- Email: [email protected]
Grating-based darkfield imaging of human breast tissue
ORIGINALARBEIT
Grating-based darkfield imaging of human breast tissue Gisela Anton 1 , Florian Bayer 1 , Matthias W. Beckmann 3 , Jürgen Durst 1 , Peter A. Fasching 3,6 , Wilhelm Haas 2 , Arndt Hartmann 4 , Thilo Michel 1 , Georg Pelzer 1 , Marcus Radicke 7 , Claudia Rauh 3 , Jens Rieger 1 , André Ritter 1 , Rüdiger Schulz-Wendtland 5 , Michael Uder 5 , David L. Wachter 4 , Thomas Weber 1,∗ , Evelyn Wenkel 5 , Lukas Wucherer 1 1
Erlangen Centre for Astroparticle Physics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erwin-Rommel-Str. 1, 91058 Erlangen, Germany 2 Pattern Recognition Lab, Friedrich-Alexander-Universität Erlangen-Nürnberg, Martensstr. 3, 91058 Erlangen, Germany 3 Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander-Universität ErlangenNürnberg, Universitätsstr. 21-23, 91054 Erlangen, Germany 4 Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Krankenhausstr. 12, 91054 Erlangen, Germany 5 Institute of Diagnostic Radiology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Maximiliansplatz 2, 91054 Erlangen, Germany 6 David Geffen School of Medicine, Devision Hematology/Oncology, University of California at Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA, USA 7 Siemens AG Healthcare Sector, Henkestr. 127, 91052 Erlangen, Germany Received 3 September 2012; accepted 10 January 2013
Abstract Mastectomy specimens were investigated using a TalbotLau X-ray imaging set-up. Significant structures in the darkfield were observed, which revealed considerably higher contrast than those observed in digital mammography. Comparison with the histomorphometric image proofs that the darkfield signal correlates with a tumor region containing small calcification grains of 3 to 30 m size.
Keywords: X-ray imaging, darkfield imaging, Talbot-Lau, mammography, breast cancer, microcalcification
Gitterbasierte Dunkelfeldbildgebung von Brustgewebe Zusammenfassung Es wurden Mastektomieproben mit Hilfe eines TalbotLau-Röntgenaufbaus untersucht, wobei Strukturen im Dunkelfeldbild auftraten, die einen deutlich höheren Kontrast aufwiesen, als er in einem konventionellen, digitalen Mammographiebild beobachtet werden konnte. Durch den Vergleich mit histomorphometrischen Bildern konnte nachgewiesen werden, dass das beobachtete Dunkelfeldsignal mit einer Tumorregion korreliert ist, die Kalzifikationen der Größe 3 bis 30 m enthält. Schlüsselwörter: Röntgenbildgebung, Dunkelfeldbildgebung, Talbot-Lau, Mammographie, Brustkrebs, Mikrokalzifikation
∗ Corresponding author: Thomas Weber, Erlangen Centre for Astroparticle Physics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erwin-RommelStr. 1, 91058 Erlangen, Germany. E-mail: [email protected] (T. Weber).
Z. Med. Phys. 23 (2013) 228–235 http://dx.doi.org/10.1016/j.zemedi.2013.01.001 http://journals.elsevier.de/zemedi
G. Anton et al. / Z. Med. Phys. 23 (2013) 228–235
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1 Introduction
2 Materials and Methods
Breast cancer is the leading cause for cancer deaths in women with about 458.000 deaths worldwide per year [1]. A diagnosis in early stages is one of the most important determinants of prognosis. Standard diagnostic methods comprise clinical examination and imaging with mammography, ultrasound and magnetic resonance imaging (MRI). Quite often palpation gives the first indication of a malignant disease. The sensitivity and the specificity of the imaging methods is known to be dependent on several factors, such as tumor size for solid lesions, the presence of microcalcifications and the contrast to the surrounding breast tissue. Especially in women with a high mammographic density and a subsequent low contrast between tumor and surrounding tissue, the incidence of breast cancer is higher, as mammographic density is one of the most important risk factors for breast cancer [2]. Microcalcifications are of special importance, because they often indicate early stages of breast cancer. Therefore an improvement of diagnostic accuracy concerning microcalcifications would lead to an earlier detection of breast cancer. Microcalcifications are usually visible in standard X-ray images when the size of the calcifications exceeds about 100 m. Effectively, calcifications are clearly visible from a size exceeding 500 m. The concordance between radiological findings of microcalcifications and histopathological correlates is quite high with about 90 to 95 % [3]. Some methods have been considered to improve the diagnostic accuracy concerning microcalcifications. Breast computed tomography might yield a further improvement of the spatial resolution [4]. However recently, several groups worldwide have performed investigations on phase-contrast X-ray imaging of breast tissue [5–8]. The grating-based Talbot-Lau method [9] delivers three kinds of images at the same time: absorption image, differential phase image and darkfield image. Absorption is sensitive to a combination of material electron density and material nuclear charge, the phase is sensitive to the electron density of the material and the darkfield is sensitive to small angle scattering ability of the material [10–15]. We employed a grating-based Talbot-Lau system for further investigation of breast imaging with this new method. While other groups especially address the sensitivity of the differential phase image [5], our work is focussed on the sensitivity of the darkfield to the contrast between microcalcifications and healthy tissue. We expect that microcalcifications lead to a darkfield signal because small calcifications grains embedded in a surrounding soft tissue cause small angle deflections of X-rays. Such deflections deteriorate the regularity of the wave front and thus induce a darkfield signal [16–22]. Endo et al. [7] have already observed a correlation of microcalcifications with darkfield signal for small mastectomy samples embedded in formalin suspension. We wanted to investigate whether such calcifications are still visible in freshly dissected breast material.
A grating-based Talbot-Lau X-ray imaging system with 25 keV design energy was set-up at the Erlangen Centre for Astroparticle Physics, Friedrich-Alexander-Universität Erlangen-Nürnberg [23]. This work was carried out in collaboration with the Karlsruhe Institute of Technology (KIT) and the company Siemens Healthcare. It was funded by the German Federal Ministry of Education and Research (BMBF) [24]. The system contained an X-ray tube Siemens MEGALIX Cat Plus 125/40/90 - 122 GW with a focus size of 0.41 operated at a current of 50 mA and a peak voltage of 40 kV. The grating G0 with a period of 24.39 m was positioned 16.6 cm downstream the tube. The π-phaseshifting grid G1 with period 4.37 m was positioned at a distance of 177.7 cm from the tube. Grating G2 was made from gold with a period of 2.4 m and a thickness of 100 m. It was positioned in the third fractional Talbot distance. The flat panel detector of type Varian PaxScan 2520D with 127 m pixel size was placed 50 cm behind G2. The specimens were positioned upstream in front of G1. In order to sample the Talbot intensity pattern, the grating G2 was shifted laterally by 8 steps with a step size of 0.6 m, i.e 8 phase steps covering two full fringe periods. For each pixel the measured intensity I as a function of the G2-position x is approximated by I(x) = a + b sin(kx + ). This function is determined with (1) and without (0) the object in the beam. The absorption is calculated as A = a1 /a0 , the differential phase shift as = 1 − 0 , the visibility as b0 /a0 respectively b1 /a1 and the darkfield as one minus the ratio of visibility with and without object: D = 1 − b1 /b0 · a0 /a1 . The size of the gratings was 2 × 6 cm2 . The image of the full breast was thus obtained by multiple acquisitions which were stitched together. The exposure time for one single acquisition was 52 s resulting in an air kerma of 4.7 mGy measured at the object position. The set-up was adjusted such that the average visibility b0 /a0 was 0.20. High visibility is an important prerequisite for image quality because the contrast-to-noise ratio for phase and darkfield signatures of an object is proportional to the visibility squared [25,26]. Six breast specimens with histologically verified breast cancers from six different patients were imaged by the new method. Patients were eligible for this study, if they had an invasive breast cancer, which was diagnosed histologically after core needle biopsy and who had an indication for surgical removal of the tumor either by mastectomy or breast conserving surgery. This study was approved by the ethics committee of the University Hospital Erlangen, medical faculty, Friedrich-Alexander-Universität Erlangen-Nürnberg and written informed consent was obtained from the patients.
1 Measurement as described in IEC60336, but at 40 kV/50 mA. The tube has a nominal focal spot value of 0.4 with respect to IEC 60336:2005.
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Figure 1. Photograph of the mastectomy specimen.
One of the analyzed specimens is a complete mastectomy specimen of 3 cm thickness (anterior-posterior), the other five specimens represent breast segment resections with an approximated volume of 3 × 5 ×1 cm3 each. All specimens contain a tumor which is visible as a region of high density in the digital radiographic image. All specimens show a high darkfield signal in the tumor region. Before surgery, digital mammographic images of the patients were taken on a Mammomat Inspiration, Siemens, Erlangen, Germany. The Mammomat takes tomographic data from which slices of the object can be reconstructed similar to CT X-ray images [27]. In addition, MRI images on a 3.0 T Siemens Magnetom, Verio, Erlangen, Germany were taken. After resection, the specimen underwent X-ray mammography (Mammomat Inspiration, Siemens, Erlangen, Germany) and the Talbot-Lau system. Further, the specimens were analyzed by complete histopathological examination.
3 Results In the following we exemplary explain our results for the full breast mastectomy specimen. Preoperative diagnostics by breast tomosynthesis2 (Fig. 2) and MRI (Fig. 3) revealed a maximum tumor diameter of 67 mm in tomosynthesis and 60 mm in MRI. The preoperative core biopsy identified an invasive ductal carcinoma with microcalcifications. A photograph (Fig. 1) of the specimen, a tomosynthesis image (Fig. 4) and the Talbot-Lau images (Fig. 5) of the resected breast were
2 Breast tomosynthesis with Siemens Mammomat Inspiration is an investigational practice and is limited by U.S. law to investigational use. It is
Figure 2. Tomosynthesis slice of the right breast of the patient in medio-lateral oblique projection. The tumor measures about 67 mm. A spiculated lesion can be delineated (white arrows) which corresponds to the breast cancer. The arrowhead points at a non suspicious macrocalcification. An area of fine microcalcifications can be suspected on high resolution viewing monitors (white circle). The white scalebar indicates a length of 15 mm.
taken within two hours after surgery. An optical image of the histological section in the region of the tumor is shown in Fig. 6. The Talbot-Lau absorption image (Fig. 5 top) delivers lower resolution than the radiographic tomosynthesis image (Fig. 4) due to the relatively large physical pixel size of 127 m of the detector used in the Talbot-Lau set-up compared to a physical pixel size of 85 m used in the tomosynthesis set-up. From visual inspection of the tomosynthesis image the specimen shows a spiculated mass lesion. Microcalcifications in an area of 1 cm diameter are suspected. The Talbot-Lau absorption image also shows the tumor with similar tumor shape as in the tomosynthesis. The differential phase image (Fig. 5 middle) seems not to contain useful information in the tumor region. Contrary, the darkfield image (Fig. 5 bottom) provides a rather high contrast in the tumor region in which microcalcifications are suspected from the tomosynthesis slice, see Figure 4.
not commercially available in the U.S. and its future availability cannot be ensured
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Figure 3. T1 weighted magnetic resonance image, after intravenous contrast agent application in axial projection (slice thickness 1.5 mm). Representative image of the spiculated mass lesion (white arrows) in the right breast with inhomogeneous contrast enhancement and a maximum extension of about 60 × 51 × 59 mm. The lesion corresponds to the patient’s breast cancer. Asterisk and black line around the tumor indicate artifacts due to patient movement. Image orientation in relation to the patient A = anterior, M = medial, L = lateral. The white scalebar indicates a length of 15 mm.
A possible reason for a darkfield signal in mammography has been assigned to calcification [6]. Indeed, histologically numerous calcification grains with size varying from 3 to 30 m diameter (Fig. 6 right) were seen in the centre of the tumor region. These rather small grains are not resolvable in the X-ray absorption image because their size is much smaller than the pixel size. Their contribution to absorption is almost negligible but their influence on the wave front of the X-ray wave field is notable in the darkfield. The noise in the darkfield is considerably higher than in the absorption image. Of importance, the visibility of the calcified tumor region is not restricted by noise but by contrast: the calcified tumor region delivers darkfield values which significantly exceed the darkfield values occurring in the rest of the breast tissue. This is not the case for the absorption image, where the calcified tumor region does not produce enhanced intensity. In order to achieve quantitative information, the regions as defined in Figure 9 are used to determine the contrast3 of the calcified tumor region (yellow box) compared to non-tumor
3
contrast is defined according to Weber as (Signalobj /Signalref ) − 1
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Figure 4. Tomosynthesis slice of the mastectomy specimen: The mass lesion corresponds to the patient’s breast cancer. Its extension including the spiculations is about 87 × 67 mm. White arrows: suspected extent of the carcinoma. White circle: Area where microcalcifications are suspected. Arrowheads: non suspicious microcalcifications. The white scalebar indicates a length of 15 mm.
region (blue box). The absorption image contains an averaged intensity of 1.117 ± 0.001 in the yellow box and 0.992 ± 0.001 in the blue box resulting in a contrast of 0.126 ± 0.002. The referring values for the darkfield are 0.396 ± 0.002 and 0.172 ± 0.001 resulting in a contrast of 1.306 ± 0.024. Thus, the darkfield shows a clear enhancement of signal at the position of the tumor. Further, the size of the darkfield signal region coincides well with the size of the calcified region in the histological image. Obviously, the darkfield provides high sensitivity and strong correlation with the region containing tiny calcification grains. In order to test our assumption that calcification grains induce signals in the darkfield image we prepared a phantom with lime powder embedded in gelatine with a total thickness of 3 cm. Two classes of grain size were taken which should represent the type of calcifications which have been observed in breast samples. The one class consisted of grains respectively platelets of the order of 1 mm in diameter and the other class contained grains of the order of 10 micrometers in diameter. The number density of the calcification grains were similar to those observed in the histological image. Figure 8 shows the absorption image and the darkfield image of the phantom taken in our Talbot-Lau set-up. These images prove the validity of our assumption that the micrometer-size grains produce a strong darkfield signal while almost no signal occurs in the absorption image.
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Figure 7. Absorption image taken with the Talbot-Lau set-up. The regions of interest for different investigations are marked by frames. The white scalebar indicates a length of 15 mm.
in Figure 10. The absorption values of the 8 pixels in a row have been averaged and the resulting absorption is plotted versus position, see Figure 10. In the same ROI the darkfield values of 8 pixels in a row have been averaged and plotted versus position. While these calcifications are clearly visible in both images the contrast in the darkfield (1.21 ± 0.04) is much higher than in the absorption image (0.161 ± 0.001). We calculated the contrast of microcalcifications in all specimens, see Table 1. Obviously, for all specimens the darkfield contrast is considerable higher than the absorption contrast.
4 Discussion Figure 5. Images of the mastectomy specimen taken with the TalbotLau set-up: absorption image A = − ln(a1 /a0 ) (top), differential phase image = 1 − 0 (middle), darkfield image D = 1 − b1 /b0 · a0 /a1 (bottom); the white scalebar indicates a length of 15 mm; the colorbars show the greyscale of the images.
A further region of the specimen - marked by frame 2 in Figure 7 - has been investigated. This region contains microcalcifications of about a millimeter size. Figure 10 shows a line profile running through one of the calcifications. Such a line profile has been determined in the red marked region
Darkfield images of breast taken with a Talbot-Lau setup have been reported by Endo et al. [7]. There, formalin fixed mastectomy slices of limited thickness 6.6 mm have been investigated. The images of the presented specimen show a high contrast for calcification clusters in the visibility-contrast image which were not visible in the absorption image. The advantage of small slices is that the visibility of the calcifications is enhanced compared to the image of the full breast. This enhancement is not only given for the absorption image, but also for the phase and the darkfield image. Accordingly, for application in mammography the advantage of the new
Figure 6. Histological image of the tumor region (H&E stains) marked by the circle in figure 4: low resolution (left), high resolution (right); microcalcifications are visible as dark spots (arrow) in the high resolution image (right); in the left image the red lines indicate the diameter of the region containing calcification grains.
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Figure 8. Absorption A = − ln(a1 /a0 ) (left) and darkfield D = 1 − b1 /b0 · a0 /a1 (right) image of a phantom consisting of several areas with lime powder with different grain sizes. The vertical artifacts in the image are an effect of the stiching process of several acquisitions. The white scalebar indicates a length of 10 mm; the colorbars show the greyscale of the images. Table 1 Measured contrast of microcalcifications to healthy tissue of breast specimens; darkfield and absorption contrast are determined with the Talbot-Lau set-up, mammography contrast is obtained from projective X-ray images taken with Siemens Mammomat Inspiration; specimen 6 is the full breast mastectomy. specimen
darkfield contrast
absorption contrast
mammography contrast
1 2 3 4 5 6
1.16 ± 0.11 0.57 ± 0.11 1.89 ± 0.27 0.96 ± 0.10 0.66 ± 0.07 1.21 ± 0.04
0.098 ± 0.005 0.054 ± 0.006 0.230 ± 0.016 0.019 ± 0.003 0.018 ± 0.002 0.161 ± 0.001
0.302 ± 0.020 0.250 ± 0.035 no data 0.058 ± 0.013 0.058 ± 0.006 0.395 ± 0.018
imaging modalities of phase and darkfield images should be proven for complete breasts. Stampanoni et al. [5] have published Talbot-Lau images of fresh native breast tissue. The authors put their focus on the differential phase information. They further combine the information from the three images into a color-coded
composite image. They prove that additional information on the tumor is achieved by this method. They do not investigate the contrast of the tumor in the single images. In their presented images absorption seems to provide the highest contrast. No prominent signals occur in the darkfield image. This is in contradiction to the results published by Endo et al. [7] as well as to our results. The non-occurance of darkfield signatures in the images of Stampanoni et al. might be due to differences in the biology of the samples. In the journal publications available for an analysis up to know only a small number of samples have been investigated so that the occurrence or non-occurrence of darkfield signals might be due to fluctuations in the selection of samples. In order to avoid the dependence on fluctuations we conclude that it is very important to correlate structures in the images with histological observations. In this work we present images of a freshly resected complete breast with a maximum thickness of 3 cm. We employed a Talbot-Lau set-up with high visibility of the Talbot intensity pattern delivering high contrast for the darkfield. For a complete breast we thus achieved - for the first time - a
Figure 9. Regions for the determination of the contrast marked in the absorption (left) as well as in the darkfield image (right); yellow: calcified tumor region, blue: outside the tumor region. The regions are at the same positions in both images. The arrowhead points at a non suspicious macrocalcification. The white scalebar indicates a length of 5 mm. The images refer to frame 1 marked in Fig. 7.
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Figure 10. Quantitative analysis of the ROI defined by frame 2 in Fig. 7. Top left: absorption image; top right: darkfield image; bottom left: line profile along the red marked band in the top left image; bottom right: line profile along the red marked band in the top right image; The white scale bar indicates a length of 5 mm.
microcalcification to healthy tissue contrast which is larger for the darkfield than for the absorption signal by a factor of 10. No compression of the breast has been applied. For the first time, we obtained such good results with a dose comparable to that applied in conventional mammography [28]. Our results indicate that the visibility of a calcified breast tumor is not restricted by noise but by contrast. With the todays given size of gratings only a small field of view can be imaged. Imaging a whole breast would take some minutes of time and some additional dose might be necessary due to the needed overlap of single pictures which have to be stiched together. But with the development of larger grids this problem will disappear completely. As the calcification grains have a considerably different refractive index compared to the surrounding tissue they seem to be the source of the darkfield signal. Due to the large distance between grains the overall density of calcified tissue is only weakly enhanced resulting in a low contrast of this tumor region in the absorption image.
5 Conclusion The results presented in this publication allow the conclusion that darkfield mammography (in vivo) will deliver
valuable image information that can surpass the contrast of normal absorption images. The applied dose would be comparable to the conventional mammography dose while three images are achieved instead of one. The darkfield image will especially provide high sensitivity to calcified breast tumors while the size of the calcification grains may be much smaller than the pixel pitch of the detector. As numerous benign breast lesions also can show microcalcification diagnostic interpretation of such small calcification grains has still to be investigated.
Acknowledgements This work was supported by the German Federal Ministry of Education and Research (BMBF) within the PHACT project. Additionally, the authors want to thank the Karlsruhe Institue of Technology (KIT) for the production of the used gratings.
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Available online at www.sciencedirect.com
Grating-based darkfield imaging of human breast tissue Gisela Anton 1 , Florian Bayer 1 , Matthias W. Beckmann 3 , Jürgen Durst 1 , Peter A. Fasching 3,6 , Wilhelm Haas 2 , Arndt Hartmann 4 , Thilo Michel 1 , Georg Pelzer 1 , Marcus Radicke 7 , Claudia Rauh 3 , Jens Rieger 1 , André Ritter 1 , Rüdiger Schulz-Wendtland 5 , Michael Uder 5 , David L. Wachter 4 , Thomas Weber 1,∗ , Evelyn Wenkel 5 , Lukas Wucherer 1 1
Erlangen Centre for Astroparticle Physics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erwin-Rommel-Str. 1, 91058 Erlangen, Germany 2 Pattern Recognition Lab, Friedrich-Alexander-Universität Erlangen-Nürnberg, Martensstr. 3, 91058 Erlangen, Germany 3 Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander-Universität ErlangenNürnberg, Universitätsstr. 21-23, 91054 Erlangen, Germany 4 Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Krankenhausstr. 12, 91054 Erlangen, Germany 5 Institute of Diagnostic Radiology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Maximiliansplatz 2, 91054 Erlangen, Germany 6 David Geffen School of Medicine, Devision Hematology/Oncology, University of California at Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA, USA 7 Siemens AG Healthcare Sector, Henkestr. 127, 91052 Erlangen, Germany Received 3 September 2012; accepted 10 January 2013
Abstract Mastectomy specimens were investigated using a TalbotLau X-ray imaging set-up. Significant structures in the darkfield were observed, which revealed considerably higher contrast than those observed in digital mammography. Comparison with the histomorphometric image proofs that the darkfield signal correlates with a tumor region containing small calcification grains of 3 to 30 m size.
Keywords: X-ray imaging, darkfield imaging, Talbot-Lau, mammography, breast cancer, microcalcification
Gitterbasierte Dunkelfeldbildgebung von Brustgewebe Zusammenfassung Es wurden Mastektomieproben mit Hilfe eines TalbotLau-Röntgenaufbaus untersucht, wobei Strukturen im Dunkelfeldbild auftraten, die einen deutlich höheren Kontrast aufwiesen, als er in einem konventionellen, digitalen Mammographiebild beobachtet werden konnte. Durch den Vergleich mit histomorphometrischen Bildern konnte nachgewiesen werden, dass das beobachtete Dunkelfeldsignal mit einer Tumorregion korreliert ist, die Kalzifikationen der Größe 3 bis 30 m enthält. Schlüsselwörter: Röntgenbildgebung, Dunkelfeldbildgebung, Talbot-Lau, Mammographie, Brustkrebs, Mikrokalzifikation
∗ Corresponding author: Thomas Weber, Erlangen Centre for Astroparticle Physics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erwin-RommelStr. 1, 91058 Erlangen, Germany. E-mail: [email protected] (T. Weber).
Z. Med. Phys. 23 (2013) 228–235 http://dx.doi.org/10.1016/j.zemedi.2013.01.001 http://journals.elsevier.de/zemedi
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1 Introduction
2 Materials and Methods
Breast cancer is the leading cause for cancer deaths in women with about 458.000 deaths worldwide per year [1]. A diagnosis in early stages is one of the most important determinants of prognosis. Standard diagnostic methods comprise clinical examination and imaging with mammography, ultrasound and magnetic resonance imaging (MRI). Quite often palpation gives the first indication of a malignant disease. The sensitivity and the specificity of the imaging methods is known to be dependent on several factors, such as tumor size for solid lesions, the presence of microcalcifications and the contrast to the surrounding breast tissue. Especially in women with a high mammographic density and a subsequent low contrast between tumor and surrounding tissue, the incidence of breast cancer is higher, as mammographic density is one of the most important risk factors for breast cancer [2]. Microcalcifications are of special importance, because they often indicate early stages of breast cancer. Therefore an improvement of diagnostic accuracy concerning microcalcifications would lead to an earlier detection of breast cancer. Microcalcifications are usually visible in standard X-ray images when the size of the calcifications exceeds about 100 m. Effectively, calcifications are clearly visible from a size exceeding 500 m. The concordance between radiological findings of microcalcifications and histopathological correlates is quite high with about 90 to 95 % [3]. Some methods have been considered to improve the diagnostic accuracy concerning microcalcifications. Breast computed tomography might yield a further improvement of the spatial resolution [4]. However recently, several groups worldwide have performed investigations on phase-contrast X-ray imaging of breast tissue [5–8]. The grating-based Talbot-Lau method [9] delivers three kinds of images at the same time: absorption image, differential phase image and darkfield image. Absorption is sensitive to a combination of material electron density and material nuclear charge, the phase is sensitive to the electron density of the material and the darkfield is sensitive to small angle scattering ability of the material [10–15]. We employed a grating-based Talbot-Lau system for further investigation of breast imaging with this new method. While other groups especially address the sensitivity of the differential phase image [5], our work is focussed on the sensitivity of the darkfield to the contrast between microcalcifications and healthy tissue. We expect that microcalcifications lead to a darkfield signal because small calcifications grains embedded in a surrounding soft tissue cause small angle deflections of X-rays. Such deflections deteriorate the regularity of the wave front and thus induce a darkfield signal [16–22]. Endo et al. [7] have already observed a correlation of microcalcifications with darkfield signal for small mastectomy samples embedded in formalin suspension. We wanted to investigate whether such calcifications are still visible in freshly dissected breast material.
A grating-based Talbot-Lau X-ray imaging system with 25 keV design energy was set-up at the Erlangen Centre for Astroparticle Physics, Friedrich-Alexander-Universität Erlangen-Nürnberg [23]. This work was carried out in collaboration with the Karlsruhe Institute of Technology (KIT) and the company Siemens Healthcare. It was funded by the German Federal Ministry of Education and Research (BMBF) [24]. The system contained an X-ray tube Siemens MEGALIX Cat Plus 125/40/90 - 122 GW with a focus size of 0.41 operated at a current of 50 mA and a peak voltage of 40 kV. The grating G0 with a period of 24.39 m was positioned 16.6 cm downstream the tube. The π-phaseshifting grid G1 with period 4.37 m was positioned at a distance of 177.7 cm from the tube. Grating G2 was made from gold with a period of 2.4 m and a thickness of 100 m. It was positioned in the third fractional Talbot distance. The flat panel detector of type Varian PaxScan 2520D with 127 m pixel size was placed 50 cm behind G2. The specimens were positioned upstream in front of G1. In order to sample the Talbot intensity pattern, the grating G2 was shifted laterally by 8 steps with a step size of 0.6 m, i.e 8 phase steps covering two full fringe periods. For each pixel the measured intensity I as a function of the G2-position x is approximated by I(x) = a + b sin(kx + ). This function is determined with (1) and without (0) the object in the beam. The absorption is calculated as A = a1 /a0 , the differential phase shift as = 1 − 0 , the visibility as b0 /a0 respectively b1 /a1 and the darkfield as one minus the ratio of visibility with and without object: D = 1 − b1 /b0 · a0 /a1 . The size of the gratings was 2 × 6 cm2 . The image of the full breast was thus obtained by multiple acquisitions which were stitched together. The exposure time for one single acquisition was 52 s resulting in an air kerma of 4.7 mGy measured at the object position. The set-up was adjusted such that the average visibility b0 /a0 was 0.20. High visibility is an important prerequisite for image quality because the contrast-to-noise ratio for phase and darkfield signatures of an object is proportional to the visibility squared [25,26]. Six breast specimens with histologically verified breast cancers from six different patients were imaged by the new method. Patients were eligible for this study, if they had an invasive breast cancer, which was diagnosed histologically after core needle biopsy and who had an indication for surgical removal of the tumor either by mastectomy or breast conserving surgery. This study was approved by the ethics committee of the University Hospital Erlangen, medical faculty, Friedrich-Alexander-Universität Erlangen-Nürnberg and written informed consent was obtained from the patients.
1 Measurement as described in IEC60336, but at 40 kV/50 mA. The tube has a nominal focal spot value of 0.4 with respect to IEC 60336:2005.
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Figure 1. Photograph of the mastectomy specimen.
One of the analyzed specimens is a complete mastectomy specimen of 3 cm thickness (anterior-posterior), the other five specimens represent breast segment resections with an approximated volume of 3 × 5 ×1 cm3 each. All specimens contain a tumor which is visible as a region of high density in the digital radiographic image. All specimens show a high darkfield signal in the tumor region. Before surgery, digital mammographic images of the patients were taken on a Mammomat Inspiration, Siemens, Erlangen, Germany. The Mammomat takes tomographic data from which slices of the object can be reconstructed similar to CT X-ray images [27]. In addition, MRI images on a 3.0 T Siemens Magnetom, Verio, Erlangen, Germany were taken. After resection, the specimen underwent X-ray mammography (Mammomat Inspiration, Siemens, Erlangen, Germany) and the Talbot-Lau system. Further, the specimens were analyzed by complete histopathological examination.
3 Results In the following we exemplary explain our results for the full breast mastectomy specimen. Preoperative diagnostics by breast tomosynthesis2 (Fig. 2) and MRI (Fig. 3) revealed a maximum tumor diameter of 67 mm in tomosynthesis and 60 mm in MRI. The preoperative core biopsy identified an invasive ductal carcinoma with microcalcifications. A photograph (Fig. 1) of the specimen, a tomosynthesis image (Fig. 4) and the Talbot-Lau images (Fig. 5) of the resected breast were
2 Breast tomosynthesis with Siemens Mammomat Inspiration is an investigational practice and is limited by U.S. law to investigational use. It is
Figure 2. Tomosynthesis slice of the right breast of the patient in medio-lateral oblique projection. The tumor measures about 67 mm. A spiculated lesion can be delineated (white arrows) which corresponds to the breast cancer. The arrowhead points at a non suspicious macrocalcification. An area of fine microcalcifications can be suspected on high resolution viewing monitors (white circle). The white scalebar indicates a length of 15 mm.
taken within two hours after surgery. An optical image of the histological section in the region of the tumor is shown in Fig. 6. The Talbot-Lau absorption image (Fig. 5 top) delivers lower resolution than the radiographic tomosynthesis image (Fig. 4) due to the relatively large physical pixel size of 127 m of the detector used in the Talbot-Lau set-up compared to a physical pixel size of 85 m used in the tomosynthesis set-up. From visual inspection of the tomosynthesis image the specimen shows a spiculated mass lesion. Microcalcifications in an area of 1 cm diameter are suspected. The Talbot-Lau absorption image also shows the tumor with similar tumor shape as in the tomosynthesis. The differential phase image (Fig. 5 middle) seems not to contain useful information in the tumor region. Contrary, the darkfield image (Fig. 5 bottom) provides a rather high contrast in the tumor region in which microcalcifications are suspected from the tomosynthesis slice, see Figure 4.
not commercially available in the U.S. and its future availability cannot be ensured
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Figure 3. T1 weighted magnetic resonance image, after intravenous contrast agent application in axial projection (slice thickness 1.5 mm). Representative image of the spiculated mass lesion (white arrows) in the right breast with inhomogeneous contrast enhancement and a maximum extension of about 60 × 51 × 59 mm. The lesion corresponds to the patient’s breast cancer. Asterisk and black line around the tumor indicate artifacts due to patient movement. Image orientation in relation to the patient A = anterior, M = medial, L = lateral. The white scalebar indicates a length of 15 mm.
A possible reason for a darkfield signal in mammography has been assigned to calcification [6]. Indeed, histologically numerous calcification grains with size varying from 3 to 30 m diameter (Fig. 6 right) were seen in the centre of the tumor region. These rather small grains are not resolvable in the X-ray absorption image because their size is much smaller than the pixel size. Their contribution to absorption is almost negligible but their influence on the wave front of the X-ray wave field is notable in the darkfield. The noise in the darkfield is considerably higher than in the absorption image. Of importance, the visibility of the calcified tumor region is not restricted by noise but by contrast: the calcified tumor region delivers darkfield values which significantly exceed the darkfield values occurring in the rest of the breast tissue. This is not the case for the absorption image, where the calcified tumor region does not produce enhanced intensity. In order to achieve quantitative information, the regions as defined in Figure 9 are used to determine the contrast3 of the calcified tumor region (yellow box) compared to non-tumor
3
contrast is defined according to Weber as (Signalobj /Signalref ) − 1
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Figure 4. Tomosynthesis slice of the mastectomy specimen: The mass lesion corresponds to the patient’s breast cancer. Its extension including the spiculations is about 87 × 67 mm. White arrows: suspected extent of the carcinoma. White circle: Area where microcalcifications are suspected. Arrowheads: non suspicious microcalcifications. The white scalebar indicates a length of 15 mm.
region (blue box). The absorption image contains an averaged intensity of 1.117 ± 0.001 in the yellow box and 0.992 ± 0.001 in the blue box resulting in a contrast of 0.126 ± 0.002. The referring values for the darkfield are 0.396 ± 0.002 and 0.172 ± 0.001 resulting in a contrast of 1.306 ± 0.024. Thus, the darkfield shows a clear enhancement of signal at the position of the tumor. Further, the size of the darkfield signal region coincides well with the size of the calcified region in the histological image. Obviously, the darkfield provides high sensitivity and strong correlation with the region containing tiny calcification grains. In order to test our assumption that calcification grains induce signals in the darkfield image we prepared a phantom with lime powder embedded in gelatine with a total thickness of 3 cm. Two classes of grain size were taken which should represent the type of calcifications which have been observed in breast samples. The one class consisted of grains respectively platelets of the order of 1 mm in diameter and the other class contained grains of the order of 10 micrometers in diameter. The number density of the calcification grains were similar to those observed in the histological image. Figure 8 shows the absorption image and the darkfield image of the phantom taken in our Talbot-Lau set-up. These images prove the validity of our assumption that the micrometer-size grains produce a strong darkfield signal while almost no signal occurs in the absorption image.
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Figure 7. Absorption image taken with the Talbot-Lau set-up. The regions of interest for different investigations are marked by frames. The white scalebar indicates a length of 15 mm.
in Figure 10. The absorption values of the 8 pixels in a row have been averaged and the resulting absorption is plotted versus position, see Figure 10. In the same ROI the darkfield values of 8 pixels in a row have been averaged and plotted versus position. While these calcifications are clearly visible in both images the contrast in the darkfield (1.21 ± 0.04) is much higher than in the absorption image (0.161 ± 0.001). We calculated the contrast of microcalcifications in all specimens, see Table 1. Obviously, for all specimens the darkfield contrast is considerable higher than the absorption contrast.
4 Discussion Figure 5. Images of the mastectomy specimen taken with the TalbotLau set-up: absorption image A = − ln(a1 /a0 ) (top), differential phase image = 1 − 0 (middle), darkfield image D = 1 − b1 /b0 · a0 /a1 (bottom); the white scalebar indicates a length of 15 mm; the colorbars show the greyscale of the images.
A further region of the specimen - marked by frame 2 in Figure 7 - has been investigated. This region contains microcalcifications of about a millimeter size. Figure 10 shows a line profile running through one of the calcifications. Such a line profile has been determined in the red marked region
Darkfield images of breast taken with a Talbot-Lau setup have been reported by Endo et al. [7]. There, formalin fixed mastectomy slices of limited thickness 6.6 mm have been investigated. The images of the presented specimen show a high contrast for calcification clusters in the visibility-contrast image which were not visible in the absorption image. The advantage of small slices is that the visibility of the calcifications is enhanced compared to the image of the full breast. This enhancement is not only given for the absorption image, but also for the phase and the darkfield image. Accordingly, for application in mammography the advantage of the new
Figure 6. Histological image of the tumor region (H&E stains) marked by the circle in figure 4: low resolution (left), high resolution (right); microcalcifications are visible as dark spots (arrow) in the high resolution image (right); in the left image the red lines indicate the diameter of the region containing calcification grains.
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Figure 8. Absorption A = − ln(a1 /a0 ) (left) and darkfield D = 1 − b1 /b0 · a0 /a1 (right) image of a phantom consisting of several areas with lime powder with different grain sizes. The vertical artifacts in the image are an effect of the stiching process of several acquisitions. The white scalebar indicates a length of 10 mm; the colorbars show the greyscale of the images. Table 1 Measured contrast of microcalcifications to healthy tissue of breast specimens; darkfield and absorption contrast are determined with the Talbot-Lau set-up, mammography contrast is obtained from projective X-ray images taken with Siemens Mammomat Inspiration; specimen 6 is the full breast mastectomy. specimen
darkfield contrast
absorption contrast
mammography contrast
1 2 3 4 5 6
1.16 ± 0.11 0.57 ± 0.11 1.89 ± 0.27 0.96 ± 0.10 0.66 ± 0.07 1.21 ± 0.04
0.098 ± 0.005 0.054 ± 0.006 0.230 ± 0.016 0.019 ± 0.003 0.018 ± 0.002 0.161 ± 0.001
0.302 ± 0.020 0.250 ± 0.035 no data 0.058 ± 0.013 0.058 ± 0.006 0.395 ± 0.018
imaging modalities of phase and darkfield images should be proven for complete breasts. Stampanoni et al. [5] have published Talbot-Lau images of fresh native breast tissue. The authors put their focus on the differential phase information. They further combine the information from the three images into a color-coded
composite image. They prove that additional information on the tumor is achieved by this method. They do not investigate the contrast of the tumor in the single images. In their presented images absorption seems to provide the highest contrast. No prominent signals occur in the darkfield image. This is in contradiction to the results published by Endo et al. [7] as well as to our results. The non-occurance of darkfield signatures in the images of Stampanoni et al. might be due to differences in the biology of the samples. In the journal publications available for an analysis up to know only a small number of samples have been investigated so that the occurrence or non-occurrence of darkfield signals might be due to fluctuations in the selection of samples. In order to avoid the dependence on fluctuations we conclude that it is very important to correlate structures in the images with histological observations. In this work we present images of a freshly resected complete breast with a maximum thickness of 3 cm. We employed a Talbot-Lau set-up with high visibility of the Talbot intensity pattern delivering high contrast for the darkfield. For a complete breast we thus achieved - for the first time - a
Figure 9. Regions for the determination of the contrast marked in the absorption (left) as well as in the darkfield image (right); yellow: calcified tumor region, blue: outside the tumor region. The regions are at the same positions in both images. The arrowhead points at a non suspicious macrocalcification. The white scalebar indicates a length of 5 mm. The images refer to frame 1 marked in Fig. 7.
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Figure 10. Quantitative analysis of the ROI defined by frame 2 in Fig. 7. Top left: absorption image; top right: darkfield image; bottom left: line profile along the red marked band in the top left image; bottom right: line profile along the red marked band in the top right image; The white scale bar indicates a length of 5 mm.
microcalcification to healthy tissue contrast which is larger for the darkfield than for the absorption signal by a factor of 10. No compression of the breast has been applied. For the first time, we obtained such good results with a dose comparable to that applied in conventional mammography [28]. Our results indicate that the visibility of a calcified breast tumor is not restricted by noise but by contrast. With the todays given size of gratings only a small field of view can be imaged. Imaging a whole breast would take some minutes of time and some additional dose might be necessary due to the needed overlap of single pictures which have to be stiched together. But with the development of larger grids this problem will disappear completely. As the calcification grains have a considerably different refractive index compared to the surrounding tissue they seem to be the source of the darkfield signal. Due to the large distance between grains the overall density of calcified tissue is only weakly enhanced resulting in a low contrast of this tumor region in the absorption image.
5 Conclusion The results presented in this publication allow the conclusion that darkfield mammography (in vivo) will deliver
valuable image information that can surpass the contrast of normal absorption images. The applied dose would be comparable to the conventional mammography dose while three images are achieved instead of one. The darkfield image will especially provide high sensitivity to calcified breast tumors while the size of the calcification grains may be much smaller than the pixel pitch of the detector. As numerous benign breast lesions also can show microcalcification diagnostic interpretation of such small calcification grains has still to be investigated.
Acknowledgements This work was supported by the German Federal Ministry of Education and Research (BMBF) within the PHACT project. Additionally, the authors want to thank the Karlsruhe Institue of Technology (KIT) for the production of the used gratings.
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