Breast Tomosynthesis

Breast Tomosynthesis Felix Diekmann, MD,* and Ulrich Bick, MD† Digital mammography has been well-evaluated for the diagnosis of breast cancer. The scientific data show that mammography alone, especially in dense breast parenchyma, has its weaknesses. These weaknesses are due to the low contrast of tumors in comparison with the surrounding parenchyma and the overlying structures that mask tumors. The initial results from tomosynthesis studies show a tendency for better imaging and higher accuracy and lower recall rates with tomosynthesis. We present in this article a literature review of the development of breast tomosynthesis and follow it with case examples. Semin Ultrasound CT MRI 32:281-287 © 2011 Elsevier Inc. All rights reserved.

What Is Tomosynthesis? The standard procedure for the early detection of breast cancer is mammography. Many studies have been performed to test this procedure under different conditions. Several studies show that at least when using mammography as a standalone procedure, the sensitivity of the technique is quite low, especially in dense breast tissue. This finding is true for both digital and film-screen mammography, although the sensitivity of digital mammography is slightly superior to that of film-screen mammography.1,2 A cause for this difference might be the “hiding” of the breast carcinomas because of the dense breast tissue. The dense breast tissue can mask the tumors by lying directly above and below the tumor in a two-dimensional (2-D) procedure. Another reason might be the low contrast of the tumors in comparison with the surrounding breast tissue. The problem of masking caused by overlying structures is at least partially solved by three-dimensional (3-D) procedures. In tomosynthesis, different angles of projection onto the object are used to create a 3-D impression of the object. There are many different technical approaches to obtaining this image. The most fundamental difference between tomosynthesis machines is the difference between slit-scan machines and flat-panel machines. In slitscan machines, both the gantry and the detector move continuously, whereas the gantry moves stepwise in flat-panel machines. Thus, the calculation of the tomosynthesis angle, the angle from which the different projections are done, is much more difficult in slit-scan machines compared with flat-panel machines. In addition, different flat-panel and slit*Department of Radiology, Charité Campus Virchow, Berlin, Germany. †Department of Radiology, Charité Campus Mitte, Berlin, Germany. Address reprint requests to Felix Diekmann, MD, Department of Radiology, Charité Campus Virchow, Augustenburger Platz 1, 13353 Berlin, Germany. E-mail: [email protected]

0887-2171/$-see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1053/j.sult.2011.03.002

scan machines have very different technical parameters. The fundamental techniques are described in several review papers,3 but the specifications of many parameters, including the exact number of projections, the dose, the tomosynthesis angle, and the postprocessing algorithms, are still a “work in progress” for most manufacturers. All tomosynthesis systems lack a true 3-D visualization of the breast with isotropic voxels, which can be achieved by using multislice computed tomography (CT). As is common in conventional tomographic procedures, there is a “smearing” of the objects through the different tomosynthesis slices. This smearing depends on the contrast, the size of the objects, the tomosynthesis angle, and the number of projections. The resolution in the third dimension (the depth of the breast), called the zresolution, is limited by this smearing effect. Some people prefer dedicated breast CT to breast tomosynthesis because of this limited z-resolution. On the other hand, one can clearly observe the depth of a tumor in a breast despite the limitations regarding the z-resolution in breast tomosynthesis because the tumor has the sharpest borders in the slice of the corresponding z-value. Thus, the masking of tumors because of overlying breast structures can be reduced by increased visibility of tumors in the image. In the future, the z-resolution of a system might be a quality-assurance parameter.

Development of Tomosynthesis: Literature Review Summary of Publications on Tomosynthesis The first highly recognized article regarding breast tomosynthesis was published by Niklason et al4 in 1997. This article was published very early in the development of the field (at least 1-2 years before digital mammography became widespread in clinical procedures), and it took quite a long time for many more articles regarding breast tomosynthesis to 281

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Rec./Phys. Clinic Future apps

1997 0

5

10

15

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Figure 1 Development of original articles in MEDLINE regarding breast tomosynthesis from 1997-2010. (Color version of figure is available online.)

appear. In 2006, more than 5 original articles dealing with breast tomosynthesis (there were more review articles before, but no clinical data) appeared in MEDLINE for the first time. The year 2010 marked the first time that there was a similar number of articles dealing with the clinical applications of breast tomosynthesis compared with basic physics articles on breast tomosynthesis. Fig. 1 shows the number of original articles regarding tomosynthesis in MEDLINE from 19972010. In total, there were only 87 articles taken into account for this analysis. Please note that this analysis is very subjective and only reveals tendencies; we apologize if we missed an article in compiling these data. Even in recent years, most published articles focus on the physics of tomosynthesis (especially compared with the number of clinical articles), indicating that the development of breast tomosynthesis is not yet finished. In fact, it is currently a rapidly changing procedure. This interpretation is also supported by the fact that only 1 system has been approved by the Food and Drug Administration. In addition, some large companies still describe their tomosynthesis products as works in progress and do not currently provide a commercially available tomosynthesis product. The technical changes can be seen from the types of physical articles and the ways in which they change over the years. For example, a simple shift-and-add algorithm was used in the very first articles. A few years later, postprocessing algorithms became much more complicated and more complex. Some companies use direct algebraic algorithms (like Hounsfield did in the very first CT trials), whereas others use the filtered-backprojection technique that is also widespread in CT imaging.3,5-7 The necessary number of projections, optimal filtering, and dose have also been investigated in several articles, especially more recently. In addition, there have been an increasing number of articles dealing with advanced applications of breast tomosynthesis since 2004. The combination of tomosynthesis with other procedures has been investigated by several groups. There is an increasing trend in the number of such articles with time. This trend could be caused by the fact that the sensitivity of mammography is limited not only by masking of tumors by dense breast tissue but also by the poor contrast of many tumors compared with the surrounding tissue. In addition, some authors claim that the overdiag-

nosis of screening mammography will not be overcome until more biological markers such as angiogenesis are taken into account, even for high-contrast objects such as ductal carcinoma in situ (DCIS) with microcalcifications. It is wellknown that many women with DCIS would never have realized that they have breast cancer if they had not taken part in screening. Prioritizing DCIS treatment will be a major task in the future, and the combination of morphology and an increased number of biological markers such as enhancement might play a key role in this effort. The poor contrast of many tumors compared with the surrounding breast tissue might be improved by the combination of tomography and additional procedures (eg, methods from nuclear medicine, contrast media, automatic ultrasound, optical procedures, and computer-assisted diagnosis [CAD]). Many articles show the feasibility of such combination procedures, but they include relatively few patients. Thus, it is not yet possible to predict the future direction of the trend for combination procedures. However, the publication of more articles regarding iodinecontaining contrast media than those of other combined modalities suggests that this procedure has a good chance of enhancing contrast in the future.

Breast Tomosynthesis: Published Clinical Articles Some studies regarding the accuracy of tomosynthesis in clinical use have been published. The number of clinical studies has increased during the past few years, as shown in Fig. 1. The clinical trials can be divided into trials with the tomosynthesis machines as add-ons to traditional digital mammography and those with the machines as stand-alone procedures as an alternative to digital mammography procedures.8-17 In general, these studies suggest that it might be useful to use breast tomosynthesis, but there is currently no proof that it is a diagnostic breakthrough. Table 1 shows some of the studies published during the last years. Note that many different machines and protocols were used in these studies, making it difficult to compare the results. A study by Gur et al16 suggested that recall rates might be reduced by the use of breast tomosynthesis. They did not find a statistically significant higher sensitivity from the use of tomography. Good et al15 also did not find any statistically significant advantages of breast tomosynthesis, but they attributed this result to the low number of patients included in their study. Similar to the study by Gur et al, Poplack et al14 did find a reduced recall rate from breast tomosynthesis. One must keep in mind for these results that recall rates vary dramatically between different screening programs; the relatively low recall rates given by the European screening guidelines are not true for every country, especially the United States. A study by Gong et al13 predicted a much higher area under the curve in their receiver operating characteristic evaluation of tomosynthesis, but they used a phantom setting. This situation is somewhat similar to that in the beginning of digital mammography in 1999, when several phantom studies predicted a breakthrough from digital mammography, but it took quite a while for the advantages of digital mam-

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Table 1 Results From Some Clinical Trials With Breast Tomosynthesis Versus 2-D Digital Mammography First Author

Year

n

Result

Poplack Good

2007 2008

98 30

Gur

2009

125

Teertstra Svahn Wallis (abstract only) Gennaro Fornvik

2010 2010 2010 2010 2010

513 50 130 200 62

Lower recall rate with tomography No significant advantage from tomography, probably because of low number of patients included Combination of tomography ⴙ DM reduces recall rates. Tomography alone has tendency to reduce recall rate. DM and tomography have similar sensitivity/specificity Tomography as an adjunct leads to significant improvements No significant differences between tomography in 2 views and DM in 2 views Tomography in 1 view not inferior to DM in 2 views Tomography superior to DM in assessment of tumor size and stage

DM, digital mammography.

mography to be proved. To the best of our knowledge, Teertstra et al12 have examined the largest population yet (n ⫽ 513), and they found similar sensitivity and specificity of tomosynthesis compared with 2-D digital mammography. This result is also somewhat reminiscent of the beginnings of digital mammography, when a study with nearly 50,000 women was necessary to prove the advantages of digital mammography over film-screen mammography. Teertstra et al reported the potential of tomosynthesis as an add-on to digital mammography. Svahn et al11 found a statistically significant advantage of tomosynthesis when combined with digital mammography of the contralateral side with 2 views. Stand-alone tomosynthesis did not reveal any statistically significant advantages compared with digital mammography in their study. Gennaro et al9 proved that breast tomosynthesis in 1 view is not inferior to digital mammography in 2 views, which allows a dose reduction. Fornvik et al8 did not report any advantages of breast tomosynthesis in the staging of tumors. However, they believe that the size of breast lesions can be estimated more accurately in breast tomosynthesis. Wallis et al18 did not see a significant difference in the area under the curve values in a receiver operating characteristic analysis of low-dose slit-scan tomosynthesis compared with 2-D digital mammography, both done in 2 views. Table 1 shows a short overview about most of the mentioned studies. The number of patients included in all studies was 1208. The studies were done with different machines, tomography angles, and settings for nearly all physical parameters. For example, the study from Wallis et al18 was performed with an extremely low dose by using a slit-scan tomography system with an extremely narrow tomography angle. Most studies were done with slightly higher doses for tomography compared with digital mammography.

Advanced Applications of Tomosynthesis As shown in Fig. 1, very early data were published for socalled advanced applications of breast tomosynthesis. Recently, there have been articles showing the feasibility of combining breast tomosynthesis with procedures from optical imaging. Another approach is to combine breast tomosynthesis with methods known from nuclear medicine.19,20 Articles showing the potential of combination of breast tomosynthesis with iodine-containing contrast media

are also very interesting.3,21 Adding contrast media to increase contrast is a well-known principle in radiology. Obviously, some groups believe that it is worth investigating the potential of iodine-containing contrast media in digital mammography and in breast tomosynthesis. One reason for this fact could be that breast tomosynthesis decreases the limitations of digital mammography regarding the masking of tumors from overlying structures, but the problem of the low contrast of tumors in comparison with surrounding tissue remains. This problem could be solved by contrast-enhanced breast tomosynthesis mammography (CETM) or, in an ideal world, the visualization of neoangiogenesis, possibly by optical imaging procedures. Fig. 2 shows an example of a CETM procedure. In this special case, we used a slit-scan tomosynthesis machine with a photon-counting detector that allows the use of the spectral imaging procedure, which is automatically combined with tomosynthesis in this prototype machine. The machine was built as part of a research project (http://www.highrex.eu). The k-edge of iodine (approximately 33.2 keV) was used for this procedure. The radiographic absorption of iodine is much lower below this k-edge and jumps to a higher level above 33.2 keV. Because the detector can split the radiograph spectra directly at the kedge of iodine, high-energy and low-energy images can be created directly from 1 scan. The advantage of this technique is that there are no movement artifacts because both images (low and high energy) are obtained from 1 scan and not 2 different exposures, as is done in other machines. These images can be recombined in another step to ensure that the iodine is seen in an optimal way in the images. If and how the dynamics of iodine enhancement (washout/wash-in are common cancer signs in MRI with contrast media) can be used for diagnostics have not yet been thoroughly evaluated. The initial results of 2-D imaging show that the overlying breast structures disturb the measurement of contrast media kinetics. In addition, the contrast medium enhancement seems to occur later in breast lesions with iodine compared with MRI with gadolinium-containing contrast medium. This phenomenon might be due to the higher contrast-medium volume necessary for imaging with iodine-containing contrast media.22,23 Fig. 2 shows an example of tomosynthesis done with 1.5 mL Ultravist 300 (ScheringBayer, Berlin, Germany) per kg body weight at a rate of 2 mL/second in which the

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Figure 2 Example of CETM. The image shows the original mammography, a 3-mm-thick slice from tomosynthesis before administration of the contrast medium, and the fusion image recombined from scan after administration of contrast medium. Note that the images on the right are from the same spectral imaging scan, so no movement artifacts are possible. The image was obtained with a prototype system from Sectra Mame, Stockholm, Sweden. (Color version of figure is available online.)

measurement was begun 120 seconds after the start of the infusion. Even without a contrast medium, the architectural distortion is seen slightly better in tomosynthesis compared with traditional digital mammography, but the tumor has a very low contrast compared with the surrounding tissue. After administration of the contrast medium, the high- and low-energy images were acquired in 1 scan, and a recombination of the images shows the tumor in its full extension. Another advanced application for tomosynthesis is CAD. It is quite logical that making diagnoses by using the large image volumes of tomosynthesis will take longer than 2-D mammography. In fact, Wallis et al18 have shown that reporting on tomosynthesis images takes much longer than 2-D mammography in the same patients (124.7 vs 70.5 seconds). With digital mammography, it is known that CAD systems have the potential to increase the possible workflow, but only if the systems are integrated quite well into the workflow. This setup might also decrease the time needed for compiling reports in breast tomosynthesis as well.24 In addition, the influence of CAD systems on the sensitivity and specificity of tomosynthesis must be examined. Because of the larger image volumes, this effect could be quite different from normal digital mammography, and especially in a screening situation, the influence could be much greater. Because interest in CAD and tomosynthesis is so obvious, some articles have been published evaluating CAD and tomosynthesis.25-28 In a very simple case, very similar algorithms were used compared with 2-D mammography on a reconstructed 2-D mammogram from the tomosynthesis stack. The advantage is that the well-known and well-tested algorithms from 2-D mammography can be used. The disadvantage is that information is lost in this procedure. How additional information from the 3-D procedure (eg, the spatial distribution of microcalcification clusters) might be used for CAD systems for tomosynthesis in the future is unclear, as is how CAD systems could influence the workflow for reading tomosynthesis images.

These issues must be evaluated in further studies. The acceptance of tomosynthesis in screening situations will likely be dependent on how well the larger data volumes of tomosynthesis can be handled in teleradiological settings and on the quality of the workflow.

Examples of Tomosynthesis Our experiences with tomosynthesis led us to believe that it helps solve problems for both benign and malignant lesions.

Malignant Lesions in Tomosynthesis In Fig. 3A, the mediolateral (ml) view in particular, architectural distortion is visible but not clear. The original craniocaudal (cc) and mediolateral oblique (mlo) views are quite normal. In Fig. 3B, there is a suspiciously enhanced area on the left side. If we look at the example from CETM (Fig. 2), we see the morphology and the enhancement from 1 procedure. If we look at the MRI scan, the morphologic information is inferior to the information given in tomosynthesis because of the much higher spatial resolution of CETM. Fig. 3C shows a tomosynthesis image without the contrast medium from the same patient as in Fig. 3A and B. The architectural distortion is much more obvious in the tomosynthesis image compared with that obtained by using 2-D mammography. On the other hand, the contrast of the tumor compared with the surrounding parenchyma is still not striking. If the tumor had no spicula, it might have been missed in this image. In this case, the combination of the information from a contrast medium procedure (MRI) and the morphologic information from tomosynthesis leaves no doubt about the diagnosis of breast cancer. The mass was biopsied stereotactically, and the diagnosis was confirmed. Even for the mammographically guided biopsy, the use of tomosynthesis

Breast tomosynthesis

Figure 3 (A) Digital mammogram of patient with relatively dense breast parenchyma of left side in 3 views (cc, ml, mlo). The pathologic changes that are visible in this mammogram are very difficult to see (zoomed area). (B) MRI of same patient with the slice taken from subtraction images 1 minute after administration of contrast medium, suspicious enhancement indicated with an arrow. (C) One-millimeter slice from tomosynthesis done without contrast medium by using Siemens Inspiration tomosynthesis, Erlangen, Germany.

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Figure 4 (A) Digital mammography. Two views (GE Essential) with no malignancy or suspicious lesion observed. (B) Digital mammography of both sides in 2 views (GE Essential), with focal asymmetric parenchyma indicated by arrow. (C) Spot compression of area of density and tomosynthesis slices from same area. (D) Maximum intensity projection of subtraction images from MRI.

Breast tomosynthesis was helpful because if it is done with the same positioning, one can estimate the depth of the lesion in the breast.

Tomosynthesis of a Benign Area Fig. 4A shows images of a patient with slightly asymmetric breast parenchyma. One can see a typical fibroadenoma calcification on the right side in the upper outer quadrant. This image was reported to be normal. The next routine follow-up examination of this patient was done two years later with the same mammography machine (GE Essential; GE Healthcare, St Giles, UK) under identical conditions but with a change in the postprocessing algorithm. In the follow-up images, a focal asymmetric parenchyma was reported (Fig. 4B). An additional spot compression was done (Fig. 4C, left image), which did not solve the problem; the dense area was visualized in a similar way. An additional tomosynthesis was performed. Some images from this tomosynthesis are seen in Fig. 4C. They do not show any suspicious areas, and the area looks more like normal breast parenchyma (Fig. 4C, right images). Combined with a very normal MRI scan (Fig. 4D), it was decided that a biopsy in this area was not necessary. One year after this decision, the patient did not show growth of that area in a follow-up examination and seems to be tumor-free.

Conclusions Digital mammography has been well-evaluated for the diagnosis of breast cancer. The scientific data show that mammography alone, especially in dense breast parenchyma, has its weaknesses. These weaknesses are due to the low contrast of tumors in comparison with the surrounding parenchyma and the overlying structures that mask tumors. The initial results from tomosynthesis studies show a tendency for better imaging and higher accuracy and lower recall rates with tomosynthesis. These findings are probably because overlying structures do not mask tumors in tomosynthesis the same way they do in 2-D mammography. To overcome the second limitation of mammography (the low contrast of tumors), combination procedures such as combining tomosynthesis with methods from nuclear medicine or with contrast media are promising tools. Which of these applications will find widespread use and what the role of tomosynthesis will be in comparison with other 3-D modalities such as MRI or dedicated breast CT depend on the results of further study.

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 353:1773-1783, 2005 2. Bick U, Diekmann F: Digital mammography: what do we and what don’t we know? Eur Radiol 17:1931-1942, 2007 3. Diekmann F, Bick U: Tomosynthesis and contrast-enhanced digital mammography: recent advances in digital mammography. Eur Radiol 17:3086-3092, 2007 4. Niklason LT, Christian BT, Niklason LE, et al: Digital tomosynthesis in breast imaging. Radiology 205:399-406, 1997 5. Wu T, Moore RH, Rafferty EA, et al: A comparison of reconstruction algorithms for breast tomosynthesis. Med Phys 31:2636-2647, 2004

287 6. Van de Sompel D, Brady SM, Boone J: Task-based performance analysis of FBP, SART and ML for digital breast tomosynthesis using signal CNR and Channelised Hotelling Observers. Med Image Anal 15:53-70, 2010 7. Bliznakova K, Kolitsi Z, Speller RD, et al: Evaluation of digital breast tomosynthesis reconstruction algorithms using synchrotron radiation in standard geometry. Med Phys 37:1893-1903, 2010 8. Fornvik D, Zackrisson S, Ljungberg O, et al: Breast tomosynthesis: accuracy of tumor measurement compared with digital mammography and ultrasonography. Acta Radiol 51:240-247, 2010 9. Gennaro G, Toledano A, di Maggio C, et al: Digital breast tomosynthesis versus digital mammography: a clinical performance study. Eur Radiol 20:1545-1553, 2010 10. Ho CP, Tromans C, Schnabel JA, et al: Classification of clusters of microcalcifications in digital breast tomosynthesis. Conf Proc IEEE Eng Med Biol Soc 1:3166-3169, 2010 11. Svahn T, Andersson I, Chakraborty D, et al: The diagnostic accuracy of dual-view digital mammography, single-view breast tomosynthesis and a dual-view combination of breast tomosynthesis and digital mammography in a free-response observer performance study. Radiat Prot Dosimetry 139:113-117, 2010 12. Teertstra HJ, Loo CE, van den Bosch MA, et al: Breast tomosynthesis in clinical practice: initial results. Eur Radiol 20:16-24, 2010 13. Gong X, Glick SJ, Liu B, et al: A computer simulation study comparing lesion detection accuracy with digital mammography, breast tomosynthesis, and cone-beam CT breast imaging. Med Phys 33:1041-1052, 2006 14. Poplack SP, Tosteson TD, Kogel CA, et al: Digital breast tomosynthesis: initial experience in 98 women with abnormal digital screening mammography. AJR Am J Roentgenol 189:616-623, 2007 15. Good WF, Abrams GS, Catullo VJ, et al: Digital breast tomosynthesis: a pilot observer study. AJR Am J Roentgenol 190:865-869, 2008 16. Gur D, Abrams GS, Chough DM, et al: Digital breast tomosynthesis: observer performance study. AJR Am J Roentgenol 193:586-591, 2009 17. Michell M, Wasan R, Whelehan P, et al: Digital breast tomosynthesis: a comparison of the accuracy of digital breast tomosynthesis, two-dimensional digital mammography and two-dimensional screening mammography (film-screen). Breast Cancer Res 11(Suppl 2):O1, 2009 18. Wallis MG, Moa E, Zanca F, et al: Comparing diagnostic accuracy of full field digital mammography and photon counting tomosynthesis: a multireader, multicentre observer study. Available at: http:// rsna2010.rsna.org/search/search.cfm?action⫽add&filter⫽Author& value⫽85702. Accessed February 2, 2011 19. Fang Q, Selb J, Carp SA, et al: Combined optical and x-ray tomosynthesis breast imaging. Radiology 20. Williams MB, Judy PG, Gunn S, et al: Dual-modality breast tomosynthesis. Radiology 255:191-198, 2010 21. Carton AK, Gavenonis SC, Currivan JA, et al: Dual-energy contrastenhanced digital breast tomosynthesis: a feasibility study. Br J Radiol 83:344-350, 2010 22. Diekmann F, Freyer M, Diekmann S, et al: Evaluation of contrastenhanced digital mammography. Eur J Radiol 2009 Nov 18 (Epub ahead of print) 23. Diekmann F, Diekmann S, Jeunehomme F, et al: Digital mammography using iodine-based contrast media: initial clinical experience with dynamic contrast medium enhancement. Invest Radiol 40:397-404, 2005 24. Diekmann F, Diekmann S, Bollow M, et al: Evaluation of a wavelet-based computer-assisted detection system for identifying microcalcifications in digital full-field mammography. Acta Radiol 45:136-141, 2004 25. Chan HP: Computer-aided diagnosis in breast tomosynthesis and chest CT. Nippon Hoshasen Gijutsu Gakkai Zasshi 65:968-976, 2009 26. Chan HP, Wei J, Sahiner B, et al: Computer-aided detection system for breast masses on digital tomosynthesis mammograms: preliminary experience. Radiology 237:1075-1080, 2005 27. Chan HP, Wei J, Zhang Y, et al: Computer-aided detection of masses in digital tomosynthesis mammography: comparison of three approaches. Med Phys 35:4087-4095, 2008 28. Singh S, Tourassi GD, Baker JA, et al: Automated breast mass detection in 3D reconstructed tomosynthesis volumes: a featureless approach. Med Phys 35:3626-3636, 2008