Community. The Medical Devices Directive was enacted to provide for a harmonized regulatory environment for all medical devices sold within the European Economic Area (EEA). All products that fall within the scope of the directive must meet certain essential safety and administrative requirements and are to be marked CE to show that they comply. Such products may then be freely sold throughout the EEA without being subject to additional national regulations.

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Page 95 the system in Europe. The device was certified as a diagnostic adjunct to mammography or physical examination in younger women with suspicious palpable breast lesions. ELECTRICAL IMPEDANCE IMAGING Transmission of a low-voltage electrical signal through the breast can be used to measure the electrical impedance of the tissues (Figure 2-8). Cytological and histological changes in cancerous tissue, including changes in the cellular and extracellular contents, electrolyte balances, and cellular membrane properties, can significantly decrease the impedance of cancerous tissue (by a factor of approximately 40 relative to that of normal tissue) (Kleiner, 1999). Electrical impedance imaging of the breast is painless, does not compress the breast, and does not use ionizing radiation. The technology also works equally well for women of all ages, including young women with dense breasts and women on estrogen replacement therapy. TransScan Medical (Ramsey, New Jersey) has developed an electrical ~ enlarge ~ FIGURE 2.8 Example of an electrical impedance image of the breast. White Spots in the center of the displays are the nipples. The white spots in the outer sectors identified by the arrows were found to be invasive ductal carcinoma on biopsy. Source: TransScan Medical, Ramsey, NJ.

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Page 96 impedance imaging device (the T-Scan 2000) as a diagnostic adjunct to X-ray mammography. The device transmits a 1-volt electrical signal through the breast via an electrode on the patient's arm. A clinician measures the electrical signal at the surface of the breast with a handheld probe containing an array of electrodes. The electrical signal is used to create a real-time, computer-displayed image of the impedance of the underlying breast tissue. Regions of low impedance suggestive of cancer are displayed as bright areas on the computer screen. The combined results of several studies conducted by TransScan Medical indicated that the T-Scan 2000, when used in conjunction with mammography with a targeted population, improved the diagnostic sensitivity by 15.6 percent and the diagnostic specificity by 20.2 percent over those of mammography alone.16 TransScan Medical has predicted, on the basis of published cancer prevalence estimates and the size of the annual screening population (25 million women in the United States), that the device could increase the number of early cancers detected by 8,000 to 9,000 and decrease the number of negative biopsies by 200,000 to 300,000. In 1999, the FDA granted premarket approval to TransScan Medical for their electrical impedance imaging device, the T-Scan 2000, for use as a diagnostic adjunct to X-ray mammography. TransScan Medical will distribute the T-Scan 2000 within the United States, and Siemens Medical Systems, Inc. (Iselin, New Jersey), has exclusive rights to distribute the T-Scan 2000 device outside of the United States. The company continues to conduct additional studies to further validate the technology. A spectroscopic electrical impedance tomography (EITS) imaging system has also been evaluated with a very small number of women. Structural features in the EITS images have correlated with limited clinical information available on participants with benign and malignant abnormalities, cysts, and scarring from previous lumpectomies and follow-up radiation therapy (Osterman et al., 2000). ELECTRONIC PALPATION Electronic palpation uses pressure sensors to quantitatively measure palpable features of the breast such as the hardness and the size of lesions17 (Oncology News, 1999). Manual physical examination of the breast currently contributes significantly to cancer detection, but it is inherently 16Center for Devices and Radiological Health, FDA, Radiological Devices Panel Meeting, August 17, 1998, accessed April 3, 2000 (http://www.fda.gov/ohrms/dockets/ac/98/transcpt/3446t1.rtf). 17The clinical assessment of electronic palpation technology: a new approach for the early detection and monitoring of breast lesions, available online (http://www.assurancemed.com/techspec.html).

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Page 97 subjective. Electronic palpation offers the potential to standardize the performance, documentation, and serial monitoring of physical breast examinations. Assurance Medical (Hopkinton, Massachusetts) and Ultratouch (Paoli, Pennsylvania) are developing electronic palpation devices. Assurance Medical has developed a system that uses an array of pressure sensors mounted in a handheld device that is gently pressed against the breast and moved over its surface (Assurancee Medical, Inc., 1999). The resistance of the breast to the device is measured by the pressure sensors and is used to create a computer-generated image of the hardness of the underlying breast tissue. This image serves as a quantitative, objective measurement of the hardness, discreteness, and size of breast lesions for diagnosis. The company is seeking FDA premarket approval for use of its device to measure and track the size of known, suspicious lesions. The company is testing the accuracy and reproducibility of its device with 400 women with manually palpable lesions. In that study, trained physicians or nurses first estimate the size of each lesion by manual palpation, and electronic palpation is then used to estimate the size of each lesion. The company hopes to demonstrate that there is less variability between size measurements taken by electronic palpation than by manual palpation. In cases in which the lesion is surgically removed, the electronic and manual palpation measurements are being compared with the size of the lesion as measured by a pathologist to assess the accuracy of the device. According to the company, preliminary studies suggest that the technology might also be useful for screening. In a study with 137 women in whom 118 lesions were identified by clinical breast examination or mammography, electronic palpation successfully identified 96 of 102 palpable lesions and 12 of 16 nonpalpable lesions, for overall sensitivities of 92 percent for electronic palpation and 86 percent for clinical breast examination. Additional studies are needed to assess the specificity of electronic palpation. A robotic device (Palpagraph™), developed by UltraTouch, has a single mechanical finger designed to mimic the action of a human finger to map relative breast density. A digital camera and other optical imaging systems create a virtual computer image of each breast consisting of cubic cells between 1 and 4 mm on a side. The robotic mechanism, guided by the virtual image, brings the mechanical finger to the center of each cell on the surface of the breast. For each surface cell, the robotic mechanism applies a series of gentle pulses to the finger, and the response is measured to fill in the underlying virtual cubic cells with density data. The finger lifts away from the breast and moves to the center of the adjacent surface cell until the entire breast, including the axillary areas, has been mapped. An average Palpagraph™ examination will take 10 to 20 min-

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Page 98 utes and does not involve breast compression. An initial study, which was undertaken in Iran, tested the device in a screening setting with 850 women. The subjects, 90 percent of whom were under age 50, were screened two to three times in 6 months. The sequential palpagrams were compared to find tumors that were growing, becoming more fixed, or becoming more dense. Palpagraphy detected 22 lumps ranging from 2 to 9 mm in diameter that warranted biopsy (those in which the diameter was greater than about 4 mm). Of these lumps, eight were judged to contain malignant cancer. No consistent effort was made to detect the 22 lesions by mammography.18 The company is now preparing for clinical trials in the United States for FDA approval of the device. The device will be tested first with a population of women referred for diagnostic workup for possible breast cancer, who will be examined by mammography, palpagraphy, and clinical breast examination. EXAMPLES OF TECHNOLOGIES IN VERY EARLY STAGES OF DEVELOPMENT Thermoacoustic Computed Tomography Thermoacoustic computed tomography (TCT) exposes the breast to short pulses of externally applied electromagnetic energy. Differential absorption induces differential heating of the tissue followed by rapid thermal expansion. This generates sound waves that are detected by an array of ultrasonic transducers positioned around the breast. Tissues that absorb more energy expand more and produce more sound. The timing and intensity of the acoustic waves are used to construct a three-dimensional image of the irradiated tissue (Kruger et al., 1999). When the incident electromagnetic energy of TCT is visible light, the thermoacoustic effect is also referred to as the “photoacoustic effect.” The photoacoustic effect was first described by Alexander Graham Bell in 1861 and has been applied primarily to the spectroscopic analysis of gases, liquids, and solids (Rosencwaig, 1975). Although the thermoacoustic effect has a long scientific history, its application to medical imaging is still in the early stages of development. TCT does not use ionizing radiation and does not compress the breast. As currently designed, the TCT ultrasonic transducers are arrayed around a hemispheric bowl that is filled with deionized water. The device is mounted beneath a table. To image the breast, the woman lays prone on the table with her breast immersed in the water through a hole in the table. The breast is scanned in approximately 1.5 minutes. 18Jeff Garwin President, UltraTouch Corporation, personal communication.

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Page 99 One major limitation of traditional X-ray mammography is that it creates a two-dimensional projection of the breast that is highly dependent upon the orientation of the breast, the X-ray source, and the detector. Because TCT images retain three-dimensional structural information, unlike the images obtained by X-ray mammography, the images of a woman's breast obtained by TCT are highly consistent. Because there is less variability in the images, changes should be more apparent and easier to track longitudinally by TCT than by X-ray mammography. Three-dimensional images are, however, potentially more difficult to display and analyze, and therefore, the time and cost required for image retrieval and analysis are potentially greater for TCT than X-ray mammography. The contrast in a TCT image is determined primarily by the electromagnetic absorption properties of the tissue being imaged (Kruger et al., 1999). Different tissues absorb electromagnetic waves of different frequencies. For radio waves in the range of 200 to 600 megahertz (MHz), there is sevenfold difference between the most and the least absorptive soft tissues. For comparison, there is only a two-fold difference between the most and the least absorptive soft tissues at X-ray frequencies (Kruger et al., 1999). In the range of 300 to 500 MHz, cancerous tissue is two to five times more absorptive than comparable noncancerous tissue, presumably because of the increased water and sodium contents of malignant cells (Chaudhary et al., 1984; Joines et al., 1980, 1994). The electromagnetic wave pulse, the acoustic properties of the tissue, the geometry of the ultrasonic detector array, and the image reconstruction algorithm determine the spatial resolutions of TCT images (Kruger et al., 1999). To date, the leading developer of TCT, Optosonics, Inc. (Indianapolis, Indiana), has achieved in vivo imaging of the human breast with a spatial resolution of 1 mm up to a depth of 40 mm.19 The development of TCT is still in its early stages.20 To date there have been no large published clinical trials, although Optosonics is planning to conduct an exploratory study with 80 women this year in conjunction with the Indianapolis Breast Center. Microwave Imaging Confocal microwave imaging is a new technique that uses the differential water content of cancerous tissue versus that of noncancerous tissue to detect tumors. The technique transmits short pulses of focused, low-power microwaves into the breast tissue, collects the back-scattered 19Robert Kruger, Optosonics, Inc., personal communication, March 8, 2000. 20The original patent for the “Photoacoustic Breast Scanner” was issued in 1998 (RA Kruger, U.S. patent 5713356).

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Page 100 energy via antennas positioned around the breast, and compounds these signals to produce a three-dimensional image of the breast. Normal tissue is mostly transparent to microwaves; however, the higher water content of malignant tissue and the differences in the dielectric properties of tumor tissue versus those of breast fatty tissue cause significantly more scatter of microwave energy, thus enabling detection of tumors (Meaney et al., 1999). Confocal microwave imaging has several attractive features. It does not require breast compression and does not use ionizing radiation. In theory it will produce a high-contrast three-dimensional image of the breast and should be equally effective for women with dense breasts. Confocal microwave imaging of the breast is being developed primarily by researchers at the University of Wisconsin-Madison, Dartmouth, and Northwestern University. The work is an extension of other non-medical applications of focused microwave imaging including groundpenetrating radar for detection of land mines and detection of concealed weapons at airports (Microwave News, 2000). Many techniques for microwave imaging of the body have been explored by other researchers, including the detection of the passive emission of microwaves by the body, microwave thermography, and active examination of the body by use of narrowband microwaves, which should provide better resolution (Larsen and Jacobi, 1986). The development of these techniques has been constrained by poor resolution, poor penetration to the required tissue depths, excessive power requirements that result in the delivery of potentially unsafe levels of microwaves to the patient, and computationally challenging techniques for image reconstruction (Bridges, 1998; Fear and Stuchly, 1999). To date, confocal microwave imaging research has emphasized theoretical validation of the technique through computer modeling (Fear and Stuchly, 1999) and measurements of the high-frequency electrical properties of excised breast tissue. As part of the modeling, researchers have considered different antenna arrangements, tumor sizes and placements, breast sizes, and tissue compositions. The results of the modeling suggest that tumors as small as 2 mm should be detectable at a depth of 4 cm. It will probably be several years before the technique is tested with any significant number of women (Hagness et al., 1998). Hall Effect Imaging Hall effect imaging (HEI) is a new general-purpose imaging technique being developed on the basis of the classical Hall effect discovered in 1879 by Edwin Hall (Graham-Rowe, 1999; Wen et al., 1998; Wen, 1999). HEI induces vibrations in charged particles by passing an electric pulse through an object while it is exposed to a strong magnetic field. The vibrating particles produce sound waves that can be detected by ultra-

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Page 101 sonic transducers and that can be used to create a three-dimensional image of the object. Different materials vibrate differently according to their electrical properties. As with other emerging imaging technologies including microwave imaging and TCT, HEI is being developed to exploit the electrical properties of tissues in the body, which vary widely with tissue type and pathological state. Although the Hall effect has been used for many years by nonmedical disciplines, it is unclear whether it will develop into a technique suitable for imaging of humans. HEI is still in its infancy: the first published account of HEI only appeared in 1998. To date HEI has been tested only with excised and simulated tissue. Perhaps the biggest limitation to the future application of the technology is the cost. As with MRI, HEI will require an expensive, superconducting magnet to produce a sufficiently strong magnetic field. Cost alone would likely limit its usefulness as a breast cancer screening technology, but if the technique is developed, it might be useful for limited, specific populations of women, as has been the case with MRI. Magnetomammography Magnetic source imaging of the breast, magnetomammography (MMG), is a new technique being investigated by using extremely sensitive Superconducting Quantum Interference Device (SQUID) magnetometers.21 Researchers hope to use SQUID magnetometers to detect magnetic, tumor-specific agents introduced into the body intravenously. This is similar in principle to scintimammography, except that magnetic agents and SQUID magnetometers will replace radionuclides and gamma cameras. SQUID magnetometers have been used clinically in a limited number of research centers for many years to detect magnetic fields produced by electrical activity in parts of the body such as the brain (magnetoencephalography) and the heart (magnetocardiography) (Clarke, 1994). MMG research is focused on developing an agent that is both magnetic and highly specific to cancerous tissue. At present, no such agent is available, and so MMG remains untested. In theory, MMG should be equally effective for women with dense breasts and would not require breast compression or ionizing radiation. One limitation of scintimammography, which MMG will similarly have to address, has been its lack of sensitivity to some types of lesions. 21Robert Kraus, Los Alamos National Laboratory, personal communication.

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Page 102 As with gamma cameras, SQUID magnetometers have poor spatial resolution. The contrast resolution may be sufficiently high to detect small tumors, provided that they have sufficient volume and provided that after injection the ratio of the concentration of the exogenous magnetic agent in the lesion to the background concentration is high. The uptake by cancerous tissue of sestamibi, one of the best agents presently available for scintimammography, is about three times that by surrounding non-cancerous tissue, but it has not yet demonstrated efficacy when it is used to detect small, nonpalpable tumors. A further difficulty is that the computational strategies needed to generate MMG images of magnetic sources are much more complex than those needed for scintimammography. Provided a suitable magnetic agent can be developed, one of the biggest obstacles to be overcome for the implementation of MMG will be cost. SQUID magnetometers are expensive to fabricate and operate. Because they are superconductors, they must be cooled with either liquid helium or liquid nitrogen, neither of which is easily available in all areas of the country. SQUID magnetometers must also often be operated in expensive, magnetically shielded environments because the physiological signals that they are designed to measure are extremely small and easily drowned out by the earth's magnetic field and other background magnetic fields. It remains to be seen whether such special provisions will be required for MMG. Three-Dimensional Interactive Visualization Three-dimensional interactive visualization techniques, including virtual reality, radically alter how individuals interact with computers to understand digital data. Many components of three-dimensional interactive visualization technology have been developed for other nonmedical applications (e.g., target recognition and flight simulators) and could potentially be applied to breast imaging. Several pioneer research groups have already demonstrated improved clinical performance using three-dimensional interactive imaging, planning, and control techniques (e.g., breast MRI). Three-dimensional interactive visualization could potentially be used in breast imaging for visualization, training, procedure planning, procedure support, and prognosis. However, significant improvements in virtual reality technologies are still required, including novel algorithms for breast imaging, before this potential can be realized. SUMMARY At present, mammography is the only technology suitable for screening of the general population for breast cancer. It therefore serves as a “gold standard” with which new technologies will be compared. How-

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Page 103 ever, this standard is imperfect, and thus, improvements in the sensitivity and specificity of mammography itself could potentially affect mortality and morbidity from breast cancer and the overall cost of screening. Many technical improvements have been made to FSM since its initial introduction, but it is not known whether these changes have led to better survival rates among screened women. Many have considered digital mammography to be a major technical improvement over traditional FSM, but studies to date have not demonstrated meaningful improvements in screening sensitivity and specificity. Although it could be argued that studies thus far have not directly tested the full potential of FFDM through the use of soft-copy image analysis, difficulties remain with regard to the limited spatial resolution and luminance range of soft-copy display. The technology could potentially facilitate novel techniques such as tomosynthesis and digital subtraction mammography with X-ray-based contrast agents, but the value of these methods has not yet been proven. Digital mammography could also potentially improve the practice of screening and diagnostic mammography in other ways, for example, by facilitating electronic storage, retrieval, and transmission of mammograms. CAD has also shown potential as a means of improving the accuracy of screening mammography, at least among less experienced readers, but again, questions remain as to how this technology will ultimately be used and whether it will have a beneficial effect on current screening practices. Mammography is particularly limited in young women. Because breast cancer is the principal cause of death for women ages 35 to 50, efforts have been made to identify alternate or complementary screening approaches for young women at high risk. Magnetic resonance imaging and ultrasound have been studied most extensively in this regard and show considerable promise for this select population. To date, however, the data are not yet sufficient to draw sound conclusions with respect to the appropriate screening applications of these technologies. That may change in the near future, as several large studies are ongoing. Ideal detection performance may ultimately depend on multimodality imaging, as no single imaging technology can provide a high signal-to-noise ratio in all circumstances or is able to detect all significant lesions. Most of the imaging technologies for breast cancer detection described in this chapter are being developed as diagnostic adjuncts to mammography, with the goal of avoiding unnecessary, invasive biopsy procedures. Some, such as ultrasound and MRI, may also be used in conjunction with new minimally invasive therapeutic methods that are under development. Other technologies, such as functional imaging modalities, offer additional promise as both detection modalities and prognostic aids and could potentially shift the paradigm of cancer detection, but advances in this area will require further research to identify the appropriate biological markers to be examined. If and when these developing technologies

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Page 104 are adopted for such diagnostic or prognostic applications, they may also be further examined as screening modalities. However, most of the technologies are not far enough along in development to adequately assess or predict their future application or value. Ultimately, a new technology for early breast cancer detection will be beneficial only if it can lead to a reduction in the morbidity and mortality associated with the disease. Thus, improved methods for early detection of breast cancer may bring new challenges as well as opportunities for intervention. If the information generated by new technologies cannot be acted upon appropriately to improve outcomes, then women are not likely to benefit from the technological advances. Furthermore, as imaging methods become better and better at finding very small, early lesions such as carcinoma in situ, treatment decisions can be difficult to make because so little is known about the malignant potential of these premalignant cells (Tabar et al., 2000). As a result, some women may face the diagnosis of breast cancer and the subsequent therapy for a lesion that may never have become a lethal, metastatic cancer. Research efforts into the biology and etiology of breast cancer must therefore also continue, as discussed in Chapter 3. Moreover, improvements in the understanding of breast cancer progression should lead to treatment advances, and these combined changes could eventually alter both the use and the assessment of imaging tools.