chapter 28 breast imaging systems: design challenges … · laurie l. fajardo the russell morgan...

28.1

CHAPTER 28

BREAST IMAGING SYSTEMS:DESIGN CHALLENGES FORENGINEERS

Mark B. WilliamsDepartment of Radiology, University of Virginia, Charlottesville

Laurie L. FajardoThe Russell Morgan Department of Radiology and RadiologicalSciences, Johns Hopkins Medical Institutions, Baltimore,Maryland

28.1 INTRODUCTION 28.1 28.5 FUTURE DIRECTIONS—28.2 BREAST ANATOMY 28.2 MULTIMODALITY IMAGING 28.1128.3 CURRENT CLINICAL BREAST REFERENCES 28.12

IMAGING 28.328.4 NEW AND DEVELOPING BREAST

IMAGING MODALITIES 28.6

Breast cancer is the second greatest cause (after lung cancer) of cancer-related death among Americanwomen, accounting for approximately 40,000 deaths each year. At the present time, early detectionand characterization of breast cancers is our most effective weapon, since local disease is in most casescurable. Breast imaging systems can thus be potentially useful if they either (1) are useful fordetection of cancers or (2) are useful for characterization of suspicious lesions that may or may notbe cancerous. Similarly, from a clinical perspective, methodologies used for breast cancer diagnosis(as opposed to therapy) fall into one of two broad categories: screening or diagnostic. Screeningpertains to the population of women exhibiting no symptoms. Diagnostic imaging (otherwise knownas problem-solving imaging) is used when there is some suspicion of disease, as a result of themanifestation of some physical symptom, of a physical exam, or of a screening study. The relativeeffectiveness of a given imaging modality at the tasks of detection and characterization determineswhether it will be employed primarily in a screening or diagnostic context. At the present time, x-raymammography is the only FDA-approved modality for screening, and is by far the most effectivemodality because of its ability to detect small cancers, when they are most treatable (i.e., prior tometastasis). The sensitivity (fraction of all cancers that are detected) by screen-film mammography isapproximately 85 percent. Ultrasound, MRI, scintimammography, and electrical impedance scanningare FDA approved as diagnostic procedures following detection of an abnormality via x-ray mam-mography.

28.1 INTRODUCTION

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Source: STANDARD HANDBOOK OF BIOMEDICAL ENGINEERING AND DESIGN

28.2 DESIGN OF MEDICAL DEVICES AND DIAGNOSTIC INSTRUMENTATION

In design of a system for either screening or diagnostic imaging of the breast, severalcharacteristics of the breast itself present unique engineering challenges. First, unlike parts of thebody supported by bone, the breast is a malleable organ. Thus obtaining the exact same configurationfor successive imaging studies is difficult, if not impossible. This complicates correlation betweenfollow-up images of a given modality, or between concurrently obtained images from two differentmodalities. A second challenge arises from the fact that cancers can arise in areas of the breast veryclose to the chest wall, which presents special difficulties. For example, the focal spot in x-raymammography must be positioned directly above the chest wall edge of the image receptor in orderto assure that x-rays passing through tissue adjacent to the chest wall are imaged. The proximity ofthe chest and shoulders also presents geometric hindrance affecting MRI coil design and nuclearmedicine scanning. A third challenging aspect of breast cancer imaging is the similarity of many ofthe physical attributes of cancerous material and normal breast tissue. For example, the x-rayattenuation and acoustic impedance of cancerous masses are very similar to those of healthyfibroglandular breast tissue. Thus the imaging process must result in a sufficiently high signal-to-noise ratio that such subtle differences can be ascertained.

The breast is composed primarily of fat and glandular tissue. The glandular tissue is sandwichedbetween layers of fat and lies above the pectoralis muscle and chest wall. The combination of the

28.2 BREAST ANATOMY

FIGURE 28.1 Schematic diagram showing the anatomy of thehuman breast.



BREAST IMAGING SYSTEMS: DESIGN CHALLENGES FOR ENGINEERS

BREAST IMAGING SYSTEMS: DESIGN CHALLENGES FOR ENGINEERS 28.3

adipose and glandular tissue provides the radiographic contrast detected on x-ray mammography.When the ratio of adipose tissue to glandular tissue in the breast is greater, greater radiographiccontrast is achieved. Breast tissue composed of only fibroglandular tissue results in a mammogramwith lesser radiographic contrast that is more difficult for radiologists to evaluate.

The breast is considered a modified sweat gland and the milk it produces is a modification ofsweat. Breast lobules, which produce milk during lactation, are connected by the breast ducts. Thebreast lobules and ducts are supported by the surrounding connective tissue. Deep and superficialfacial layers envelop the stromal, epithelial, and glandular breast elements. Cooper’s ligaments, acriss-crossing network of fibrous supporting structures, course between the deep and superficiallayers of fascia. Surrounding the cone of glandular tissue is a layer of subcutaneous fat.

The nipple and areola contain erectile smooth muscle as well as sebaceous glands. Between fiveand nine separate ductal systems intertwine throughout the breast and have separate openings at thenipple. Each major lactiferous duct extends from the nipple-areolar complex into the breast in abranching network of smaller ducts. The area drained by each duct network is called a lobe, orsegment, of the breast. The duct network is lined by two types of cells, an inner epithelial layersurrounded by a thinner layer of myoepithelial cells. The final branch from a segmental duct is calledthe extralobular terminal duct and terminates in several acini. The anatomic unit comprising theextralobular duct and its lobule of acini is histologically designated as the terminal ductal lobular unit.It is postulated that most cancers arrive in the extralobular terminal ducts, just proximal to the lobule.

Figure 28.1 is a schematic drawing depicting the anatomy of a healthy breast.

X-ray mammography is a projection onto two dimensions of the three-dimensional x-ray attenuationdistribution of the breast. By federal regulation (the Mammography Quality Standards Act), dedicatedand specialized radiographic equipment must be used for mammography. Mammographic systemsutilize x-ray tubes with small focal spot size (0.1 mm and 0.3 mm nominal diameters), high-resolu-tion x-ray receptors, and scatter reduction grids between breast and receptor. The x-ray focal spot ispositioned directly above the edge of the image receptor closest to the patient, so that structuresimmediately adjacent to the chest wall may be visualized. A typical screening mammogram consists oftwo views of each breast. The two views are separated by approximately 45 to 60°, in order to helpresolve ambiguities produced by overlapping breast structure in a given projection. In addition, oneview maximizes visualization of the structures near the lateral portion of the breast, such as theaxiallary lymph nodes. Both are obtained with the breast under compression, using a flat acrylicpaddle with low x-ray attenuation. Compression reduces the amount of scatter radiation reaching thedetector by reducing the breast thickness, and also spreads out the tissue, thereby reducing theamount of structural overlap in the projection image.

Follow-up diagnostic procedures include additional x-ray views (magnification views, spot views,or unusual projections such as lateral views), ultrasound, and, more recently, MRI and nuclearmedicine imaging (positron emission mammography or single gamma emission scintigraphy). Wefirst present an overview of some of the technical aspects of screening mammography, then describechallenges associated with current and upcoming diagnostic imaging techniques.

X-ray Mammography Image Considerations. X-ray mammography is perhaps the most exacting ofall x-ray based imaging tasks. The main reasons for this are (1) the small difference in x-rayattenuation properties between various breast structures, and between normal and cancerous tissue,and (2) the requirement that physically small objects such as microcalcifications be imaged withenough clarity to be detected by the radiologist (microcalcifications are calcium-containing depositsthat are associated with early breast cancers, although many calcifications are merely benign

28.3 CURRENT CLINICAL BREAST IMAGING

28.3.1 Screening and Diagnostic Mammography





growths). Clinically significant microcalcifications may be 0.2 mm or less in size. They often appearin clusters, and their individual shapes and relative orientations can be a clue as to the likelihood ofan associated malignancy. The simultaneous requirements of high-contrast resolution and high spatialresolution, along with the desire to minimize radiation dose to the breast, dictate that the image sensorhave high sensitivity, low noise, and a narrow point response function. In addition, depending on thesize and composition of the breast, the range of x-ray fluence incident on the sensor surface in agiven mammogram can be 400:1 or more (Johns and Yaffe, 1987; Nishikawa et al., 1987). Thus thesensitivity and resolution must be maintained over an appreciable dynamic range.

Film-Based Imaging. Most mammography is currently performed using screen-film systems; that issystems that employ image receptors consisting of film placed in direct contact with an x-ray-to-lightconverting screen. The screen-film combination, housed in a light-tight cassette, is placed below thebreast, with a rotating anode x-ray tube placed 60 to 65 cm above the cassette. A major technicalchallenge in screen-film mammography arises from the fact that the film is used both as an acquisi-tion and display medium. That means that system parameters such as film speed, detection and lightconversion efficiency of the screen, and x-ray spectrum must be chosen not only to maximize theefficiency of the image acquisition process, but also to result in the optimum film darkening tomaximize the visual contrast between structures when the film is viewed on a light box. Furthermore,as with other film-based imaging procedures, there is an inescapable trade-off between image contrastand dynamic range. One motivation for the development of digital detectors to replace screen-filmreceptors in mammography is the desire to increase dynamic range without a concomitant loss ofimage contrast.

Digital Mammography Current Technologies for Image Acquisition. The principal motivations for thedevelopment of electronic receptors to replace film-based receptors are (1) the limited dynamic rangeof x-ray intensities over which the sensitivity of film-based systems is appreciable and (2) the inherentnoise properties of film due to the random distribution of the grains on the film substrate (Nishikawaand Yaffe, 1985). The desire to overcome these limitations, coupled with the advantages inherent inhaving images in digital form (e.g., computer-aided diagnosis, easier image storage, remote transmis-sion of images), has led to the development of several technical solutions to digital mammographicimage acquisition during the past decade. Leading large area technologies for full-field digital mam-mography currently include: (1) CsI(Tl) converters coupled via demagnifying fiber-optic tapers toarrays of charge coupled devices (CCDs), (2) CsI(Tl) converters coupled to arrays of amorphoussilicon (a-Si) photodiodes that are read out using a-Si thin-film-transistor (flat panel) technologies,and (3) storage phosphor plates (typically europium-doped barium fluorobromide) that retain ametastable latent image during x-ray exposure that can be de-excited and quantified using a raster-scanned laser beam. On the horizon is a second type of flat panel detector, which uses a layer ofamorphous selenium instead of the CsI(Tl)-photodiode combination. This is a so-called direct conver-sion detector, in which absorbed x-rays generate electron-hole pairs in the selenium, rather than usingan intermediate x-ray to visible-photon conversion stage and a photodetector to generate charge. Ineach of the above digital mammography detectors, the detector area is equal to the imaged area. Afourth approach uses a slot shaped CCD-based detector that spans the imaged area in one dimension(the chest wall to nipple direction), and is scanned from left to right during image acquisition. The x-ray beam, collimated to a similar slot shape, is scanned in synchrony with the detector. With the firstthree technologies, x-ray targets (molybdenum or rhodium) and filtration (molybdenum or rhodium)combinations similar to those used in screen-film mammography are employed. For the fourthtechnology, a tungsten target is used, and the tube voltage is somewhat higher than that used with Moor Rh targets.

Figure 28.2 compares analog (screen-film) and digital cranial-caudal images of the right breast ofa woman with moderately radiodense breast tissue and an irregularly-shaped mass with spiculatedmargins in the lateral aspect of the breast. The digital image (Fig. 28.2b) shows improved contrast,enhanced depiction of the suspicious mass and better visualization of peripheral tissue and skin linethan the analog image (Fig. 28.2a).





As of this writing, two manufacturers have received approval from the Food and DrugAdministration (FDA) to market full-field digital mammography (FFDM) systems (one is an x-rayphosphor/flat panel system, the other is a scanned CCD-based system), and at least two othermanufacturers are in the process of gathering data for submission to the FDA for approval.

Challenges Facing Digital Mammography. Although detector development is well under way,there are major challenges that must be addressed before digital mammography becomes a clinicalmainstay. Perhaps the most immediate obstacles have to do with image display. The very large size ofthe digital images (up to 30 megapixels, with 12 to 16 bits per pixel) far exceeds the matrix size (upto 2000 × 2500 pixels) and grayscale depth (typically 8 bits) of current commercially available high-resolution displays. Furthermore, a typical screening study involves simultaneous viewing of fourcurrent views (two per breast) alongside the corresponding four views from the previous screeningstudy. Partially for this reason, many early practitioners of FFDM use laser film printers to producehard copies of the digitally obtained mammograms, so that they can be viewed on a conventionallight box, alongside the previous (analog) study.

Another area of ongoing research is the development of image processing techniques for bothlaser film and grayscale monitor viewing. In the former case (hard copy display), the characteristicsof the laser film automatically apply a nonlinear dynamic range compression to the digital pixelvalues. In the case of workstation viewing (soft copy display), it is desirable to limit the amount oftime that the radiologist must spend adjusting the image display (i.e., adjusting the range of pixelvalues mapped into the available grayscale levels of the display), so some means of reducing thedynamic range in the mammogram without compromising image quality is needed. One approachbeing tested is thickness compensation (Bick et al., 1996; Byng et al., 1997). This is a software

FIGURE 28.2 Analog (left) and digital cranial-caudal images of the right breast of a woman with moderately radiodensebreast tissue and an irregularly-shaped mass with spiculated margins. The improved contrast, enhanced depiction of thesuspicious mass and better visualization of peripheral tissue and skin line in the right image are a result of the largerdynamic range of the digital receptor.





technique that compensates for the decrease in attenuating thickness near the breast periphery bylocating the region between the area of uniform thickness (where the breast is in contact with the flatcompression paddle) and the skin line. Pixel values corresponding to that region are scaled downwardto make their values more similar to those in the region of uniform thickness.

Diagnostic Ultrasound. Ultrasound (US) is used as a diagnostic (as opposed to screening) breastimaging modality, in part because it lacks the sensitivity of x-ray mammography for small masses andfor microcalcifications. However, US is recommended by the American College of Radiology as theinitial imaging technique for evaluation of masses in women under 30 and in lactating and pregnantwomen. In the majority of breast-imaging cases, the primary diagnostic use of ultrasound is thedifferentiation of solid masses from fluid-filled cysts. There has been a general lack of confidence,however, in the ability of US to characterize solid masses as benign versus malignant. Although atleast one study has reported that benign and malignant solid breast masses could be differentiatedbased on US alone (Stavros et al., 1995), subsequent studies have not confirmed this hypothesis, andit is now generally believed that at the present time there are no ultrasound features that, by them-selves, are sufficient evidence to forgo biopsy. Newer techniques being explored to improve theability of US to differentiate benign and malignant masses include intensity histogram analysis(Kitaoka et al., 2001) and disparity processing, in which the sonographer slightly varies the pressureof the probe on the breast surface, and the apparent displacement of the tissue is measured by analysisof the correlation between images obtained at different parts of this compression cycle (Steinberg etal., 2001). This measurement of the elastic properties of the lesion is similar to that employed inbreast elastography (briefly described below). In addition to these diagnostic tasks, US also plays amajor role in biopsy guidance.

One technical issue affecting US is that its results tend to be more operator-dependent than theother modalities because of variations in positioning of handheld transducers. Automated transducersare much less operator-dependent than handheld transducers. However, handheld transducers permita more rapid exam, and are better suited for biopsy guidance.

While x-ray mammography is unquestionably the leading currently available modality for earlydetection of small cancers, it suffers from a relatively low positive predictive value (the fraction oflesions identified as positive that ultimately turn out to be positive). As a result, 65 to 85 percent ofall breast biopsies are negative (Kerlikowske et al., 1993; Kopans, 1992). Therefore, adjunct modali-ties that can differentiate benign and malignant lesions detected by mammography are consideredhighly desirable. In a recent report issued by the National Research Council, the Committee onTechnologies for the Early Detection of Breast Cancer identified the breast imaging technologies andtheir current status, as shown in Table 28.1 (Mammography and Beyond, 2001).

The x-ray imaging modalities have been discussed above. Below, we discuss some of the moreadvanced (i.e., they have been written up in the scientific literature, and have undergone at leastpreliminary clinical evaluation) and most promising adjunct modalities: breast MRI,scintimammography, breast PET, and electrical impedance imaging. We also briefly discuss opticalimaging and elastography.

At present, mammography is the primary imaging modality used to detect early clinically occultbreast cancer. Despite advances in mammographic technique, there are limitations in sensitivity and

28.4 NEW AND DEVELOPING BREAST IMAGING MODALITIES

28.4.1 Introduction

28.4.2 MRI





specificity that remain. These limitations have stimulated exploration into alternative or adjunctiveimaging techniques. MRI of the breast provides higher soft tissue contrast than conventional mam-mography. This provides the potential for improved lesion detection and characterization. Studieshave already demonstrated the potential for breast MRI to distinguish benign from malignant breastlesions and to detect mammographically and clinically occult cancer (Dash et al., 1986; El Yousef etal., 1984; Stelling et al., 1985). The first studies using MRI to detect both benign and malignantbreast lesions concluded it was not possible to detect and characterize lesions on the basis of signalintensities on T1 and T2 weighted images (Dash et al., 1986; El Yousef et al., 1984; Stelling et al.,1985). However, reports on the use of gadolinium enhanced breast MRI were more encouraging.Cancers enhance relative to other breast tissues following the administration of intravenous Gd-DTPA(Kaiser and Zeitler, 1989). Indeed, in one study, 20 percent of cancers were seen only after theadministration of Gd-DTPA (Heywang et al., 1989). In addition, 2 studies reported on MRI detectionof breast cancer not visible on mammography (Harms et al., 1993; Heywang et al., 1989). Thedetection of mammographically occult multifocal cancer in up to 30% of patients has led to therecommendations that MRI can be successfully used to stage patients who are potential candidates forbreast conservation therapy (Harms et al., 1993).

However, the presence of contrast enhancement alone is not specific for distinguishing malignantfrom benign breast lesions. Benign lesions frequently enhance after Gd injection on MRI, includingfibroadenomas, benign proliferative change, and inflammatory change. To improve specificity, someinvestigators recommend dynamic imaging of breast lesions to evaluate the kinetics of enhancement(Heywang et al., 1989; Kaiser and Zeitler, 1989; Stack et al., 1990). Using this technique, cancers

TABLE 28.1 Breast-Imaging Technologies

*Status description:- Technology is not useful for the given application.NA No data are available regarding use of the technology for given application.0 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.+ Clincial data suggest that 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 the technology could be useful in selected situations because it adds (or is equivalent) to existing

technologies, but not currently recommended for routine use.+ + + The technology is routinely used to make clinical decisions for the given application.Source: From Mammography and Beyond (2001).





have been found to enhance intensely, in the early phases of the contrast injection. Benign lesionsenhance variably but in a more delayed fashion than malignant lesions.

Because x-ray mammography is limited by its relatively low specificity, MRI has been suggestedas an adjunct imaging study to evaluate patients with abnormal mammograms. One application ofbreast MRI may be to reduce the number of benign biopsies performed as a result of screening anddiagnostic mammography workup. To distinguish benign from malignant breast lesions using MRIscanning, most investigators rely on studying the time course of signal intensity changes of a breastlesion after contrast injection. However, among reported studies, the scan protocols varied widelyand differ with respect to emphasis on information acquired. For example, Boetes et al. (Boetes etal., 1994) used a protocol consisting of a single-slice, nonfat, suppressed gradient echo imagingsequence with 2.6 × 1.3-mm in-plane spatial resolution (10-mm slice) at 2.3-s time intervals. Theyused the criterion that any lesion with visible enhancement in less than 11.5 s after arterialenhancement was considered suspicious for cancer. These criteria resulted in 95 percent sensitivityand 86 percent specificity for the diagnosis of cancer. Similar sequences have been reported byothers using protocols with the time resolution varying from 6 to 60 s. However, problems locatinga lesion on the precontrast images in order to perform a single-slice dynamic enhanced examinationand the need to detect and evaluate other lesions within the breast, have resulted inrecommendations that a multislice technique that captures dynamic data from the entire breast afterinjection of contrast is necessary (Gilles et al., 1994; Hickman et al., 1994; Perman et al., 1994).These investigators advocate using multislice two-dimensional (2D) gradient echo, 3D gradientecho, and echo planar techniques with the time resolution varying from 12 s to 1 min, varyingspecial resolution and varying section thickness. Keyhole imaging techniques that dynamicallysample the center of k-space after contrast administration have been suggested as a technique toobtain dynamic high-resolution 3D images of the entire breast (Van Vaals et al., 1993). However,the spatial resolution of enhanced tissue is limited with keyhole techniques because only part of thebreast is sampled after contrast is injected. Keyhole imaging is criticized as being suboptimal forassessing lesion architecture.

Also widely varying among investigators are their criteria used for differentiating benign frommalignant lesions. Criteria vary from simplistic models that report the percent of lesion enhancementat 2 min following contrast injection to more sophisticated physiologic models that take into accountthe initial T1 characteristics of a lesion and calculate Gd concentration as a function of time in orderto extract pharmacokinetic parameters. Thus, wide variability in the accuracy cited by theseinvestigators for differentiating benign from malignant lesions has been reported (66 to 93 percent)(Daniel et al., 1998; Esserman et al., 1999; Gilles et al., 1994; Hickman et al., 1994; Hylton, 1999;Orel et al., 1994; Perman et al., 1994; Van Vaals et al., 1993). Despite the many differing techniques,it is clear that there is a tendency for cancer to enhance more rapidly than benign lesions after bolusinjection of Gd chelate. However, it is also clear that overlap exists in dynamic curves betweencancerous and no cancerous lesions, resulting in false negative diagnosis in all reported series andfalse positive diagnosis in many.

Alternative approaches to characterizing enhancing lesions on breast MRI include extractingarchitectural features that describe breast lesions. The superior soft tissue contrast of MRI and use ofhigher spatial resolution techniques have prompted investigations in this area and the development ofa potential lexicon that might be widely applicable to the reporting and interpretation of breast MRIscans (Gilles et al., 1994; Nunes et al., 1997; Orel et al., 1994; Schnall et al., 2001). Such anadvancement would improve the widespread general reliability and comparability among breast MRIexaminations performed from one institution to another. Clearly, the relative importance of spatialand temporal resolution in this regard requires further evaluation.

Other reported investigations of breast MRI suggest that MRI can demonstrate more extensivecancer than indicated by mammography or predicted by clinical breast examination. Severalinvestigators have now demonstrated that MRI can detect breast cancer that is mammographicallyoccult (Harms et al., 1993; Heywang et al., 1989), and suggest that MRI may have a role as ascreening examination for patients with a high genetic predisposition to breast cancer and in thosepopulations of women having extremely radiodense breast tissue on x-ray mammography.





Nuclear imaging involves the injection of pharmaceutical compounds that have been labeled withradioisotopes. The compounds are selected such that they couple to some sort of biological processsuch as blood flow, metabolic activity, or enzyme production, or such that they tend to accumulateat specific locations in the body, e.g., binding to certain cell receptor sites. Thus the relativeconcentrations of these radiotracers in various areas of the body gives information about therelative degree to which these biological activities are occurring. Measurement of this concentrationdistribution therefore provides functional information very different from the structural informa-tion supplied by modalities such as x-ray mammography and ultrasound. For this reason, nuclearmedicine techniques are being explored as adjunct imaging approaches to the structurally orientedx-ray mammography.

Nuclear medicine tracers being considered for breast imaging can conveniently be divided intotwo groups: those emitting single gamma rays and those emitting positrons. In both cases, theconcentration distribution in the breast is mapped by one or more imaging gamma detectors placedin proximity to the patient. In the case of single gamma emitters, the gamma detectors are equippedwith some type of physical collimators whose function is to create a unique correlation between apoint on the detector surface and a line through the spatially distributed radioactivity source (e.g.,the breast). Physical collimation is not necessary in the case of positron emitting isotopes becauseof the near colinearity of the gamma ray pair produced by annihilation of the emitted positron witha nearby electron. However, opposing gamma detectors and timing circuitry must be used to detectthe two gamma rays of a pair in coincidence. Below we discuss some of the unique challengespresented by nuclear imaging of the breast, and describe some technical solutions currently beingexplored.

Scintimammography Conventional scintimammography. Breast scintigraphy (orscintimammography) is nuclear medicine imaging of the breast using a single gamma emittingtracer and an imaging gamma detector fitted with a collimator. Recent studies suggest thatscintimammography can provide diagnostic information complementary to that of x-ray mammog-raphy (Allen et al., 2000; Buscombe et al., 2001; Palmedo et al., 1998; Scopinaro et al., 1997).Comparable performance has been reported between scintimammography and contrast-enhancedMRI as adjuncts to x-ray mammography (Imbriaco et al., 2001). Like contrast-enhanced MRI,scintimammography is particularly useful for women with radiodense breasts, for whom mammo-graphic interpretation can be difficult.

Technical challenges associated with scintimammography are: (1) positioning the camera close tothe breast, (2) dealing with the significant scatter radiation arising from gamma rays emitted fromregions of the heart and liver, and (3) correcting for contrast degradation due to partial volumeaveraging and attenuation of gamma rays emitted from the lesion. The first of these issues is drivenby the fact that the spatial resolution of cameras with parallel hole collimators is approximately alinear function of the distance between source and collimator. To date, scintimammography has beenperformed primarily using conventional gamma cameras, with the patient lying prone on a table withholes for the breasts. Prone positioning is favored over supine positioning because gravity acts to pullthe breast tissue away from the chest wall. Typically two lateral views are obtained, and one anterior-posterior view to aid in medial-lateral tumor localization. The majority of clinical trials to date haveemployed one of two 99mTc-labeled Pharmaceuticals; sestamibi or tetrafosmin. Reported values forsensitivity and specificity for planar scintimammography performed under these conditions varyaccording to several factors, a principle one being the distribution of lesion sizes represented in theparticular study. In a three-center European trial, sensitivities of 26, 56, 95, and 97 percent werereported for category pT1a (<0.5 cm), pT1b (0.5 to 1.0 cm), pT1c (1.0 to 2.0 cm), and pT2 (>2 cm)cancers, respectively (Scopinaro et al., 1997). A recent clinical trial (134 women scheduled for openbreast biopsy were enrolled) investigating the use of prone 99mTc-sestamibi scintimammography forpT1 tumors (4.7% pT1a, 46.7% pT1b, and 48.6% pT1c) reported sensitivity, positive predictivevalue, negative predictive value and accuracy of 81.3, 97.6, 55.6 and 83.6 percent, respectively

28.4.3 Nuclear Imaging Methods





(Lumachi et al., 2001). The corresponding values for x-ray mammography were 83.2, 89.9, 48.6,and 79.1 percent. A European multicenter trial evaluating palpable and nonpalpable breast lesionsdemonstrated an overall sensitivity and specificity of 80 and 73 percent, respectively (Bender et al.,1997). These and other early studies reveal that while scintimammography has excellent sensitivityfor tumors larger than about 1 cm, sensitivity is generally poor for smaller, nonpalpable, or mediallylocated lesions.

Dedicated Cameras. One reason for the low sensitivity of conventional scintimammography forsmall lesions is that it is difficult to position the conventional Anger cameras close to the breast. Thisis due to their large size, and their appreciable inactive borders. The result is that the lesion-to-collimator distance can often exceed 20 cm. At this distance, the spatial resolution of conventionalgamma cameras with high-resolution parallel-hole collimators can be 15 to 20 mm. Thus countsoriginating from the lesion are smeared out over a large area of the image, and small lesions,providing few counts, are lost. One potential method for improving sensitivity is the development ofsmaller gamma cameras with narrow inactive borders, permitting camera placement adjacent to thechest wall, and near the breast. Several groups have developed such dedicated breast gamma cameras(Majewski et al., 2001; Pani et al., 1998). Early clinical evaluation of these dedicated systems hasshown promising results (Scopinaro et al., 1999).

Positron Emission Mammography. In positron emission mammography (PEM), positron-emittingradiotracers are utilized, rather than single-gamma-ray emitters. Radiotracer location within the breastis determined by detection of the pair of simultaneously emitted 511-keV gamma rays resulting whenthe positron annihilates with an electron in the breast. Timing coincidence circuitry is used to identifygamma rays originating from a single annihilation event. To date, breast PET has been based prima-rily on assessment of either glucose metabolic rate via 2-[18F]fluoro-2-deoxyglucose (FDG) or ofestrogen or progestin receptor density using 16�-[18F]fluoroestradiol (FES). In a prospective study of144 patients (185 breast lesions), FDG-PET showed a sensitivity of 68.2 and 91.9 percent for pT1and pT2 tumors, respectively. The overall specificity was only 75.5 percent. However, the positivepredictive value (fraction of cases positive on PET that were shown by histology to be malignant) was96.6 percent. A recent Japanese study compared FDG PET and sestamibi SPECT in the detection ofbreast cancer and of axillary node metastases (Yutani et al., 2000). The study concluded that MIBI-SPECT is comparable to FDG-PET in detecting breast cancer (overall sensitivities of 76.3 and 78.9percent, respectively) but that neither FDG-PET nor MIBI-SPECT is sufficiently sensitive to rule outaxillary lymph node metastasis.

As in the case of single-gamma breast imaging, dedicated small-field-of-view gamma cameras arebeing developed (Doshi et al., 2000; Raylman et al., 2000; Thompson et al., 1994). The emphasis todate has been on two-head systems with planar, opposing detectors, rather than the typical ringstructure used in whole-body PET scanners. Technical challenges for breast PET are similar to thosecited above for single-gamma imaging. In addition, because scattered gamma rays and randomcoincidences (arising from two different annihilation events) add to the true coincidences to give thetotal number of counted coincidences, the counting rates encountered in PET are significantly higherthan those in single-gamma breast imaging, placing more stringent requirements on the readoutelectronics.

Electrical impedance scanning (EIS) relies on the differences in conductance and capacitance(dielectric constant) between healthy tissue and malignant tissue. Studies have reported both con-ductivity and capacitance values 10 to 50 times higher in malignant tissue than in the surroundinghealthy tissue (Jossinet, 1996; Morimoto et al., 1993). A commercial EIS scanner called T-scan,developed by Siemens Medical, was approved by the FDA in 1999 to be used as an adjunct tool tomammography (Assenheimer et al., 2001). That device uses a patient-held metallic wand and ascanning probe that is placed against the skin of the breast to complete the electrical circuit. 1.0 to2.5 volts ac is used. Conductive gel is used to improve conductivity between the skin of the breast

28.4.4 Electrical Impedance Scanning





and the scanning probe. The scanning probe is moved over the breast and its sensors (256 sensorsin high-resolution mode and 64 sensors in normal-resolution mode) measure the current signal atthe skin level.

In a study to determine the accuracy of EIS in the differentiation of benign and malignant breastlesions (MRI), 100 mammographically suspicious lesions were examined using EIS, and histologywas acquired through either lesion biopsy or surgical excision. EIS correctly identified 50 of 62malignant lesions (81 percent overall sensitivity), and 24 of 38 benign lesions (63 percentspecificity). Negative predictive value and positive predictive value of 67 and 78 percent wereobserved, respectively. A three-dimensional electrical impedance scanner has also been constructedand tested clinically (Cherepenin et al., 2001). The primary technical challenges for EIS centeraround the reduction of the high false-positive rate due to artifacts produced in imaging superficialskin lesions, and resulting from poor contact or air bubbles (Malich et al., 2001).

Techniques for using optical radiation for breast imaging (sometimes referred to as optical mammog-raphy) have been under development for more than a decade. The principle obstacles to bothstructural and functional optical breast imaging are the significant levels of attenuation and scatteringof optical photons in biological tissue. Because of its relatively low attenuation in human tissue, nearinfared (NIR) radiation is the wavelength band most frequently employed in optical breast imaging.NIR breast imaging can be described as either endogenous or exogenous. The former relies on the IRabsorption of hemoglobin and deoxyhemoglobin and on the differences in vasculature betweennormal and malignant tissues (angiogenesis). The latter utilizes injected NIR-excitable fluorescentdyes to increase contrast between tumors and surrounding healthy tissue.

Elastography is a technique whose goal is to characterize breast masses by measuring their elasticproperties under compression. Studies of excised breast specimens have demonstrated that while fattissue has an elastic modulus that is essentially independent of the strain level (the amount ofcompression), normal fibroglandular tissue has a modulus that increases by 1 to 2 orders ofmagnitude with increasing strain (Krouskop et al., 1998). Furthermore, carcinomas are stiffer thannormal breast tissue at high strain level, with infiltrating ductal carcinomas being the stiffest type ofcarcinoma tested (Krouskop et al., 1998).

There is a general consensus in the breast-imaging community that no single imaging modality islikely to be able to detect and classify early breast cancers, and that the most complete solution fordiagnostic breast imaging is likely to be some combination of complementary modalities. However,again the unique properties of the breast create challenges for successfully merging the information.In particular, the mechanically pliant nature of the breast permit optimization of breast shape for theparticular modality used (compressed for x-ray mammography, coil-shaped for breast MRI,pendulant for breast scintigraphy, etc.). The result is that multimodality image fusion is extremelydifficult. One approach to overcoming this problem is to engineer systems permitting multimodalityimaging of the breast in a single configuration. Toward this end, a system combining digital x-raymammography and planar gamma emission scintigraphy has been developed (Williams et al., 2002).The system employs an upright mammography gantry that is fitted with both a CCD-based x-raydetector and a high-resolution gamma camera. The latter is mounted on a retractable arm. The digitalmammogram is first obtained with the gamma camera retracted, and the breast under mild compres-sion. Then, without removing the compression, the gamma camera is positioned immediately abovethe paddle and the scintigram is obtained. The x-ray and gamma ray images are then fused to obtainthe dual modality image. Figure 28.3 shows an x-ray and gamma ray image, respectively, obtainedon the system. The dual modality scanner is currently being evaluated for its ability to distinguish

28.4.5 Other Techniques

28.5 FUTURE DIRECTIONS—MULTIMODALITY IMAGING





benign and malignant lesions in patients scheduled for biopsy at the University of Virginia. Thesystem is only one example of many other possible multimodality breast imaging approaches that aresure to be developed in the upcoming years.

Allen, M. W., Hendi, P., Schwimmer, J., Bassett, L., and Gambhir, S. S.(2000). “Decision analysis for the cost effectiveness ofsestamibi scintimammography in minimizing unnecessary biopsies,” Quarterly Journal of Nuclear Medicine, 44(2): 168–185.

Assenheimer, M., Laver-Moskovitz, O., Malonek, D., Manor, D., Nahaliel, U., Nitzan, R., and Saad, A. (2001). “The T-SCANtechnology: electrical impedance as a diagnostic tool for breast cancer detection,” Physiological Measurement, 22:1–8.

Bender, H., Kerst, J., Palmedo, H., Schomburg, A., Wagner, U., Ruhlmann, J., and Biersack, H. J. (1997). “Value of (18)fluoro-deoxyglucose positron emission tomography in the staging of recurrent breast carcinoma,” Anticancer Research, 17:1687–1692.

Bick, U., Giger, M., Schmidt, R., Nishikawa, R. M., and Doi, K. (1996). “Density correction of peripheral breast tissue on digitalmammograms,” Radiographics, 16:1403–1411.

Boetes, C., Barentsz, J., Mus, R., et al. (1994). “MRI characterization of suspicious breast lesions with a gadolinium-enhancedturbo FLASH subtraction technique.” Radiology, 193:777–781.

Buscombe, J. R., Cwikla, J. B., Holloway, B., and Hilson, A. J. (2001). “Prediction of the usefulness of combined mammographyand scintimammography in suspected primary breast cancer using ROC curves,” Journal of Nuclear Medicine, 42(1):3–8.

Byng, J., Critten, J., and Yaffe, M. (1997). “Thickness-equalization processing for mamographic images,” Radiology, 203:568.

Cherepenin, V., Karpov, A., Korjenevsky, A., Kornienko, V., Mazaletskaya, A., Mazourov, D., and Meister, D. (2001). “A 3D elec-trical impedance tomography (EIT) system for breast cancer detection,” Physiological Measurement 22:9–18.

Daniel, B., Yen, Y., Glover, G., Ikeda, D., Birdwell, R., Sawyer-Glover, A., Black, J., Plevritis, S., Jeffrey, S., and Herfkens, R. (1998).“Breast disease: dynamic spiral MR imaging,” Radiology, 209:499–509.

FIGURE 28.3 Scintigram (left) and digital mammogram (right) from the dual modality scanner at the University of Virginia. Note the correlationbetween the locations of the three areas of increased radiotracer uptake on the scintigram and the three areas of increased radiodensity on themammogram.

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chapter 28 breast imaging systems: design challenges … · laurie l. fajardo the russell morgan...

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