Wo m e n ’s I m a g i n g • R ev i ew Kopans Digital Breast Tomosynthesis

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Women’s Imaging Review

Daniel B. Kopans1 Kopans DB

Digital Breast Tomosynthesis From Concept to Clinical Care OBJECTIVE. The purpose of this article is to describe the development of digital breast tomosynthesis (DBT) and to describe its advantages over 2D mammography for breast cancer screening. CONCLUSION. Mammographic screening has dramatically reduced breast cancer deaths, but it does not depict all cancer early enough to result in a cure. In addition, because of the recall rates associated with mammography, efforts are underway to reduce access to screening. Use of DBT improves sensitivity and specificity, and there is no longer a need to obtain full-exposure 2D mammograms. DBT will replace standard 2D mammography for breast cancer screening.

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Keywords: breast, breast cancer, digital breast tomosynthesis, mammography, screening DOI:10.2214/AJR.13.11520 Received July 2, 2013; accepted after revision August 25, 2013. 1 Departments of Radiology, Harvard Medical School and Massachusetts General Hospital, Avon Comprehensive Breast Evaluation Center, ACC Ste 240, 15 Parkman St, Boston, MA 02114. Address correspondence to D. B. Kopans ([email protected]).

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he uninformed have suggested that mammography is an outdated technology. The high-dose industrial-film studies from the 1960s were replaced in the 1970s by the xeroradiographic technique with its wide exposure latitude and edge enhancement. Film-screen combinations in the 1980s had improved contrast resolution and further reduced exposure levels. Digital mammography, developed in the 1990s and implemented in the first decade of the 21st century, manifested further improvements [1]. Digital mammography not only has the advantages common to all digital imaging techniques but also has opened up opportunities for greatly improving x-ray imaging of the breast. Digital breast tomosynthesis (DBT) is a technology made possible by the development of digital detectors. DBT is poised to further improve the ability to detect more cases of breast cancer at a smaller size and earlier stage while offering greater screening accuracy. The American Cancer Society [2] estimated that during 2013, 232,340 new cases of invasive breast cancer and another 55,000 cases of ductal carcinoma in situ (DCIS) would be diagnosed among women in the United States and that approximately 39,620 women would die of breast cancer. Excluding skin cancer, breast cancer is the most commonly diagnosed cancer among American women and is the leading cause of nonpreventable cancer death among these women. Randomized

controlled trials, the only way to prove that a screening test saves lives, have shown that early detection with mammographic screening can reduce the death rate approximately 30% [3]. This statistic has been confirmed in observational studies that have shown that when screening is introduced into a general population, the death rate from breast cancer declines at an even higher rate for women 40 years old and older [4–12]. For the 50 years between 1940 and 1990, the death rate from breast cancer remained unchanged in the United States. Mammographic screening began in the mid 1980s in sufficient numbers to be reflected in a sudden increase in national breast cancer incidence [12]. Mammographic screening does not save lives immediately owing to length bias, but deaths begin to decline 5–7 years after the institution of screening [13, 14]. As expected, several years after the start of screening, in 1990, the death rate from breast cancer began a sudden decline. Since 1990 the death rate from breast cancer, an indicator unaffected by leadtime bias, has decreased more than 30% [15]. This means that each year there are more than 30% fewer deaths of breast cancer than would have occurred had there not been any screening. Study results have suggested that most of the decline in deaths is due to earlier detection [4–6, 10]. Although there have been important improvements in therapy, oncologists recognize that therapy saves lives when breast cancer is found and treated at a smaller size and

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Kopans earlier stage. Mammographic screening represents one of the major medical advances of the past 50 years. We all hope for a universal cure, or a safe method to prevent breast cancer, but neither is on the horizon. While we wait for a therapeutic breakthrough, early detection is making a major difference by saving tens of thousands of lives each year. Efforts to add to the success of mammography include the possible use of ultrasound for screening [16] and of MRI to try to detect additional cancer earlier [17]. Although it is clear that these technologies can depict mammographically and clinically occult tumors, they have not been tested in randomized controlled trials, so there is no direct proof that their use will save lives. Despite having been proven to save lives in randomized controlled trials, mammographic screening has been under attack, and its so-called false-positive rate has been cited as a major reason to deny women access to screening [18]. The false-positive rates of ultrasound and MRI, however, are much higher than those of mammographic screening. Furthermore, until recently, ultrasound screening was performed with handheld devices, making it time-consuming and operator dependent. Automated ultrasound units have become available, but it remains to be shown that their implementation can enhance the proven decrease in breast cancer deaths that has been found conclusively with screening mammography [19]. DBT addresses many of the concerns raised about conventional mammographic screening. Not only are additional small malignant tumors found with DBT, but DBT also produces fewer recalls (pejoratively called false-positives) from screening than does conventional 2D mammography. False-Positives Although the most scientifically rigorous of tests—randomized controlled trials—have shown that mammographic screening reduces deaths from breast cancer, efforts to deny women access to screening persist [20]. Opponents of screening have focused on the harms of screening, suggesting that women should forgo screening because of the rate of false-positive results. In 2009 the United States Preventive Services Task Force (USPSTF) argued that because of false-positive findings, women in their 40s should not undergo screening [18]. The task force neglected to explain that the majority of so-called falsepositives occurred among women recalled

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for additional imaging evaluation because of screening findings. The vast majority of these women have a few extra mammographic images or an ultrasound examination and are found to have nothing of consequence. In fact, among 1000 women screened in the United States, approximately 100 (10%) are recalled for additional evaluation. This percentage is the same as that for women recalled after an abnormal cervical cancer (Pap) screening test result. Among the 100 recalled, approximately 56 undergo mammography with additional views or an ultrasound examination that shows no cancer. Another 25 will have a probably benign finding and will be asked to return for follow-up in 6 months. Only 1–2% (19/1000) of the women screened will be advised to undergo imagingguided needle biopsy with local anesthesia, and 6 of the 19 will be found to have breast cancer. The percentage of women undergoing biopsy because of mammographically detected cancer who prove to have breast cancer (20–40%) is higher than the percentage of women who wait until a lump is palpable and is biopsied. Only 15% of the lumps prove to be cancer [21]. This is a higher false-positive rate than for mammographically instigated biopsy, and palpable tumors are at a larger size and later stage than those detected with mammography. Overdiagnosis and Overtreatment Mammographic screening has been castigated with false assertions that it leads to overdiagnosis and that treating cancer that would never become clinically evident results in overtreatment. At a fundamental level this is nonsense because the diagnosis is not determined by mammography but is decided by pathologists. Faulting mammography for overtreatment ignores the fact that it is oncologists who determine therapy. Even if mammography did cause overdiagnosis, which it does not, women should not be denied access to screening as a result of these assertions. Randomized controlled trials are the only way to directly measure overdiagnosis, and the trials have shown that the rate of overdiagnosis is at most 10% [22] and likely is less than 1% [23]. A 2012 paper that suggested massive overdiagnosis [24] was based on faulty estimates of what the incidence of breast cancer would have been had there been no screening. With use of a more reliable estimate, there is no overdiagnosis of invasive breast cancer [25]. DCIS is a controversial lesion, but efforts have been underway for years to better tai-

lor therapy for these lesions. It is possible that the fact that the annual incidence of invasive breast cancer has dipped below what would have been expected suggests that the removal of DCIS from the population, as a consequence of mammographic screening, has resulted in a decline in subsequent invasive cancer. Nevertheless, several analyses [22, 23, 26–30] and an overview of various studies have shown that the authors who concluded that massive overdiagnosis occurs based their estimates on faulty methods [31]. Opponents of screening have never explained why, if tens of thousands of malignant tumors would disappear on their own if left undetected, there is not a single credible report of invasive breast cancer disappearing on its own. Mammographic screening saves lives with little or no overdiagnosis. All major groups, including the United States Preventive Services Task Force, agree that annual screening beginning at the age of 40 years saves the most lives. Continuous efforts have been underway for decades to improve on mammography. Xeroradiography improved on the film mammography of the 1960s. This was replaced when film-screen mammography yielded high-quality images at lower radiation doses. In the 1980s improvements in analog film-screen mammography were made, but the technology was reaching its limits and the improvements were incremental. Digital mammography was slower in development than the use of digital detectors for bone, chest, and other organ imaging because the U.S. Food and Drug Administration (FDA) required digital mammography to be validated in the premarket approval process— unlike the other radiographic tests approved under the 510(k) process for approval of medical devices. The Digital Mammographic Imaging Screening Trial showed that digital mammography was comparable to if not slightly better than analog film-screen mammography for premenopausal women, women with dense breasts, and those younger than 50 years (who are mostly all the same women) [1]. The development of digital detectors for mammography opened new and important avenues of exploration to improve the radiographic detection of breast cancer. My colleagues and I at Massachusetts General Hospital [32] found in animal models that digital subtraction angiography can depict the neovascularity that develops with malignant tumors. Jong et al. [33] conducted studies using digital detectors to perform contrast subtraction mammography after IV injection of iodinated contrast medium. Lewin et al. [34] pio-

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Digital Breast Tomosynthesis neered the use of K-edge dual-energy spectral imaging. This technique allows visualization of the IV contrast blush caused by the neovascularity recruited by malignant breast tumors. Digital mammography will permit dual-energy subtraction that may enhance the detection of microcalcifications. The development of digital detectors made it possible for my colleagues and me to develop DBT. Digital Breast Tomosynthesis: Historical Development In 1978, while reviewing specimen radiographs of surgically excised breast lesions detected mammographically to confirm removal of the lesion, I recognized how much more clearly I could see these lesions imaged outside the breast than I could the poor-definition lesions imaged inside the breast. The poorer in vivo definition was in large part due to the structure noise of the normal breast tissue obscuring the lesions. In those days linear and polycycloidal tomography (laminography) was being used to reduce structure noise in chest radiography and abdominal imaging. CT was in its infancy. There was great concern in the 1970s over radiation risk to the breast, and because the available tomographic techniques required high doses, they were not useful for breast cancer screening. I read about the concept of tomosynthesis and realized that it could provide me with the imaging answers I was seeking with no increase

in radiation dose. However, the technique required computers and digitally acquired images, so I had to wait until the 1990s for the development of digital detectors. Tomosynthesis is a concept that was first described in the 1960s. The basic principles of tomosynthesis were reviewed by Miller et al. in 1971 [35]. Richard Moore, head of breast imaging research in my department, and I were joined in 1992 by Loren Niklason as the department physicist, and I set the goal that we would develop the technique that I named digital breast tomosynthesis. Niklason, Laura Niklason, and another physicist, Bradley Christian, worked out the physics, and we imaged phantoms and mastectomy material by manually moving the x-ray gantry to collect projection images from different angles. This team at the Massachusetts General Hospital was the first to prove that tomosynthesis could be applied to the evaluation of the whole breast [36], and we improved the fundamental technique [37]. Several grants have supported our development of this technology. GE Healthcare built the first whole-breast DBT system for us under grant BC970208 from the U.S. Army. We performed the first studies, which involved several hundred volunteers, beginning in 2000 [38]. This work, also supported by GE Healthcare, showed that DBT was able to greatly improve the conspicuity of lesions (Fig. 1) and reduce the recall rate from screening. We received

a patent on the technology [39]. Moore and I persuaded major manufacturers of the importance of DBT, triggering their development efforts. Massachusetts General Hospital licensed the patent to GE Healthcare. How Does Digital Breast Tomosynthesis Work? DBT is a form of limited-angle tomography. Low-dose full field projection images of the breast are obtained from different angles with x-rays passing through the breast from different directions (Fig. 2). This takes advantage of parallax. The projection of structures onto the detector that are closer to the detector will appear to move over a shorter distance between images than projection of structures that are farther away from the detector. The simplest way to synthesize planes through the breast is by instructing the computer to align all of the projection images so that structures in the plane of interest all align precisely. In this way structures in the plane of interest are registered and reinforced by the number of projection images obtained, whereas structures not in the plane of interest are misregistered with one another and fade into the background. The computer can then be instructed to shift the images and add them again (hence the name shift and add) to obtain a different plane. In this way any and all planes can be synthesized through the entire breast from a small number of projecFig. 1—57-year-old woman with breast cancer. Comparison of standard 2D versus digital breast tomosynthesis (DBT). A, Standard 2D digital mammogram shows very dense breast. B, DBT plane clearly shows breast tumor. C, DBT enlargement shows lesion.

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Kopans tion images. The structures in each plane are more clearly visible without the interference of tissue in front or in back of the plane of interest. In fact, all of the projection images are included in every synthesized slice, but because the information is misregistered, the out-of-plane information fades into the background with the plane of interest reinforced as many times as the number of projection images obtained. Each projection image requires only a fraction of the total dose of a full 2D mammogram because all of the projection images are added together to synthesize the planes. This means that DBT can be performed at the same total radiation dose used for 2D mammography. Although the risk to a differentiated (mature) breast from mammographic doses is very low, and perhaps nonexistent [40], DBT need not increase the total dose for mammography. There are various ways to process DBT images. From the start my colleagues and I have used an iterative maximum likelihood technique developed with collaborators at Brandeis

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University [41]. This improves the visualization of masses and soft-tissue margins but is computationally demanding. Computer processors have become powerful and inexpensive enough that the iterative approach can be used in practice. Some manufacturers are using filtered back projection because it is fast and enhances the conspicuity of calcifications. There is a great deal of interest in improving reconstruction algorithms. It is not yet clear which will be preferable for imaging the breast. DBT has been described as 3D mammography, but this is not entirely correct. The images contain a great deal of 3D information because the technique is limited-angle tomography, and because the data are not collected from a full 180–360° around the breast, there is uncertainty in the z direction. To put it simply, unless one can see behind every structure with projection images, there will be uncertainty in the z dimension. For this reason, the voxels are not cubic; they are nonisotropic. In other words, although the x and y dimensions of the voxel are limited by

the resolution of the detector, the z dimension is uncertain and is spread in a diamond shape above and below the plane. Its dimensions are related to the angle of the arc through which the projection images were obtained. The larger the arc of collection, the better defined is z. Because of the uncertainty of z, the thickness of each plane is not well defined. The planes defined by DBT are described by their separation. Most researchers have used 1 mm as the distance between planes, but any separation can be synthesized. Cubing the voxel would have great value because the existence of true 3D data would allow comparison between studies obtained at different times to highlight changes in the breast over time, an important sign of possible malignancy. CT of the breast can allow cubic voxels because data are obtained over 360°, but imaging the entire breast with CT, especially the axillary tail, is problematic. Furthermore, because more images are required, the radiation dose must increase to maintain the same spatial resolution and signal-to-noise raX-ray

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Normal breast tissue Cancer

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A Individual projection images

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Fig. 2—Shift and add. Adapted with permission from [50] A, Diagram shows breast with normal tissue and cancer hidden behind it. B, Diagram shows that digital breast tomosynthesis takes advantage of parallax and fact that projection of structures at different levels above detector move differing distances across detector. Projection of normal tissue structure moves over longer distance than cancer, which is closer to detector. C, Projection images show breast from differing angles. D, Computer can be used to align and add images so that structures in specific plane above detector register on all images and reinforce one another, whereas out-ofplane structures are misregistered and fade into background. Diagram shows normal tissue structure is reinforced, and plane containing cancer is misregistered and fades into background. E, Diagram shows that computer shifts and adds projection images and that out-of-plane normal tissue is misregistered and fades into background, whereas plane containing cancer is reinforced three times, and lesion becomes clearly visible.

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Digital Breast Tomosynthesis tio. Perhaps the development of CT with 180° collection would allow cubing the voxel at high resolution and lower dose. At present, DBT is the best compromise for keeping the dose the same as for 2D mammography with full resolution in the xy plane while providing the advantages of a tomographic approach. The Advantages of Digital Breast Tomosynthesis DBT was developed in an effort to improve on the major success of mammography. It was developed for breast imaging because the normal structures of the breast can obscure malignant tumors. In addition, the superimposition of structures in the breast can form a summation shadow, which appears to be a lesion when none is present. Both problems complicate the interpretation of conventional 2D mammograms. DBT is an evolutionary technology that builds on the success of 2D mammography. It improves the ability to detect breast cancer while reducing the false-positive, or recall, rate. This is unusual. Usually, to increase the sensitivity of a technology, the threshold for intervention must be lowered, which increases the false-positive rate and reduces specificity. DBT has the unique advantage of improving both sensitivity and specificity. Early studies showed that DBT, by markedly reducing the structure noise of normal breast tissues, can improve the conspicuity of lesions. Because one can better see the margins of lesions without the interference of superimposed normal breast tissue, DBT improves the differentiation of benign from malignant lesions [42]. Almost all studies have shown that use of DBT significantly decreases the recall rate after screening compared with use of 2D conventional mammography [43, 44]. Results of more recent analyses suggest that the screening recall rates in the United States may be reduced 30–40% with the use of DBT [45, 46]. Is Imaging of Calcifications a Limitation of Digital Breast Tomosynthesis? Clarity: Details and Contrast Concern has been raised about the ability to detect and analyze calcifications with DBT. The ability to remove structure noise and display separate planes through the breast is the main benefit of DBT. This is true for calcifications and for masses. Just as with masses, normal tissues can obscure clustered calcifications. In a small number of cases early in their experience, Poplack et al. [47] found that

the DBT depiction of the deposits was inferior to the 2D mammographic depiction in 8 of 14 (57%) cases. That study, however, was performed with a DBT system in which the detector elements were binned. To improve the efficiency of that particular system, pixels were added together and averaged, effectively increasing the pixel size. This meant that the spatial resolution was markedly reduced. It is not surprising that calcifications were not seen with the same clarity. In a reader study, Spangler et al. [48] found that full field digital mammography was slightly more sensitive in the detection of calcifications than DBT was, but it is not clear from the paper whether the readers used the slab images (recombining slices into thick sections). Furthermore, I believe that the research device that they used was similar to that used by Poplack et al. [47] and that the pixels were binned. This would reduce the spatial resolution of DBT to well below that of 2D images. Both would have resulted in suboptimal image quality for the DBT readings. My colleagues and I conducted a study [49] using a system that did not bin the pixels and used the full resolution of the detector. We found that calcifications were seen with greater clarity with DBT than with digital mammography in 42% of side-by-side comparisons in 119 cases. In 50% of the cases the calcifications were seen with equal clarity with the two techniques. In only 8% of the cases were calcifications seen with greater clarity on 2D digital mammograms. If the full resolution of the detector is used for DBT, calcifications are seen with equal or greater clarity with DBT versus 2D digital mammography in 92% of cases. Perception Although calcifications are seen with greater clarity on DBT images once they have been detected, a cluster of calcifications may not be easily perceived with DBT. Because planes through the breast are presented, as the reader pages through the individual synthesized planes, one plane may reveal a single calcification; the next may contain two calcifications; the next plane, none; the next, three; and so on (Fig. 3). Consequently, the reader may not perceive the cluster. Moore realized that this problem of perception may be ameliorated by putting the planes back together in a slab that is then moved through the breast volume by use of a maximum intensity projection within the slab [50]. The clusters become readily apparent in the volume rendering of the DBT planes.

To avoid the problem of perceiving clustered calcifications, the initial premarket approval Hologic received from the FDA for DBT required that full-exposure 2D mammograms be obtained with every DBT screening study. Although radiation risk to the breast is, at worst, a theoretic issue for women 40 years old and older but likely of no consequence [40], requiring 2D fulldose projection images essentially doubles the dose. Nevertheless, having the full 2D projection image allows readers to perceive clustered calcifications at the usual detection level. As our study showed [49], once a cluster is identified, it is seen with equal or greater clarity on DBT images. This may lead to greater diagnostic accuracy. Because of their high contrast, calcifications are fairly easily seen on standard 2D images. It is not surprising that the screening studies to date [51, 52] conducted with DBT have not shown an increase in detection of the clustered calcifications that are frequently associated with DCIS. Use of DBT certainly will not increase the false-positive rate by increasing the detection of clustered calcifications. At the same time, as long as volume imaging remains available, DBT does not reduce the ability to detect clustered calcifications. It is less desirable to have to double the dose and obtain full-exposure 2D images along with the DBT projection images. The companies developing DBT systems have recognized this limitation and have responded and adapted the slab approach. However, instead of moving a thick plane through the breast, they have taken the synthesized planes and put them all back together to produce a synthesized full 2D projection. This will provide radiologists with a familiar road map from the 2D image and permit the perception of calcifications using the synthetic 2D projection. My assessment of preliminary comparisons between synthetic 2D reconstructions and fulldose projection 2D images suggests that the synthesized 2D images provide even greater clarity than a full-exposure projection image. In May 2013, the FDA approved Hologic’s synthesized 2D images, called C-View. GE Healthcare has developed V-Preview, and other companies have developed similar technology. When the synthesized 2D projection images are approved, the need for any fullexposure 2D images, with the attendant increased dose, is eliminated. Computer-aided detection has also been developed for DBT, and this will also aid in the detection of clustered microcalcifications [53].

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Kopans

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C Fig. 3—Diagrams show how calcifications can be difficult to perceive on planes through volume but are more easily appreciated on slab images. Adapted with permission from [50] A, Cluster of calcifications is perceived because on 2D mammogram distribution catches reader’s attention. B, Clustering can be difficult to perceive as a reader pages through volumes because brain does not appreciate cluster. C, Cluster becomes evident when planes are put together to make slab and slab is moved through volume by use of maximum intensity projection within slab.

Digital Breast Tomosynthesis for Diagnostic Imaging There is some question as to how best to use DBT in breast evaluation. Should DBT be used for screening or for diagnostic evaluation? In a study comparing two-view 2D mammography with single-view (mediolateral oblique [MLO]) DBT among women with a clinically evident abnormality or among women who had been recalled after screening, DBT was superior to 2D mammography, having greater sensitivity and negative predictive value than 2D mammography [54]. In another study comparing DBT with diagnostic mammographic supplemental views for women with noncalcified masses and architectural distortion, receiver operating curve analysis showed DBT to be superior to supplemental 2D mammographic views [55]. DBT may be superior to standard supplemental diagnostic mammographic evaluation, but the added expense is unlikely to justify it exclusively for

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this purpose. Furthermore, if DBT is used only for diagnosis, its main advantages will be lost. Additional foci of cancer have been detected with DBT in a diagnostic setting (women with known cancer), but the only way for DBT to fulfill its real advantage will come from screening and early detection. Using DBT for screening is the only way for it to depict cancer that may be overlooked at 2D screening, and the utility of DBT in reducing recall rates after screening will not be realized if it is not used for screening. Digital Breast Tomosynthesis Is a Screening Test Almost all reader studies have shown that 2D mammography plus DBT is superior to 2D mammography for the detection and diagnosis of breast cancer with a concomitant reduction in false-positive results (recalls from screening). What many do not realize is that reader studies can only be biased against DBT.

To be recruited to participate in reader studies, an individual woman must have had something detected on her 2D mammogram. In this way there is little opportunity for lesions to be found only with DBT that are not evident on 2D mammograms. In theory, in reader studies, DBT can never be better than 2D mammography because all lesions are, at least initially, visible on the 2D images. That DBT has done as well as it has is due to the fact that even lesions seen on 2D mammograms are seen with greater conspicuity on DBT images. The first major prospective study that proved that cancer overlooked on 2D mammograms or not visible on 2D mammograms can be detected with DBT (in screening) was conducted in Oslo, Norway [51]. The preliminary results were published in January 2013. In that study 2D and DBT images were collected for 12,631 women recruited before undergoing any imaging and had both standard 2D mammograms and DBT images in two projections. The read-

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Digital Breast Tomosynthesis ers first interpreted the standard 2D images and then the 2D plus DBT images. The results showed that 6.1 cases of cancer were found for every 1000 women screened with 2D mammography alone. This rate increased 27% to 8.0 cases of cancer per 1000 examinations when DBT was added to mammography. In that study the recall rate decreased 15%, which is fairly high given that the recall rate in Norway is lower to begin with than that in the United States. Perhaps the most important finding was that there was a 40% increase in detection of invasive cancer when DBT was used. There was no increase in the detection of DCIS. This finding should be good news for those who are concerned about overdiagnosis. The importance of DCIS is highly debatable, but it is clear that the death rate is decreased by the early detection of small invasive lesions. The Oslo study provides strong evidence supporting the value of DBT as a primary screening test. In April 2013, investigators from Italy and Australia published the results of the Screening with Tomosynthesis or Standard Mammography (STORM) trial [52], in which 7292 women 54–63 years old were screened. The investigators detected 59 cases of breast cancer, 52 of which were invasive cancer in 57 women. With 2D mammography alone, 39 of 59 (66%) cases of cancer were detected. An additional 20 of 59 cases of cancer (34% of the total) were detected when DBT was added to 2D imaging. With 2D mammography alone, the cancer detection rate was 5.3 cases per 1000 screens. This increased to 8.1 cases of cancer per 1000 screens when DBT was combined with 2D mammography. The investigators estimated that DBT combined with 2D mammography could have reduced the recall rate 17.2%. The Oslo and STORM trials clearly showed that as my colleagues and I predicted, DBT used in conjunction with 2D mammography for screening increases the rate of detection of invasive cancer (improved sensitivity) and reduces the recall rate (increased specificity). Now that 2D images can be synthesized from the DBT collection, there is no valid scientific argument against the adoption of DBT as the standard mammographic screening test. One-View or Two-View Digital Breast Tomosynthesis? When my colleagues and I developed DBT, we believed that because the projection images were obtained from multiple angles, the craniocaudal projection would not be necessary and only the MLO projections would be

needed. We found in a review of more than 400 cases of cancer identified with conventional mammography, all but four were in the FOV of the MLO projection (Kopans DB, et al., unpublished data). It now appears that some malignant breast tumors may have limited x-ray attenuation in the MLO projection and produce greater x-ray attenuation on the craniocaudal view. It appears that some form of craniocaudal projection is useful along with the MLO DBT. In a reader study Gennaro et al. [56] found that DBT in the MLO projection plus a single standard craniocaudal projection is not inferior to standard MLO and craniocaudal projections. What has not been studied, to my knowledge, is the need for DBT in both the MLO and the craniocaudal projections. Future studies will evaluate this question. The development of synthetic 2D images from the DBT collection may make the question moot. Not All Digital Breast Tomosynthesis Systems Are the Same The fundamental principle behind DBT takes advantage of parallax from the projection images obtained at varying angles. There are numerous ways to image the breast from different angles. The x-ray tube may be moved while the breast and detector are held stationary. The tube and detector may move. The motion of the two can vary. Physics would suggest that the greater the angle through which the x-ray tube is moved, the better is the z resolution. Arguments have been made that varying the dose among the various projection images can improve the synthesized images. Almost certainly the application of higher dose (greater photon flux) will improve image quality. Another factor in DBT is the technology involved in the detector system. The GE Healthcare detector operates with epitaxial cesium iodide crystals. The x-ray photons are converted to light photons, which are then converted to an electric signal. Technologies entailing amorphous selenium are used to convert x-ray photons directly into electronic signals. The various detectors have differing characteristics. In general it takes longer to read out the amorphous selenium detectors. This has meant that the early-generation devices that include these detectors had to bin the pixels. Binning may permit the detector to be read out more efficiently, but binning reduces spatial resolution. This is almost certainly the reason that detectors with binned pixels produce DBT images that are not equal in quality to 2D unbinned im-

ages. That the GE Healthcare detector does not require pixel binning is likely the reason that calcifications are seen with greater diagnostic clarity with the GE Healthcare system [49] than with other systems [47]. The best combination and number of projection images has not been determined, nor is it clear which angles are best for collecting these images. Another unknown factor is the optimum dose distribution from the various angles. The composition of the x-ray source (focal spot type) can affect the images, and it remains to be seen whether one detector technology is better than another. Although the effects of breast motion during acquisition of the projection images have not been studied, it is fairly certain that it is better to collect the images over a shorter time than a longer time to reduce the risk of motion. The contribution of motion to the degradation of the synthesized images, however, is not clear. Speed of acquisition is directly related to the speed at which the information can be read from the detector and how quickly the detector can collect the next image. Other factors that will influence image quality are the various elements of noise contributed by the system and the breast and how that noise is handled. GE Healthcare has developed a method for performing DBT with a moving grid. This should improve image quality by reducing scatter. A number of ways have been developed to combine projection images to synthesize planes through the breast. The original approach was called shift and add. More complex algorithms have been developed that reduce the contributions of structures that are out of plane. The physics suggests that some form of iterative maximum likelihood algorithms is best at reproducing both calcifications and masses [41]. Algorithms also have been developed to reduce the repetitive outof-plane artifacts that are most prominent when only shift and add approaches are used. Interpretation Times Another concern that has been expressed is that it takes longer to page through tens of DBT planes to cover the breast than it does to look at two conventional mammographic projections of each breast. My colleagues and I (Kopans DB, et al., unpublished data) compared reading times for both approaches and found that the time to read the studies is only slightly increased for tomosynthesis if only MLO DBT is required (compared with MLO and craniocaudal 2D images). If both projections are used for DBT (MLO and cra-

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Kopans niocaudal), the reading time increases [57]. As with the length of time that it takes to review a standard mammogram, the time will likely vary with the individual reader, but just as they have become facile reading CT cross sections instead of abdominal radiographs, radiologists will adapt to reading tomosynthesis images. The Breast Imaging Division at Massachusetts General Hospital has almost completely converted to allDBT screening, and we have adapted with no interruption. Although it may take longer to read screening DBT studies, accounting for total radiologist time should recognize the decrease in recalls for diagnostic imaging afforded by DBT screening. Diagnostic imaging takes much longer than screening, ranging from a few minutes to several hours. This time savings should be counted and can be added to offset the extra time needed for interpreting screening studies. There is an advantage to reading tomosynthesis images because the breast is imaged in the same projection as is used for conventional mammography, so a radiologist just learning to read DBT studies is immediately familiar with the structures and patterns. There is a rapid learning curve. The major difference is that the structures and patterns are seen with greater clarity on DBT images because they are no longer superimposed and obscured. DBT is a mammogram—only better. Why Does Digital Breast Tomosynthesis Reduce the Need for Diagnostic Mammography? One of the main advantages of tomosynthesis of the breast is that the confusion caused by structure noise (normal breast tissue) superimposing on conventional 2D images is eliminated in tomosynthesis. This greatly alters the diagnostic sequence of events after the screening study. If tomosynthesis becomes the screening study, the need for recalling patients for diagnostic evaluation will markedly decrease. To appreciate this, one need only review the sequence of events that may occur after a screening study. Using tomosynthesis as the screening study reduces recall rates in the following way. The first reason that a patient is recalled after a conventional mammographic screening examination for additional (diagnostic) evaluation is that the radiologist has seen something on the screening study that he or she is not certain is even real. In our experience, 25% of the women recalled after screening are found merely to have superimposition of normal tissue that

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forms a summation shadow that looks like a lesion. With conventional imaging, the patient is recalled, and several (sometimes many) additional images are obtained to try to determine whether a real lesion is present in the breast or if summation of normal structures has been found. DBT eliminates this reason for recall because tissues no longer are superimposed, so summation shadows cannot occur. The next reason to recall a patient for diagnostic evaluation after screening is that the radiologist is convinced that there is a real abnormality but can only see it in one of the two screening projections. If the supposed abnormality is seen in only one view, then its 3D location within the breast is not known. If the finding is of concern, the patient must be recalled for additional imaging to determine the 3D location of the finding in the breast. Because DBT is cross-sectional, the location of a lesion is never in doubt. Its x and y coordinates are measurable on the slice, or plane, on which it is seen, and its z location is calculated on the basis of the slice number on which it is best seen, the thickness of the breast when the images were acquired, and the number of planes needed to go from one side of the breast to the other. For example, if a lesion is best seen on plane 33 and it took 66 planes to go through the breast, the lesion is in the center of the breast (33/66). The z location is easily calculated from the planes, so the radiologist knows how far the plane is above the plane of the detector. Thus DBT eliminates the second reason for recalling a patient from screening for additional mammography. Finally, the radiologist recalls women after screening to get a better look at the shape and margins of masses and the morphologic features and distribution of calcifications. Because all of these are better seen with DBT, this reason for recall is also eliminated. If it can be shown that the use of DBT eliminates the need for magnification mammography, then the only reason to recall women after screening would be that they need ultrasound or imaging-guided biopsy. The use of DBT for screening will likely eliminate the need for most diagnostic mammography. My colleagues’ and my preliminary research experience suggests that we can go directly to breast biopsy if the DBT screening study shows a suspicious lesion. In a pilot study many years ago, we found that we could use DBT to confirm the location of a lesion and position a guidewire to direct surgical excision. Techniques are being developed to use DBT to guide vacuum-assisted biopsy.

Some authors have suggested that there is a long learning curve for interpreting breast DBT. My experience is that there is little or no learning curve. The rules for mammographic interpretation apply to breast tomosynthesis. Some of the structures that DBT shows are frequently hidden on standard mammograms. Biopsy scars after surgery with benign results are usually not evident on standard mammograms, but they are often seen on DBT images. This is not a problem because the history and location of a biopsy clarify the observation. Radial scars stand out on DBT images and are a source of falsepositive findings. These idiopathic, benign lesions are fairly uncommon, so they should not be too much of a problem. Many radial scars are associated with atypia or DCIS, so their detection and biopsy may help to better define which women are at high risk. There will no doubt be other findings that are more evident at DBT. It is expected that new signs will be discovered that will increase the cancer detection rate. A more detailed analysis of the greater clarity with which lesion margins are seen may assist in improving separation of benign and malignant lesions to further reduce the need for biopsy of lesions that prove to be benign. Most of the learning associated with DBT has to do with using the workstations. As these tools become user-friendly, the interpretation of breast tomosynthesis images will also be facilitated. Having the 2D images synthesized from the DBT data will perfectly register the 2D image with the DBT planes, which will greatly facilitate interpretation. Does Digital Breast Tomosynthesis Require Increasing the Dose for Mammography? It is clear that radiation risk to the breast is related to the age at which the individual is exposed. By the time a woman is 40 years old—the recommended start of routine screening—the breast has matured and is, essentially, resistant to radiation [58]. Data from previous situations in which women were exposed to much higher than mammographic doses show no increased risk of development of breast cancer, and millions of women have undergone mammography since the early 1990s. If the radiation from mammography had been causing cancer, the incidence of breast cancer would have increased toward the end of the 1990s, but it decreased. Nevertheless, in our research studies, my colleagues and I have kept the dose for the DBT

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Digital Breast Tomosynthesis examination less than the combined dose for the standard two-view (MLO and craniocaudal) mammographic examination [46–48]. In May 2013, the FDA approved Hologic’s synthetic 2D mammograms. Because there is no longer a need to obtain full 2D images along with DBT, the dose for DBT will decrease to within the range of that for standard 2D mammography. Should Digital Breast Tomosynthesis Replace Conventional Mammography for Screening? Because the FDA has approved the synthesis of 2D mammographic images from DBT acquisition, there should be little reason not to convert screening to DBT. There is no longer a reason to expose the patient to additional radiation dose to obtain images in the standard 2D projections. Acquisition of the synthetic images will mean that the proven utility of 2D mammography in reducing deaths of breast cancer will be retained. DBT, moreover, creates opportunities to detect malignant tumors that are hidden on 2D mammograms and to decrease the recall rate. The argument that mammographic screening leads to overdiagnosis has been disproved. There is no reason to believe that the invasive cancers found with DBT alone are not clinically relevant. These may in fact represent the interval cancers that have been missed with conventional mammography. Some of these lesions will represent cancer that is occult on 2D mammograms and found with ultrasound or MRI, perhaps reducing the need to screen with these technologies. That use of DBT does not increase the detection rate of DCIS should eliminate that as a concern. DBT is simply a better mammogram. Resources spent on randomized controlled trials would be better spent evaluating tests such as MRI and ultrasound for general population screening where there is no proof of benefit. Future Advances The development of digital detectors has opened opportunities to improve on breast cancer detection. DBT will be the platform on which other technologies, such as PET/ CT, are added to provide synergy. My colleagues and I have already shown that optical imaging is improved by coupling it with high-resolution structural information from DBT [59]. We are studying the 3D mechanical properties of the breast tissues when compressed for a DBT examination in an effort

to detect stiff tissues that may indicate the presence of occult malignant lesions [60]. Ultrasound can depict mammographically occult malignant tumors, but it has a high false-positive rate. We hope to introduce ultrasound into the DBT system and scan breasts in the same position used for the DBT study to acquire registered and fused ultrasound/DBT images. Other incremental advances are becoming available. Numerous efforts are being made to improve on image acquisition and on reconstruction algorithms that should only improve on the technology that already improves on conventional mammography. Conclusion The development of digital detectors for mammography has opened opportunities to use x-ray imaging to improve the ability to detect and diagnose breast cancer. DBT has taken decades to move from a concept to clinical care. It is still early in its development, yet it should help to increase the sensitivity and specificity of mammography. There is great hope for the development of new and improved therapies and ways to prevent breast cancer, but mammography is here and has been found to be decreasing deaths. DBT should be able to build on this major success. References 1. Pisano ED, Gatsonis C, Hendrick E, et al. Diagnostic performance of digital versus film mammography for breast-cancer screening. N Engl J Med 2005; 353:1773–1783 2. American Cancer Society. Cancer facts & figures 2013. Atlanta, GA: American Cancer Society, 2013 3. Smith RA, Duffy SW, Gabe R, Tabár L, Yen AM, Chen TH. The randomized trials of breast cancer screening: what have we learned? Radiol Clin North Am 2004; 42:793–806 4. Tabár L, Vitak B, Chen HH, Yen MF, Duffy SW, Smith RA. Beyond randomized controlled trials: organized mammographic screening substantially reduces breast carcinoma mortality. Cancer 2001; 91:1724–1731 5. Duffy SW, Tabar L, Chen H, et al. The impact of organized mammography service screening on breast carcinoma mortality in seven Swedish counties. Cancer 2002; 95:458–469 6. Otto SJ, Fracheboud J, Looman CW, et al. Initiation of population-based mammography screening in Dutch municipalities and effect on breastcancer mortality: a systematic review. Lancet 2003; 361:1411–1417 7. van Schoor G, Moss SM, Otten JD, et al. Increasingly strong reduction in breast cancer mortality

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