Titanium Contrast-Enhanced Mammography (TiCEM) White Paper

White paper Titanium Contrast-Enhanced Mammography (TiCEM) Expand your diagnostic insights Johannes G Korporaal, PhD, Mathias D Hörnig, Thomas Mertelmeier, PhD and Axel Hebecker, PhD SIEMENS siemens.com/mammography Healthineers White paper · Titanium Contrast-Enhanced Mammography (TiCEM) Contents 1. Introduction 3 2. Contrast-enhanced imaging 4 2.1 Physiology 4 2.2 Contrast enhancement in healthy breast tissue 5 2.3 Contrast enhancement in tumors 5 2.4 Measuring contrast enhancement: dynamic or static 6 2.5 Safety ........ 6 3. Dual-energy imaging 7 3.1 Attenuation of X-rays 7 3.2 Why dual-energy imaging? 8 3.3 Choice of X-ray spectra 9 3.4 Image processing 10 4. TiCEM – Titanium Contrast-Enhanced Mammography 11 4.1 Clinical workflow 11 4.2 Image acquisition 12 4.3 Image post-processing 13 5. Clinical performance ........ 14 5.1 Sensitivity and specificity 14 5.2 TiCEM studies and sample cases 15 6. Discussion & conclusions 19 6.1 Clinical indications for TiCEM 19 6.2 Comparison with MRI 19 6.3 Combinations with other technologies 20 6.4 Conclusions 21 7. Abbreviations 22 8. References 23 Please note: In this white paper, the term CEDEM refers to the methodology in general (also known as CESM). TiCEM refers to the product implementation of Siemens Healthineers. 2 Titanium Contrast-Enhanced Mammography (TiCEM) · White paper 1. Introduction Full-field digital mammography (FFDM) is Siemens Healthineers has entered the CEDEM currently the gold standard when it comes to market with its unique TiCEM application as breast cancer screening [1]. It delivers high-reso- an option on the MAMMOMAT Revelation, lution images of the breast in a short amount featuring a dedicated titanium filter that offers of time. However, there is one limitation inher- key advantages. This white paper will: ent in this acquisition method: tissue superim- position. To help solve this issue, digital breast present the scientific background and • tomosynthesis (DBT) has been introduced in opportunities for the CEDEM methodology; clinical practice in recent years. It provides highlight the specific features of TiCEM and • 3D information on breast tissue by acquiring its clinical workflow; images at different angles and results in higher review the scientific literature for the most • cancer detection rates [2–4]. DBT is becoming prominent achievements to date; and an established method in clinical routine, and discuss clinical and technological challenges. • may in the near future replace digital mammog- raphy as the breast screening imaging modality The first part of this white paper (Chapters 2 of choice. and 3) will have an educational character, with Both FFDM and DBT are morphological tech- a strong focus on imaging principles. The second niques, showing tissue structures rather than part will provide more technical and clinical physiology. Although this might be sufficient to details about TiCEM (Chapters 4 and 5), and detect abnormalities in a screening setting, for the final part discusses its current status as diagnostic workup of recalled women, addi- well as future directions (Chapter 6). tional functional imaging techniques might offer a significant diagnostic advantage by visualizing atypical physiological processes. For X-ray mammography systems, contrast- enhanced dual-energy mammography (CEDEM) is the functional imaging technique that has shown the greatest potential in this respect. CEDEM is a combination of contrast-enhanced (CE) imaging, known from computed tomogra- phy (CT), angiography and magnetic resonance imaging (MRI), and dual-energy (DE) imaging, known from CT and dual-energy X-ray absorpti- ometry (DXA). 3 White paper · Titanium Contrast-Enhanced Mammography (TiCEM) 2. Contrast-enhanced imaging 2.1 Physiology The use of contrast agents is common practice After an iodinated contrast agent has been in radiology, for example in CT [5], MRI [6] and intravenously injected, it will traverse the lungs ultrasound (US) [7]. The purpose of injecting and the heart (twice) before it enters the sys- a contrast agent is to increase the visibility of temic circulation. From the aorta, the contrast vascular structures or to visualize contrast agent is then distributed throughout the body to agent uptake in tissues. As contrast enhance- the organs and tissues. Although a large part of ment depends on the tissue type, pathological the contrast agent will stay within the arteries processes might show abnormalities in contrast during its first pass through the body, over time agent uptake and enable detection of malig- the contrast agent will leak out of the capillar- nancies. And since mammography is based on ies into the extravascular extracellular space, the attenuation of X-rays, the choice of iodine- also known as interstitial fluid. Depending on based contrast agents, which are also used in the blood flow, on the volume percent of extra- CT, is obvious. vascular extracellular space and on vessel per- meability (“leakiness”), a certain amount of contrast agent will accumulate in a tissue and give rise to a signal enhancement during imag- ing (Figure 1). The entire process of how contrast agents behave inside the human body is called contrast agent kinetics, and can be described by means of tracer kinetic models [8, 9]. Cell Capillary Pixel / Voxel . Contrast agent Extravascular extracellular space Figure 1: Depending on vessel permeability, blood flow and the amount of extravascular extracellular space, part of the contrast agent will accumulate in a tissue and give rise to a signal enhancement during imaging. ........ 4 Titanium Contrast-Enhanced Mammography (TiCEM) · White paper 2.2 Contrast enhancement in healthy of breast cancer risk [11]. The amount of BPE is breast tissue subjectively described as minimal, mild, moder- ate or marked enhancement [11–14] and can The human breast consists primarily of two dif- lead to decreased visibility of enhancing lesions, ferent types of tissue: adipose and fibroglandu- as these stand out less clearly from the back- lar tissue. The contrast agent uptake in adipose ground at higher BPE levels. tissue is typically very low, leading to almost no contrast enhancement over time [10]. Fibro- 2.3 Contrast enhancement in tumors glandular tissue, on the other hand, has a good vascular network and thus is well perfused. For most invasive tumors, the formation of new However, the blood vessels are not highly per- blood vessels, called angiogenesis, is one of the meable, which results in a slow contrast agent pathophysiological processes characteristic of uptake, a low amplitude and the contrast tumor growth [15]. Tumor cells initiate the for- enhancement typically showing a plateau mation of new vasculature from pre-existing (Figure 2) [10]. vessels, often resulting in an irregular bed of This contrast agent uptake of healthy glandular leaky vessels. These abnormalities in tissue tissue has been described in scientific literature perfusion and contrast agent leakage lead to as background parenchymal enhancement increased visibility of tumors in contrast- (BPE) and is a well-known phenomenon in MR enhanced scans. The reason for this is that a lot imaging [11]. It is usually present in a bilateral, of contrast agent is taken up by the tumor tissue symmetrical distribution [11], with asymmetri- due to the good blood supply. Furthermore, the cal BPE being seen due to benign and malignant leaky vessels allow the contrast agent to move causes [12]. BPE is known to fluctuate with into and out of the tumor tissue rapidly, a pro- breast density, hormone levels (e.g. phase of the cess commonly referred to in MRI literature as menstrual cycle, menopause, hormone therapy) wash-in and wash-out [10]. Typical contrast- and radiation therapy [11, 12], and has been enhancement curves observed in the human demonstrated to be an independent predictor breast are shown in Figure 2. Large, feeding arteries Tumor tissue (malignant) Breast tissue (glandular) Contrast enhancement 0 1 2 3 4 5 6 Time (min) Figure 2: Differences in physiology, predominantly blood flow and vessel permeability, are reflected in the shapes and amplitudes of enhancement curves. Over time, all tissues will reach stable plateau phases, with tumor tissue generally having a higher enhancement level than healthy breast tissue (BPE) [10]. Please note: The purpose of this figure is to illustrate different enhancement patterns in general. The curves shown are estimated based on tracer kinetic models and are not actually measured inside a female breast. 5 White paper · Titanium Contrast-Enhanced Mammography (TiCEM) 2.4 Measuring contrast enhancement: As a result, imaging the arterial phase of dynamic or static contrast enhancement is not possible. However, the contrast enhancement is more stable after It would be desirable to perform repeated the arterial peak (Figure 2), allowing for a larger measurements over time to obtain information timing window to perform the measurements. about the contrast agent dynamics and to cap- Also, differences in contrast agent uptake ture the arterial phase of tumor enhancement between malignant lesions and healthy tissue characterized by a steep upslope and a rapid still permit differentiation of malignancies. wash-out. This approach has been tested by Second, differences in contrast agent uptake subtracting a baseline image prior to injection should be derived from independent measure- from the subsequent images, as it is known from ments at single time points, as no baseline angiography procedures, for example. However, image (acquired prior to the injection) will be in clinical studies this so-called temporal sub- available. And since the iodinated contrast traction mammography [16] has not been able agent is not visible in a routine mammogram to consistently demonstrate distinctly different [21], there is a need for a different approach to patterns for benign and malignant lesions [17]. extract the iodine signal at a single time point. Furthermore, the most prominent factors hin- This is where the dual-energy methodology dering a successful implementation of this comes into play, as will be explained in the dynamic acquisition method are the high next chapter. cumulative radiation dose of repeated acquisi- tions, the necessity for repeated contrast agent injections for each view and breast, as well as 2.5 Safety the breast compression that hinders normal blood flow into the breast [16–20]. As with all intravenous contrast agent injec- tions, allergic reactions may occur, but can This has two important implications for the almost entirely be prevented by following implementation and workflow of CEDEM. First, regular safety guidelines for iodinated contrast the compression-induced restriction of blood agents [22, 23] as well as local standard flow into the breast means that patient posi- operating procedures. tioning, breast compression and image acquisi- tion should take place after the injection has been completed. 6 Titanium Contrast-Enhanced Mammography (TiCEM) · White paper 3. Dual-energy imaging In FFDM, images are generated by measuring 3.1 Attenuation of X-rays the attenuation of X-rays that have passed through the breast. Because of the working prin- In X-ray based imaging modalities, the contrasts ciple of X-ray tubes, the photons in the X-ray in the final image originate from differences in beam do not all have the same energy; they X-ray absorption inside a scanned object. X-ray have different energies, resulting in an X-ray absorption in turn depends on both the physical spectrum (Figure 3). The shape of an X-ray density and chemical composition of the object. spectrum depends on: The effect of chemical composition on X-ray absorption can be described by means of the the peak voltage of the X-ray tube (kV); • mass attenuation coefficient, which is material- the anode material; and • specific and depends on the photon energy. the filtering of the X-ray beam. • This energy dependence is illustrated in Figure 4, which shows the mass attenuation coefficients The peak voltage determines the highest photon for several types of tissue as a function of pho- energy in the X-ray spectrum, whereas the ton energy [24]. The higher the mass attenuation anode material influences the distribution of coefficient of a material is, the more photons energies present in the spectrum. It is important are absorbed. Since breast tissue is a mixture to filter the X-ray beam before it reaches the of adipose and soft tissue (glandular or tumor patient, to reduce the number of low-energy tissue), the curve for breast tissue (black line photons. These would merely lead to higher in Figure 4) lies between the curves for adipose radiation doses but would not contribute to the and soft tissue. image. With additional filtering, specific photon energies can be filtered out of the beam, to increase or decrease the average energy of the X-ray spectrum (see paragraph 3.3). Filters Intensity Spectrum kV Anode X-Rays Photon Energy Figure 3: The shape of an X-ray spectrum depends on the peak voltage of the X-ray tube (kV), the anode material and the filtering of the X-ray beam. 7 White paper · Titanium Contrast-Enhanced Mammography (TiCEM) Adipose Tissue (ICRU-44) Breast Tissue (ICRU-44) 100 Soft Tissue (ICRU-44) Cortical Bone (ICRU-44) Iodine 10 1 Mass attenuation coefficient [cm2/g] 0.1 10 20 30 40 50 60 Photon energy [keV] Figure 4: Mass attenuation coefficients for several types of tissue [24]. The higher the mass attenuation coefficient of a material is, the more photons are absorbed. The K-edge of the iodine atom leads to a sudden increase in the mass attenuation coefficient at 33.2 keV. 3.2 Why dual-energy imaging? Especially in dense breasts, where the iodine contrast might be hidden under or confused Whereas standard mammography is performed with high-intensity fibroglandular tissue in a using one X-ray spectrum (“single-energy”), the normal, single-energy mammogram, dual- term “dual-energy” refers to imaging a tissue energy acquisitions can have a definite using two different spectra. Its advantage is that advantage, as illustrated in Figure 5. two materials can be discriminated if the differ- Despite the much higher mass attenuation ence in their mass attenuation coefficient is sig- coefficient of iodine compared to soft tissue, nificantly different for the two X-ray spectra. the iodinated contrast agent cannot be seen in Since both tumor tissue and healthy fibroglan- normal FFDM images (single-energy), although dular tissue are soft tissues, they have the same present in the tissue [21]. This is due to its very mass attenuation coefficient for all energies low concentration, resulting in only very slightly (dashed blue line in Figure 4) and cannot increased pixel intensities. immediately be differentiated by means of Therefore, contrast-enhanced dual-energy dual-energy imaging. However, as explained mammography is a result of: in Chapter 2, differences in iodine uptake between healthy glandular and tumor tissue differences in the mass attenuation coeffi- • exist. And as the mass attenuation coefficient cient between breast tissue and iodine; and between soft tissue and iodine is significantly differences in contrast agent uptake between • different (Figure 4), an iodine map can be tumor and fibroglandular tissue. calculated, showing contrast agent uptake, being indicative for tumor tissue. 8 Titanium Contrast-Enhanced Mammography (TiCEM) · White paper 3.3 Choice of X-ray spectra than that K-edge will be absorbed. This results in an abrupt, very well defined end of the spec- When performing dual-energy mammography, trum and allows for precise shaping of the X-ray two different X-ray spectra must be selected. spectrum. Finding a good combination of X-ray spectra is For the high-energy spectrum, the use of addi- a complex task and will unquestionably involve tional filtering with high-Z (high atomic number) a trade-off, since many factors need to be taken materials is also beneficial. By increasing the into account. filter thickness, the average beam energy can The mass attenuation coefficient of iodine be increased and the spectrum will become nar- shows a characteristic step at 33.2 keV, the rower. However, a thicker filter will also absorb so-called K-edge (Figure 4). This is an important more X-rays and therefore necessitates a higher peak, since for photon energies just below 33.2 tube output to obtain the same radiation dose keV, the attenuation will be much lower com- in the tissue. So, the maximum filter thickness pared to photon energies just above this K-edge. is always dependent on the maximum output Since the attenuation of breast tissue is almost of the X-ray tube and should be tailored to its the same either side of 33.2 keV, a difference in heat capacity. iodine contrast in the mammogram can be Together with other practical constraints, such expected for X-ray spectra just below and just as the maximum available space in the filter above 33.2 keV. So from a physics point of view, box, the availability of the filter material and two narrow spectra, one just before and one just the processing options and costs, the selection after the K-edge of iodine, would be optimal. of a good combination of X-ray spectra is chal- For the low-energy spectrum, filter materials lenging and trade-offs are unavoidable. with K-edges just below 33.2 keV are of interest, because almost all photons with energies higher LE Insight CEM LE Insight CEM Figure 5: Clinical example of a 52-year-old female presenting a palpable tumor in her left breast (two foci, invasive ductal carcinoma (IDC) grade 1 with parts of ductal carcinoma in situ (DCIS)). The low-energy (LE) images show dense fibroglandular tissue, without clear lesions taking up contrast agent. In the recombined Insight CEM image, the anatomical background is neutralized by the weighted subtraction and the lesion becomes clearly visible. (Images courtesy of Dr. I. Vejborg, Copenhagen, Denmark) ........... 9 White paper · Titanium Contrast-Enhanced Mammography (TiCEM) 3.4 Image processing When high- and low-energy mammograms are in alignment, a particular material, for example As CEDEM is implemented on a standard mam- soft tissue or iodine, can be highlighted by mography system, the high-energy (HE) and removing the other materials from the image. low-energy (LE) images must be acquired suc- This can be done using a weighted subtraction. cessively, resulting in a time difference between By adjusting the weighting factor to a certain the two acquisitions. For this reason, image material, the contrast difference produced in acquisition is performed during the venous that material by the two different X-ray spectra phase, where the changes in contrast enhance- can be neutralized, resulting in suppression of ment over time are only minor. Because of the the material in the final image. In the case of time difference between the successive acquisi- contrast-enhanced dual-energy mammography, tions, patient motion may occur even though the image contrasts for fibroglandular tissue the breast is compressed. In such cases, image will be removed from the image, resulting in an registration could be of help before further pro- increased image contrast of the iodine uptake cessing of the LE and HE images. inside the breast (Figure 6). LE HE Insight CEM Figure 6: Clinical example of a 65-year-old female who underwent a TiCEM examination. The low-energy (LE) image shows at least one suspicious hyperdense area inside the fibroglandular tissue. After the weighted subtraction of the high-energy (HE) image (see Chapter 4.3), the recombined Insight CEM image reveals the contrast agent uptake without masking of the fibroglandular tissue. Histological analysis confirmed an invasive ductal carcinoma (IDC) grade 2 as well as a high-grade ductal carcinoma in situ (DCIS) with comedo necrosis and calcifications. (Images courtesy of Prof. Dr. D. Uhlenbrock, Dortmund, Germany) 10 Titanium Contrast-Enhanced Mammography (TiCEM) · White paper 4. TiCEM – Titanium Contrast- Enhanced Mammography With the introduction of the MAMMOMAT 4.1 Clinical workflow Revelation, Siemens Healthineers has imple- mented its CEDEM application as Titanium The clinical workflow for a TiCEM examination Contrast-Enhanced Mammography (TiCEM). (Figure 7) starts with the injection of the iodin- TiCEM aims at improving diagnostic accuracy ated contrast agent by means of a power injec- in the detection and characterization of breast tor. At the time of injection, the breast is not tumors, by incorporating functional (yet) compressed, to allow for normal tissue information. perfusion and unhindered inflow of the contrast agent into the breast. The dosage of the contrast agent is typically weight-dependent and varies between institutions (Table 1). Study Dosage Iodine Flow Scan delay Power [mL/kg] concentration [mL/s] [min] injector [mg/mL] [25] 1.5 300 3 2 Yes [26] 1.5 300 3 2 Yes [27] 1.5 300 3 2 Yes [28] 1.5 300/350 3 2.5–5 Yes [29] 1.5 350 3 2 Yes [30] 1.5 350 3 2 Yes [31] 1.5 350 3 2 Yes [11] 1.5 350 3 2.5 Yes [32] 1.5 350 3 2 Yes (max 90mL) [33] 90mL 350 3 2 Yes for all [34] 1.5 370 3 2 Yes [35] 1.5 370 3 2 Yes [36] 2.0 400 3.5 1–1.5 Yes Table 1: Injection protocol parameters from scientific literature. Note that in these studies the iodine dose (dosage x concentration) ranges from 0.45 to 0.80 gI/kg (grams of iodine per kilogram body weight), which is almost a two-fold difference. ........... 11 White paper · Titanium Contrast-Enhanced Mammography (TiCEM) Repeat for additional views LE HE .......... (=FFDM) 49kV+Ti Injection of Approx. Patient Acquisition of Acquisition Display of iodinated 1.5 – 2 minutes positioning and low-energy image of high-energy low-energy & contrast agent waiting time compression image Insight CEM at the AWS Figure 7: Simplified workflow illustration. The workflow may vary depending on the method used, patient situation and individual preferences. After a waiting time of approximately 2 minutes 4.2 Image acquisition (see Table 1), the woman is positioned at the MAMMOMAT Revelation and the breast is The LE image is acquired first, all acquisition compressed. Then, a low-energy (LE) and a parameters being identical to those of a normal high-energy (HE) image are acquired succes- FFDM acquisition with a tungsten (W) anode sively and an Insight CEM image, a recombined target with a 50μm rhodium (Rh) filter and a image of that view (see 3.4), is calculated. tube voltage between 28 and 32kV. As previously These steps are then repeated for each addi- explained (Chapter 3), the contrast agent tional view, without the need to perform a new uptake, although present in the tissue, is contrast agent injection. practically invisible in this LE image [21]. The time window for performing multiple views Subsequently, the HE image is acquired at 49kV with a single contrast agent injection lasts up to with the unique titanium filter, which substan- 10 minutes [28], although the views should be tially reduces the X-ray tube load and enables acquired without any unnecessary delays. The uninterrupted acquisitions. Compared to other order in which the views are acquired seems to potential filter candidates such as a 0.3mm be of little clinical significance [28] and does copper filter, the 1mm titanium filter allows for not appear to affect image quality [30]. a 60% higher tube output at equal image qual- ity (Figure 8) [39]. This results in a lower risk of Care should be taken when handling the con- tube overheating and means that, even for thick trast agent to avoid contamination of the detec- and dense breasts requiring a higher average tor or the skin with pure contrast agent, as this glandular dose (AGD), sufficient tube power is might mimic calcifications or result in artifacts available to obtain adequate image quality. [37, 38]. 12 Titanium Contrast-Enhanced Mammography (TiCEM) · White paper 35 Compression plate 30 25 Uniform breast Variable 20 thickness breast thickness < 15 10 Detector Tube yield [µGy/mAs] 5 0 40 45 50 Tube voltage [kV] 1 mm Ti 0.3 mm Cu Figure 8: Simulated tube outputs in μGy/mAs of a Figure 9: The TiCEM image post-processing suppresses tungsten anode target with a 1.0 mm titanium and artifacts at the borders of the breast, where the 0.3mm copper filter (650mm from focal spot) [39]. compressed breast thickness is not uniform. The 1mm titanium filter allows for a 60% higher tube output at equal image quality. The radiation dose (AGD) of the LE acquisition 4.3 Image post-processing equals that of a normal FFDM acquisition, whereas the additional dose of the HE acquisi- To obtain the recombined image, called Insight tion can reach a maximum of ~50% of the nor- CEM, image processing of the LE and HE images mal AGD of an FFDM image. As TiCEM exami- is required. A weighted subtraction of the loga- nations will be performed only in the context rithmic high-energy (HE) and low-energy (LE) of diagnostic work-up and not screening, this images is performed: increase in radiation dose can be justified in ln(Insight CEM) = ln(HE) – w * ln(LE) [eq. 1], view of the increased diagnostic power to detect or rule out lesions. where ln is the natural logarithm and w the weighting factor [36]. The TiCEM image post- processing suppresses artifacts at the borders of the breast, where the compressed breast thickness is no longer constant (Figure 9) [34, 36]. 13 White paper · Titanium Contrast-Enhanced Mammography (TiCEM) 5. Clinical performance In contrast to FFDM, there are no standardized enhancement can also be found in benign interpretation criteria for the evaluation of breast lesions [41]. Interestingly, a detailed breast lesions in CEDEM. Nonetheless, in scien- description of, and systematic correlation tific literature the application of BI-RADS between the particular enhancement behaviors descriptors for MRI has been shown to be useful and the different lesion types is lacking, whereas for describing enhancement in recombined most cases with false positive and false nega- images [13]. Contrast enhancement is often tive findings have been extensively described, classified according to a four-point scale, e.g. e.g. [26, 28, 32, 40, 42–45, 33, 46]. none, mild, moderate or marked, and mass and non-mass enhancement are described sepa- When it comes to diagnostic accuracy, sensitiv- rately [12, 36, 40]. ity and specificity have been measured in sev- eral studies and summarized in a systematic Reading of TiCEM examinations is generally review by Tagliafico et al [47]. They found a very performed by looking at the paired LE and high overall sensitivity of 98%, a very low speci- Insight CEM images, without incorporating the ficity of 58% and an area under the ROC curve HE image. As the Insight CEM image primarily of 0.93 [47]. These numbers should, however, be shows iodine uptake and not morphological interpreted with caution, as most studies are structures, the LE image can be used for navi- based on highly selected case series and prone gating lesions inside the breast. The reading to selection bias. This means that the study solution syngo.Breast Care offers dedicated lay- cohorts had a very high prevalence of breast outs for TiCEM examinations and enables tog- cancer (up to 100% [26]), thereby prejudicing gling between the LE and Insight CEM images. these diagnostic measures of CEDEM. 5.1 Sensitivity and specificity Several studies have investigated the sensitivity and specificity of the CEDEM methodology. For such an analysis, positive and negative findings need to be defined and thus malignant and benign findings described (see Table 2). Reports in scientific literature have shown contrast enhancement in almost all malignant lesions of the breast, although contrast Malignant Benign Invasive ductal carcinoma Fibroadenoma Intramammary lymph node Invasive lobular carcinoma Simple cyst Sclerosing adenosis Ductal carcinoma in situ Reactive changes / benign Atypical lobular hyperplasia Invasive mucinous carcinoma Apocrine changes / metaplasia Ductectasia Invasive micropapillary Papilloma Fibrosis carcinoma Superposition Ductal hyperplasia Cylindrical cell changes Lobular carcinoma in situ Old hematoma Flat epithelial atypia Inflammation Table 2: Several malignant and benign lesions and subtypes of invasive cancers have been reported in scientific literature [26]. 14 Titanium Contrast-Enhanced Mammography (TiCEM) · White paper 5.2 TiCEM studies and sample cases In a clinical feasibility study, Knogler et al. used After adding Insight CEM images to the FFDM the TiCEM prototype in 15 patients with suspi- findings, the BI-RADS assessment changed in 10 cious findings from FFDM (ACR BI-RADS 4 & 5) out of 15 patients (66.7%). This demonstrated [36]. Imaging was performed 60-90 seconds the feasibility and additional value of the TiCEM after administration of the contrast agent. For prototype in a clinical setting (Figure 10) [36]. the interpretation of the Insight CEM images, the criteria from the MRI part of the BI-RADS The following clinical cases (Figures 10–13) were lexicon were used. TiCEM revealed more lesions gathered from the clinical use tests performed than FFDM alone, and all malignant lesions prior to the market introduction of the showed a strong contrast enhancement. Benign MAMMOMAT Revelation. lesions showed moderate or no enhancement. LE Insight CEM LE Insight CEM Figure 10: Clinical example of a 71-year-old asymptomatic female who underwent a TiCEM examination. The LE images of the left breast show one suspicious mass (arrow head) and three fibroadenomas (arrows), one of them being calcified. On the Insight CEM images the three fibroadenomas did not enhance, as expected (see 5.1). The suspicious mass showed contrast agent uptake and was proven to be a 4-mm IDC with associated DCIS. (Images courtesy of Dr. L. Pina, Pamplona, Spain) ........... 15 White paper · Titanium Contrast-Enhanced Mammography (TiCEM) LE Insight CEM LE Insight CEM Figure 11: Clinical example of a 56-year-old woman presenting redness and warming of the skin. The LE images of the right breast show a retromammilar unsharp 37-mm lesion suspicious for abscess. The Insight CEM images do not show contrast agent uptake inside the lesion, whereas the boundary area shows enhancement, being indicative for a chronic active inflammation. Histology confirmed this lesion to be an abscess (benign finding). (Images courtesy of Prof. Dr. D. Uhlenbrock, Dortmund, Germany) 16 Titanium Contrast-Enhanced Mammography (TiCEM) · White paper LE Insight CEM LE Insight CEM Figure 12: Clinical example of a 60-year-old woman who underwent a TiCEM examination. The LE images of the left breast show two suspicious lesions inside the fatty breast. The Insight CEM images show contrast agent uptake inside these lesions, being indicative for malignancy, which was confirmed by histology (IDC). (Images courtesy of Dr. I. Vejborg, Copenhagen, Denmark) 17 White paper · Titanium Contrast-Enhanced Mammography (TiCEM) LE Insight CEM LE Insight CEM Figure 13: Clinical example of a 71-year-old female with a palpable lump in her left breast who underwent a TiCEM examination. The LE images show an irregular mass, but as the margins are not clearly seen, it is difficult to assess the cancer size. The Insight CEM images clearly show the size and extent of the lesion, which was proven to be a 30-mm invasive lobular carcinoma. (Images courtesy of Dr. L. Pina, Pamplona, Spain) 18 Titanium Contrast-Enhanced Mammography (TiCEM) · White paper 6. Discussion & conclusions Currently, neither European nor American Clarification of inconclusive findings • guidelines for contrast-enhanced dual-energy after conventional imaging or ultrasound mammography exist. Consequently, there are Detection of occult lesions • no recommended acquisition and injection Pre-operative staging, assessment of • protocols, and image interpretation is reader- multifocality and multicentricity dependent. Further investigations are needed Monitoring of the effectiveness of neo- • to find out the indications for which TiCEM is adjuvant systemic therapy the method of choice compared to the other imaging modalities that are available for Because of the contrast agent injection, TiCEM women requiring diagnostic workup. These will most probably only be used for diagnostic future studies should be performed in workup, and not considered for breast unselected cases, since the currently available screening. evidence is highly biased due to the fact that it is based on study cohorts with extremely high proportions of breast cancer [47]. 6.2 Comparison with MRI To date, breast MRI is the gold standard func- 6.1 Clinical indications for TiCEM tional imaging technique for women requiring diagnostic workup. Guidelines for image acqui- Since the physiological processes imaged with sition and image interpretation exist [48] and TiCEM are similar to breast MRI, it is expected clinical indications have been defined. However, that many indications for breast MRI could also MRI also has some disadvantages compared apply to TiCEM. The most probable indications to TiCEM, potentially making the latter a cost- would then be: effective alternative to MRI (see Table 3). Advantages of breast MRI and TiCEM Breast MRI TiCEM Standard of care in diagnostic workup Imaging both breasts simultaneously No radiation dose No breast compression necessary Dynamic imaging possible Better availability Lower costs Shorter examination time Improved workflow Imaging of calcifications Imaging of patients with implants /pacemaker Imaging of patients with claustrophobia Imaging possible for patients unable to assume prone position Table 3: Advantages of breast MRI and TiCEM 19 White paper · Titanium Contrast-Enhanced Mammography (TiCEM) Direct comparison of contrast-enhanced MRI 6.3 Combinations with other examinations with TiCEM images should be made with caution. Although contrast agent technologies behavior is expected to be the same [30] and some studies found good correlation between In principle, the TiCEM approach could be com- the two techniques [11, 13], the image contrasts bined with other technologies such as tomosyn- are based on different physical principles: X-ray thesis, grid-less acquisition (PRIME) and biopsy. attenuation (TiCEM) versus magnetic suscepti- The use of contrast-enhanced dual-energy bility (MRI). In the case of MRI, a very high sensi- tomosynthesis (CEDET) is still in an early tivity and thus high signal for the gadolinium- experimental phase, and only a few groups have based contrast agent can be achieved by been conducting research on this subject [50– selecting the right imaging sequence, even at 55]. Most notably, the group under W. Zhao [54] very low concentrations of the contrast agent. is investigating the potential role of CEDET with X-ray attenuation, by contrast, is not sensitive a Siemens Healthineers prototype system study- to the iodinated contrast agent alone and ing acquisition physics and protocols. Of partic- follows the regular laws governing X-ray ular interest is the lesion localization capability absorption, which is dependent on the in 3D with CEDET. However, in the scientific liter- materials imaged, their thicknesses and ature, there is no consensus on whether this densities, and on the X-ray energies. combination might deliver valuable additional The scientific literature delivers mixed results in diagnostic information, as compared with that studies comparing the diagnostic performance provided by TiCEM and tomosynthesis as stand- of breast MRI with CEDEM. Some studies con- alone techniques [56]. clude in favor of CEDEM, with e.g. a lower num- Siemens Healthineers’ PRIME technology, ber of false positive findings [16, 28, 33] and enabling dose reduction through grid-less lower number of false negative findings for acquisition, might help to reduce the radiation CEDEM compared to MRI [32]. At the same time, dose in TiCEM examinations significantly. other studies report a higher false negative rate However, because of the different X-ray scatter for CEDEM [42] and a lower cancer detection properties with LE and HE spectra, as well as rate of index cancers for CEDEM compared to the complexity of the image recombination breast MRI [42, 33]. The results of these studies process, application of PRIME to TiCEM should, however, be interpreted with caution, examinations is challenging and currently as the study setups differed, the case numbers under evaluation in a clinical study. were very low and the inclusion criteria, imaging equipment, injection protocols and image inter- Based on the rationale of performing an image- pretations differed between the studies. guided biopsy with the same modality that was used to detect the lesion, CEDEM-guided biopsy One scientific study from Patel et al concludes might become a clinical need in the future and that CEDEM is a cost-effective modality and a has already been discussed in the scientific realistic substitute for breast MRI [49]. However, community [57, 58]. that publication uses sensitivity and specificity values that come from studies suffering from selection bias (see paragraph 5.1) and will most probably give too optimistic a picture of CEDEM. Whether CEDEM will become a cost-effective alternative to breast MRI is currently unknown and will depend on the scientific and technolog- ical developments that will take place in both modalities over the coming years. 20 Titanium Contrast-Enhanced Mammography (TiCEM) · White paper 6.4 Conclusions Siemens Healthineers launched TiCEM with its unique HE spectrum and an optimized titanium filter, which reduces X-ray tube load to enable seamless examinations. TiCEM delivers addi- tional diagnostic information for more confi- dent decision-making and helps to detect or rule out lesions. Being an integrated functional- ity of the MAMMOMAT Revelation, TiCEM can help reduce scheduling conflicts and workload on other modalities and could become a cost- effective alternative to breast MRI. Finally, guidelines are needed to achieve international standards in acquisition techniques and image interpretation. 21 White paper · Titanium Contrast-Enhanced Mammography (TiCEM) 7. 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The British journal of radiology 83(988):344–50. 25 On account of certain regional limitations of sales rights and service availability, we cannot guarantee that all products / services / features included in this brochure are available through the Siemens Healthineers sales organi- zation worldwide. Availability and packaging may vary by country and are subject to change without prior notice. The information in this document contains general descriptions of the technical options available and may not always apply in individual cases. Siemens Healthineers reserves the right to modify the design and specifications contained herein without prior notice. Please contact your local Siemens Healthineers sales representative for the most current information. In the interest of complying with legal requirements con- cerning the environmental compatibility of our products (protection of natural resources and waste conservation), we may recycle certain components where legally permis- sible. 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