ORIGINAL ARTICLE
A Novel Approach to Contrast-Enhanced Breast Magnetic Resonance Imaging for Screening High-Resolution Ultrafast Dynamic Imaging Ritse M. Mann, MD, PhD,* Roel D. Mus, MD,* Jan van Zelst, MD,* Christian Geppert, PhD,Þ Nico Karssemeijer, PhD,*þ and Bram Platel, PhD* Objectives: The use of breast magnetic resonance imaging (MRI) as screening tool has been stalled by high examination costs. Scan protocols have lengthened to optimize specificity. Modern view-sharing sequences now enable ultrafast dynamic whole-breast MRI, allowing much shorter and more cost-effective procedures. This study evaluates whether dynamic information from ultrafast breast MRI can be used to replace standard dynamic information to preserve accuracy. Materials and Methods: We interleaved 20 ultrafast time-resolved angiography with stochastic trajectory (TWIST) acquisitions (0.9 1 2.5 mm, temporal resolution, 4.3 seconds) during contrast inflow in a regular highresolution dynamic MRI protocol. A total of 160 consecutive patients with 199 enhancing abnormalities (95 benign and 104 malignant) were included. The maximum slope of the relative enhancement versus time curve (MS) obtained from the TWIST and curve type obtained from the regular dynamic sequence as defined in the breast imaging reporting and data system (BIRADS) lexicon were recorded. Diagnostic performance was compared using receiver operating characteristic analysis. Results: All lesions were visible on both the TWIST and standard series. Maximum slope allows discrimination between benign and malignant disease with high accuracy (area under the curve, 0.829). Types of MS were defined in analogy to BIRADS curve types: MS type 3 implies a high risk of malignancy (MS 913.3%/s; specificity, 85%), MS type 2 yields intermediate risk (MS G13.3%/s and 96.4%/s), and MS type 1 implies a low risk (MS G6.4%/s; sensitivity, 90%). This simplification provides a much higher accuracy than the much lengthier BIRADS curve type analysis does (area under the curve, 0.812 vs 0.692; P = 0.0061). Conclusions: Ultrafast dynamic breast MRI allows detection of breast lesions and classification with high accuracy using MS. This allows substantial shortening of scan protocols and hence reduces imaging costs, which is beneficial especially for screening. Key Words: breast cancer, dynamic contrast-enhanced (DCE) breast MRI, contrast enhancement versus time curve, ultrafast dynamic MRI, MRI protocol length reduction, screening, costs (Invest Radiol 2014;49: 579Y585)
D
ynamic contrast-enhanced (DCE) breast magnetic resonance imaging (MRI) is the most sensitive method for the detection of breast cancer currently available. Recent evaluations have shown that
Received for publication January 2, 2014; and accepted for publication, after revision, February 17, 2014. From the *Radboud University Nijmegen Medical Centre, Department of Radiology, Nijmegen, the Netherlands; †Siemens Medical Solutions, New York, NY; and ‡FraunHofer MEVIS, Bremen, Germany. Conflicts of interest and sources of funding: This work was supported by the European Unions Seventh Framework Programme FP7 under grant agreement 306088. Supplemental digital contents are available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.investigativeradiology.com) Reprints: Ritse M. Mann, MD, PhD, Radboud University Nijmegen Medical Centre, Department of Radiology (766), PO Box 9101, 6500 HB Nijmegen, the Netherlands. E-mail: [email protected]. Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 0020-9996/14/4909Y0579
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MRI is superior to mammography and ultrasound not only in the detection of invasive breast cancer but also in the detection of ductal carcinoma in situ (DCIS), the noninvasive precursor of breast cancer.1 In meta-analysis, an overall sensitivity of 90% has been reported.2 The potential of breast MRI is likely even higher because expert centers worldwide consistently report sensitivities of greater than 95%, for example, by introducing 3-T MRI and high-relaxivity contrast agents, which have been associated with an increase in sensitivity.3Y5 Based on these evaluations, it has been concluded that breast MRI should be regarded as an independent modality for the early detection of breast cancer.6 Despite its excellent performance, the use of MRI for breast cancer screening has thus far been restricted to patients at very high risk for the development of breast cancer. In terms of cancer detection, MRI has been shown superior to mammography also for women at intermediate risk. Nevertheless, recent cost-effectiveness evaluations have clearly shown that costs in non-BRCA mutation carriers may exceed $100,000 per life year gained, especially in women younger than 50 years.7 The need for cost reduction of MRI scanning itself is evident from the fact that costs in MRI screening are most influenced by the actual price of the MRI.8,9 In recent years, most research in breast MRI addressed the less than perfect specificity of the technique, because breast MRI has a high sensitivity for both malignant and benign disease. Standard DCE breast MRI consists of 3 bilateral T1-weighted spoiled gradient echo acquisitions. These are respectively obtained before contrast administration, at the peak of contrast enhancement around 90 seconds after administration, and in the late phase 5 to 7 minutes after contrast administration.10,11 Structured reporting according to the breast imaging reporting and data system (BIRADS) lexicon, which takes lesion shape, margin, internal enhancement, and shape of the contrast enhancement versus time curve into account,12 improves lesion classification. The dynamic evaluation relies mainly on the contrast washout phase. To further improve specificity, this protocol has been expanded with a highresolution T2 sequence and diffusion-weighted imaging (DWI).13Y17 An up-to-date breast MRI protocol takes between 12 and 20 minutes, and in most centers, no more than 2 breast MRI examinations per hour are performed on a single MRI scanner.5 The task to increase the specificity of breast MRI has therefore reduced its feasibility as a screening tool, lengthening both the examination and the time needed for interpretation and thus increasing the costs. However, the positive predictive value of an MRI finding at DCE-MRI only is at approximately 40%, already as high as the positive predictive value for mammographic abnormalities in screening.18,19 Therefore, there is uncertainty whether further additions in a screening setting are justified. To increase the usefulness of breast MRI as a screening tool, Kuhl et al20 recently proposed a streamlined protocol that reduces imaging time to approximately 3 minutes. The proposed protocol acquires only the precontrast and first postcontrast acquisition and evaluates lesions on the maximum-intensity projections and subtraction series. All dynamic information, the T2, and DWI are discarded. This yields a negative predictive value of 99.8% in screening. However, especially for the classification of small mass-like lesions, the typical finding in screening,21,22 additional dynamic information is important.5,21,23,24 www.investigativeradiology.com
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This implies the need for a dynamic scan protocol, while imaging time should not be extended. Recently, new k-space acquisition strategies have been introduced for dynamic breast MRI. These ultrafast sequences, such as time-resolved angiography with stochastic trajectories (TWIST), 4-dimensional timeresolved magnetic resonance angiography with keyhole, time-resolved imaging of contrast kinetics, and switch on the fly technique, can be used to capture the inflow of contrast in breast lesions.25Y29 All techniques heavily undersample the outer part of k-space but share data points between successive time points (aptly named view sharing) to increase the obtained spatial resolution to diagnostic quality. Sophisticated sampling patterns are used to minimize the disadvantages of view sharing. The rate of enhancement can still be accurately measured for each individual time point as the contrast in an image is determined by the center of k-space that is fully acquired.30 This is also visually highly attractive because successive maximum-intensity projections now can be presented as a high-quality movie of contrast inflow (Fig. 1, Supplemental Movie 1 [Supplemental Digital Content 1, which shows the typical enhancement pattern of an invasive ductal carcinoma in the right breast. Note that after the heart, but before anything else, the tumor enhances in a further nearly black breast. This ‘‘light bulb’’ effect greatly facilitates lesion detection. The vessels often observed on MIP projections of subtraction images from breast MRI are usually venous in origin, as is shown by the enhancement of the draining vessel after the enhancement of the tumor; http://links.lww.com/RLI/A147] and Supplemental Movie 2 [Supplemental Digital Content 2, which shows an multifocal invasive lobular cancer in the right breast. Dorsal a larger invasive mass is seen. More anteriorly an area of non-mass like enhancement enhances somewhat slower. This area consists mainly of lobular carcinoma in situ with microinvasion. Nonetheless, based upon morphology also the anterior lesion is easily classified as suspicious; http://links.lww.com/RLI/A148]. The potential of these new breast MRI techniques for screening has not yet been explored. In this work, we used a TWIST technique to obtain images of both breasts with diagnostic spatial resolution while simultaneously capturing the inflow of contrast in breast lesions. The total duration of this sequence is only 102 seconds. We assessed lesion visibility on these images and evaluated the maximum slope of the contrast enhancement versus time curve (MS) as a novel dynamic parameter to differentiate between benign and malignant breast disease. The aim of our study was to compare MS with the classic dynamic parameter in conventional DCE-MRI: the curve type as defined by the BIRADS lexicon.
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used for acquisition of inflow kinetics.31,32 Patients were positioned in the prone position with their arms down. The coil was adjusted to the breast size, but no compression was applied. Contrast administration (0.1 mmol/kg Dotarem [gadoteric acid 0.5 mmol/mL]; Guerbet, Villepinte, France) was performed through an intravenous (IV) cannula placed in the cubital vein. The power injector (Medrad, Warrendale, PA) was started immediately after completion of the first population of k-space in the TWIST sequence at a rate of 2.5 mL/s. The contrast bolus was followed by a 20 mL saline flush. Figure 2 provides a schematic drawing of the protocol with the dynamic data that can be extracted from the contrast-enhanced sequences, and specific scan parameters are listed in Table 1.
Image Evaluation All breast MRI scans were reported for clinical use by dedicated breast radiologists with at least 5 years of experience in breast MRI. A commercially available dedicated breast MRI workstation was used (DynaCAD, Invivo, Philips, Best, the Netherlands). For this study, the dynamic sequences of all enhancing lesions were reevaluated by 1 of 2 independent readers with more than 7 years’ experience in breast MRI. They were blinded to patient history and any information on the lesion except for its location. When the lesion was visible, relative enhancement versus time curves were created from both the TWIST series and the volumetric interpolated breath-hold examination (VIBE) series. For the TWISTacquisitions, the strongest enhancing voxels were regarded as being the most representative for the lesion. Consequently, the curve that was taken to represent the lesion was obtained from a 3 3 1 voxel region that showed the highest peak enhancement, which was determined with the aid of a color map of peak enhancement generated by DynaCAD. The most suspicious BIRADS curve was extracted from the VIBE acquisitions with the aid of a color-coded washout overlay. Both curves were extracted independently. Curves from the TWIST data were printed and presented in random order to 2 readers who determined MS in consensus. At this stage, no images of the tumor were provided. The MS was determined by drawing a tangent along the steepest (usually first) part of the curve. The slope of the tangent (percentage relative enhancement/second [%/s]) was then calculated (Fig. 3). The BIRADS curve types were determined by another independent reader.
Pathology MATERIALS AND METHODS Patients From January 2011, all patients were scanned using an institutional review boardYapproved breast MRI protocol that incorporated ultrafast TWIST acquisitions during the inflow of the contrast agent. The need for informed consent was waived by the institutional review board. We retrospectively evaluated the prospectively acquired database for all patients who presented with abnormalities between January 2011 and December 2011. In this period, 1031 patients were scanned. All patients with enhancing lesions that were histopathologically assessed (either benign or malignant) were included, as well as all patients with lesions that were at least 2 years stable (regarded as benign). Consequently, 160 consecutive patients who presented with 199 enhancing lesions were included.
Imaging We performed a bitemporal breast MRI protocol on 3-T MRI scanners (Siemens Magnetom Trio/Siemens Skyra) using a 16channel bilateral breast coil (Siemens, Erlangen, Germany). The protocol is an improvement of earlier published protocols that can be 580
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Information on histopathology of biopsied lesions was extracted from the pathology reports created at the time of treatment. These reports were created by 1 of 2 dedicated breast pathologists with at least 10 years of experience in breast pathology. For benign lesions, results of histopathological biopsy were considered conclusive. Lesions stable for more than 2 years were also regarded as benign. For malignant lesions, histopathological reports of the surgical specimen were retrieved.
Statistics We performed an receiver operating characteristic (ROC) analysis of the discriminating power of the MS, using histopathology or follow-up as ground truth. We subsequently defined cutoff values of the slope to classify lesions as low risk (MS 1, G15% chance of being malignant), intermediate risk (MS 2, 915% and G85% chance of being malignant), and high risk (MS 3, 985% chance of being malignant) in analogy to the classic washout analysis. Subsequently, we compared the predictive value of these thus created MS types with the conventional BIRADS curve types using ROC analysis. The areas under the curve (Az) were compared using the method of DeLong et al.33 Calculations were performed in SPSS * 2014 Lippincott Williams & Wilkins
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Ultrafast Dynamic Breast MRI
FIGURE 1. Selected stills (maximum intensity projections) from a movie of contrast inflow. In A, only the pulmonary artery enhances. In B, the contrast has reached the aorta. In C, the tumor in the right breast starts to enhance, just as the overlying infiltrated skin. In D, the tumor stands out like a light bulb in a further empty breast. In E, the draining veins become visible, and in F, minimal normal glandular tissue enhancement is seen.
statistics 20 (IBM SPSS, Hong Kong, China) and Medcalc 12.3 (Medcalc software, Mariakerke, Belgium). P values less than than 0.05 were considered significant.
RESULTS Lesions In total, 199 enhancing lesions were evaluated; 95 proved to be benign and 104 were malignant. The specifications of the lesions are * 2014 Lippincott Williams & Wilkins
presented in Table 2. All lesions were visible on the TWIST and VIBE acquisitions (relative sensitivity, 100%).
Maximum Slope Discriminating between benign and malignant lesions using MS achieves an Az of 0.829. The discriminating power of the MS is significantly better than that of the BIRADS curve types, which achieved an Az of 0.692 (P = 0.0036). www.investigativeradiology.com
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FIGURE 2. Schematic drawing of the breast MRI scan protocol: The TWIST acquisitions allow evaluation of the contrast inflow in the lesion, whereas the VIBE acquisitions are used for 3 time point analysis, creating the classic contrast enhancement versus time curve.
Specific Cutoff Values Based upon the ROC curve, a sensitivity of 90% can be achieved at a specificity of 67% when regarding all lesions with a maximum slope higher than 6.4%/s to be malignant. Similarly, 85% specificity is achieved at 65% sensitivity when regarding lesions with a maximum slope of more than 13.3%/s to be malignant. Consequently, we propose the use of cutoff values of 6.4%/s to differentiate low-risk from intermediate-risk lesions and 13.3%/s to differentiate intermediate-risk from high-risk lesions. This yields 3 MS types analogue to the classic curve types (Table 3). This can also be depicted graphically. When the ratio between the x- and y-axis of a grid of relative enhancement versus time is kept constant, the curve type can be appreciated by evaluation of the angle from the baseline as depicted in Figure 4. By clustering the data in MS types, only minimal discriminating power is lost. The Az of the MS type is 0.812, and significantly
outperforms BIRADS curve type analysis (P = 0.012). Figure 5 depicts the ROC curves.
DISCUSSION Maximum slope as a dynamic parameter achieves a much higher accuracy in the differentiation between benign and malignant breast lesions than BIRADS curve type analysis does. Thus, MS can replace conventional dynamic information in streamlined breast MRI protocols aimed at screening and can also be used for lesion classification in state-of-the-art breast MRI protocols. We did not evaluate the value of TWIST for evaluation of morphological parameters that are normally also used for lesion classification as that was not the focus of the study. The high spatial resolution that is achieved nevertheless meets the requirements of all breast MRI guidelines.10,11 This explains why, in our study, the relative sensitivity of TWIST when compared with that of VIBE for the
TABLE 1. Specific Scan Parameters of the Bitemporal Breast MRI Protocol
Spatial resolution, mm Number of time points Temporal resolution (per time point), s FOV TE/TR, ms FA b values Parallel imaging factor (GRAPPA) Reordering Central zone Sampling density outer zone
DWI
VIBE (T1)
TWIST (T1)
T2
1.5 1.5 4.0 1 186 340 60/6400 NA 50, 800 2 Standard NA NA
0.9 0.8 1.0 5 (1 pre, 4 post) 80 360 1.71/5.50 20 NA 3 3D centric NA NA
1.0 0.9 2.5 20 (1 pre, 19 post) 4.32 360 2.02/3.96 20 NA 3 Standard 15% 10%
1.3 1.1 2.5 1 88 340 143/3220 80 NA 3 Standard NA NA
High-resolution VIBE acquisitions are obtained before and 4 times after contrast administration. They are interleaved with a series of 20 ultrafast TWIST acquisitions before and during the inflow of the contrast agent. The first TWIST acquisition populates the entire k-space and lasts 17 seconds; subsequent acquisitions sample the central zone and replace 10% of the outer k-space data per time point in a stochastic filling pattern. The dynamic sequences are preceded by a diffusion-weighted series and followed by a T2-weighted TSE acquisition. DWI indicates diffusion-weighted imaging; FA, flip angle; FOV, field of view; GRAPPA, generalized autocalibrating partially parallel acquisition; MRI, magnetic resonance imaging; NA, not applicable; TE/TR, echo time/repetition time; TSE, turbo spin echo; TWIST, time-resolved angiography with stochastic trajectories.
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TABLE 3. Clinical Meaning of MS Types MS Type 1 2 3
MS, %/s
Clinical Meaning
G6.4 Q6.4, G13.3 Q13.3
Cancer unlikely (G15%) Cancer equivocal Cancer likely (985%)
MS indicates maximum slope of the relative enhancement versus time curve.
FIGURE 3. Determining the MS. A tangent is drawn along the steepest part of the curve. The slope of the tangent is calculated by dividing the relative enhancement over time.
detection of the index lesion was 100%. The different approach in image acquisition using TWIST does not seem to influence the sensitivity of the technique, at least in retrospection. Because of the high spatial resolution, morphological information is preserved and reporting of the TWIST images according to the BI-RADS lexicon is possible. In computer-aided analysis of morphological parameters, identical diagnostic value for TWIST and VIBE acquisitions was found.34 Whether this holds also true for human readers remains to be investigated in prospective clinical trials, possibly opening the possibility of a TWIST-only screening protocol with an unprecedented total acquisition time of 102 seconds. The fact that breast MRI is not as far introduced in breast screening as could be expected based on the high gain in sensitivity over mammography is probably mainly cost based. The exact costs of breast MRI are highly variable. This depends on standards of specific countries. However, in literature, estimated costs for cost-effectiveness analysis range between $277 and $965 and average around $500 (€369) for a 30-minute scan.7Y9,35,36 Using ultrafast MRI, a total ‘‘inroom time’’ of 10 minutes including 8 minutes for the positioning of women on the MRI table should be feasible, allowing up to 6 women per hour and thus saving more than $300 per woman scanned. Because patients are required to lie motionless in a narrow tube during the procedure, a substantial shortening of the acquisition time also makes the examination more acceptable to women with slight symptoms of claustrophobia.37,38
Some drawbacks of breast MRI as a screening tool remain present: (1) the need for IV gadolinium-based contrast administration, which implies the need for placement of an IV cannula; (2) the risks associated with contrast administration, including allergic reactions (usually mild) and (rarely) nephrogenic systemic fibrosis in women with severely impaired renal function39,40; and (3) the need to evaluate premenopausal women in the right period of the menstrual cycle, as enhancing glandular tissue may otherwise obscure lesions.41,42 When using breast MRI for screening, the preservation of specificity is still a major issue. The high sensitivity of MRI for both benign and malignant disease implies detection of many benign lesions that would otherwise remain occult. Benign lesions may easily mimic early breast cancer as both often present as a relatively indistinct small mass. The following need to biopsy many benign lesions places a high emotional burden on women screened and adds substantial additional costs to screening.9,36,43,44 This is the reason that a high-resolution T2 sequence that provides detailed morphological information and may show necrosis and edema in and around breast lesions is added to state-of-the-art breast MRI protocols.13,14 Furthermore, DWI has also been added because cellular density is generally high in breast cancers, and consequently, diffusion is restricted, thus allowing some further differentiation.15Y17 However, these techniques are additional to DCE-MRI and cannot replace the dynamic
TABLE 2. Histopathology of Included Lesions Malignant
Benign
Lesion Type
n
IDC ILC DCIS Pathologic Lymph nodes Other
104 70 18 10 3 3
Lesion Type
n
Stable lesion (no pathology) Fibroadenoma Lymph node Inflamed cyst Microcysts Adenosis Other
95 32 29 7 6 5 5 11
IDC indicates invasive ductal carcinoma; ILC, invasive lobular carcinoma; DCIS, ductal carcinoma in situ.
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FIGURE 4. Evaluation of inflow curve types by upslope angle from the baseline. In the proposed grid (relative enhancement of 1000% on the y-axis equals 90 seconds on the x-axis), an angle of 50- or more classifies a lesion as probably malignant. An angle of 30- or less classifies a lesion as probably benign. An exemplary curve of a probably malignant lesion is drawn in gray. The white line corresponds to the actual slope. www.investigativeradiology.com
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FIGURE 5. ROC curves of MS as continuous variable, MS type using the specific cutoffs described above, and the BIRADS curve type.
information that is in small mass lesions of vital importance to differentiate between benign and malignant disease.45 Nevertheless, T2 and DWI may still provide additional information on top of morphology and MS, although the magnitude is unknown. Whether subsequent full state-of-the-art breast MRI after abnormal streamlined screening breast MRI examinations can further reduce unnecessary biopsies thus remains to be investigated. The underlying pathophysiology of MS is not easily explained. In empirical studies, MS is governed by the first pass of the contrast agent through the lesion and hence shows perfusion.46 Nevertheless, the temporal resolution applied in this study (4.32 seconds) is not sufficiently high to capture only perfusion effects. Consequently, the curve shape is strongly influenced by early leakage of contrast from the vessels into the extravascular extracellular space, a process that is governed by the transfer constant (or Ktrans), which is dependent on the permeability surface area of the vessels in the tumor.47 Studies that modeled dynamic information obtained from fast acquisitions at a much lower spatial resolution than applied in this study showed that Ktrans values, or variations thereof, are indeed a very strong discriminators between benign and malignant disease.31,48Y51 Nevertheless, these techniques have so far not surfaced in clinical practice because of the difficulties associated with this modeling, which include the determination of an arterial input function that is often not robust.52 Moreover, modeling techniques for breast imaging are not commercially available and therefore not accessible outside research facilities. In contrast, MS can be used instantaneously as no dedicated software is required. The use of a TWIST sequence for breast MRI has been described before. Herrmann et al26 showed in a small pilot study in 14 patients (of which 4 had an abnormality) that TWIST can be used to obtain dynamic images at a very high temporal resolution. The first part of the contrast enhancement versus time curve could only be fully appreciated with very fast sequences (5.7 seconds in their protocol). They also showed that benign lesions enhance later than malignant ones, which is in line with older studies that used single slice techniques to capture contrast inflow in breast lesions.53 A further 584
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advantage of the TWIST sequence is that, because of the data sharing between successive time points, the sequence proved robust against motion artifacts. Tudorica et al54 recently also described the use of TWIST for breast MRI. Although they did not reduce the temporal resolution further than 18 seconds, they showed that the resulting images are very comparable with images from conventional sequences. Furthermore, they showed that the dynamic data from the TWIST sequences are also well suited for quantitative pharmacokinetic analysis, yielding a maximum specificity of 91% at a sensitivity of 100% using the $Ktrans technique.50 Le et al55 recently showed that TWIST can be combined with a DIXON technique, allowing fatsuppressed imaging at high speed. Our study has limitations. The proposed cutoff values for MS are probably dependent on many technical parameters such as contrast agent, contrast dose, and specific scan protocol settings and need to be verified. However, the simple observation that the steeper MS, the higher the likelihood of malignancy is likely holds true regardless of these factors, which allows fast implementation in clinical practice. Although evaluation of MS can be performed without dedicated software, the use of a dedicated breast MRI workstation is still recommended for image registration, the creation of subtraction series, and simple color-coded overlays.56 It is already possible to create a colorcoded overlay of MS on several commercially available software tools. Despite the good classification properties of MS, it remains essential to evaluate morphology, although this was outside the scope of the current investigation.5,10,11 By definition, 10% of malignant lesions has an MS type 1, and these should not be missed. Some cancer types, most notoriously DCIS and low-grade invasive lobular carcinoma, enhance less because of the relative paucity of neovascularization and the maturation of the new formed vessels.57,58 Morphologically, these lesions often present as non-mass-like enhancement. It is therefore not surprising that in our study, the group of malignancies with an MS type 1 consists of 4 pure DCIS cases, 2 DCIS cases with small invasive foci, 1 diffuse growing invasive lobular carcinoma, 1 tubular carcinoma, 1 pathological lymph node, and only 1 mass-like invasive ductal carcinoma. Before screening regimens can be converted to ultrafast breast MRI, a prospective study in a screening setting comparing the performance of TWIST-only imaging with that of a full state-of-the-art breast MRI protocol is still mandatory. However, it does not require a whole new learning curve for reporting radiologists, as most of the evaluation techniques are identical to current clinical practice. In conclusion, we present a novel approach to dynamic breast MRI that combines common morphologic evaluation with dynamic information from the contrast wash-in phase rather than washout phase. The accuracy of MS is significantly higher than that of conventional BIRADS curve type analysis, which implies that the washout phase no longer needs to be imaged, while specificity may be improved. The substantial shortening of breast MRI protocols thus achieved may allow cost-effective breast MRI screening in a much larger population than is currently possible, including women with an intermediate lifetime risk based on family history and women with very dense breasts. REFERENCES 1. Kuhl CK, Schrading S, Bieling HB, et al. MRI for diagnosis of pure ductal carcinoma in situ: a prospective observational study. Lancet. 2007;370: 485Y492. 2. Peters NH, Borel Rinkes I, Zuithoff NP, et al. Meta-analysis of MR imaging in the diagnosis of breast lesions. Radiology. 2008;246:116Y124. 3. Carbonaro LA, Pediconi F, Verardi N, et al. Breast MRI using a high-relaxivity contrast agent: an overview. AJR Am J Roentgenol. 2011;196:942Y955. 4. Kuhl CK. Breast MR imaging at 3 T. Magn Reson Imaging Clin North Am. 2007;15:315Y320, vi. 5. Pinker-Domenig K, Bogner W, Gruber S, et al. High resolution MRI of the breast at 3 T: which BI-RADS(R) descriptors are most strongly associated with the diagnosis of breast cancer? Eur Radiol. 2012;22:322Y330.
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6. Boetes C, Mann RM. Ductal carcinoma in situ and breast MRI. Lancet. 2007;370:459Y460. 7. Saadatmand S, Tilanus-Linthorst MM, Rutgers EJ, et al. Cost-effectiveness of screening women with familial risk for breast cancer with magnetic resonance imaging. J Natl Cancer Inst. 2013;105:1314Y1321. 8. Pataky R, Armstrong L, Chia S, et al. Cost-effectiveness of MRI for breast cancer screening in BRCA1/2 mutation carriers. BMC Cancer. 2013;13:339. 9. Griebsch I, Brown J, Boggis C, et al. Cost-effectiveness of screening with contrast enhanced magnetic resonance imaging vs x-ray mammography of women at a high familial risk of breast cancer. Br J Cancer. 2006;95:801Y810. 10. Mann RM, Kuhl CK, Kinkel K, et al. Breast MRI: guidelines from the European Society of Breast Imaging. Eur Radiol. 2008;18:1307Y1318. 11. Sardanelli F, Boetes C, Borisch B, et al. Magnetic resonance imaging of the breast: recommendations from the EUSOMA working group. Eur J Cancer. 2010;46:1296Y1316. 12. Ikeda DM, Hylton NM, Kuhl CK, et al. BI-RADS: magnetic resonance imaging, 1st edition. In: D’Orsi CJ, Mendelson EB, Ikeda DM, et al, eds. Breast Imaging Reporting and Data System: ACR BI-RADSVBreast Imaging Atlas. Reston, VA: American College of Radiology; 2003. 13. Baltzer PA, Dietzel M, Kaiser WA. Nonmass lesions in magnetic resonance imaging of the breast: additional T2-weighted images improve diagnostic accuracy. J Comput Assist Tomogr. 2011;35:361Y366. 14. Dietzel M, Baltzer PA, Vag T, et al. The necrosis sign in magnetic resonancemammography: diagnostic accuracy in 1,084 histologically verified breast lesions. Breast J. 2010;16:603Y608. 15. Sinha S, Lucas-Quesada FA, Sinha U, et al. In vivo diffusion-weighted MRI of the breast: potential for lesion characterization. J Magn Reson Imaging. 2002;15:693Y704. 16. Guo Y, Cai YQ, Cai ZL, et al. Differentiation of clinically benign and malignant breast lesions using diffusion-weighted imaging. J Magn Reson Imaging. 2002;16:172Y178. 17. Ei Khouli RH, Jacobs MA, Mezban SD, et al. Diffusion-weighted imaging improves the diagnostic accuracy of conventional 3.0-T breast MR imaging. Radiology. 2010;256:64Y73. 18. Saslow D, Boetes C, Burke W, et al. American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. CA Cancer J Clin. 2007;57:75Y89. 19. Kuhl C, Weigel S, Schrading S, et al. Prospective multicenter cohort study to refine management recommendations for women at elevated familial risk of breast cancer: the EVA trial. J Clin Oncol. 2010;28:1450Y1457. 20. Kuhl CK, Schrading S, Strobel K, et al. Accelerated breast MRI for breast cancer screening. ASCO. J Clin Oncol. 2013;31(suppl 26; abstr 1):2013. 21. Schrading S, Kuhl CK. Mammographic, US, and MR imaging phenotypes of familial breast cancer. Radiology. 2008;246:58Y70. 22. Kriege M, Brekelmans CT, Peterse H, et al. Tumor characteristics and detection method in the MRISC screening program for the early detection of hereditary breast cancer. Breast Cancer Res Treat. 2007;102:357Y363. 23. Schnall MD, Blume J, Bluemke DA, et al. Diagnostic architectural and dynamic features at breast MR imaging: multicenter study. Radiology. 2006;238:42Y53. 24. Gutierrez RL, DeMartini WB, Eby PR, et al. BI-RADS lesion characteristics predict likelihood of malignancy in breast MRI for masses but not for nonmasslike enhancement. AJR Am J Roentgenol. 2009;193:994Y1000. 25. Cprum CA, Babcock A, Idiyatullin D, et al. The utility of sweep imaging with Fourier transform (SWIFT) in breast cancer. Proc Intl Soc Mag Reson Med. 2012;20:457. 26. Herrmann KH, Baltzer PA, Dietzel M, et al. Resolving arterial phase and temporal enhancement characteristics in DCE MRM at high spatial resolution with TWIST acquisition. J Magn Reson Imaging. 2011;34:973Y982. 27. Mann RM, Mus RD, Geppert C, et al. Ultrafast dynamic imaging of the breast at diagnostic spatial resolution using TWIST. Proc Intl Soc Mag Reson Med. 2011;19:1016. 28. Pickles MD, Gibbs P, Bayram E, et al. TRICKS based DCE-MRI: a potential route to both high spatial and high temporal resolution breast dynamic datasets. Proc Intl Soc Mag Reson Med. 2012;20:1482. 29. Saranathan M, Rettmann DW, Hargreaves BA, et al. High spatio-temporal resolution breast dynamic contrast enhanced MRI at 3 T. Proc Intl Soc Mag Reson Med. 2012;20:456. 30. Le Y, Kipfer H, Majidi S, et al. Application of time-resolved angiography with stochastic trajectories (TWIST)-Dixon in dynamic contrast-enhanced (DCE) breast MRI. J Magn Reson Imaging. 2013;38:1033Y1042. 31. Veltman J, Stoutjesdijk M, Mann R, et al. Contrast-enhanced magnetic resonance imaging of the breast: the value of pharmacokinetic parameters derived from fast dynamic imaging during initial enhancement in classifying lesions. Eur Radiol. 2008;18:1123Y1133. 32. Pinker K, Grabner G, Bogner W, et al. A combined high temporal and high spatial resolution 3 tesla MR imaging protocol for the assessment of breast lesions: initial results. Invest Radiol. 2009;44:553Y558.
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33. DeLong ER, DeLong DM, Clarke-Pearson DL. Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. Biometrics. 1988;44:837Y845. 34. Platel B, Mus R, Welte T, et al. Automated characterization of breast lesions imaged with an ultrafast DCE-MR protocol. IEEE Trans Med Imaging. 2013. [Epub ahead of print]. 35. Moore SG, Shenoy PJ, Fanucchi L, et al. Cost-effectiveness of MRI compared to mammography for breast cancer screening in a high risk population. BMC Health Serv Res. 2009;9:9. 36. Taneja C, Edelsberg J, Weycker D, et al. Cost effectiveness of breast cancer screening with contrast-enhanced MRI in high-risk women. J Am Coll Radiol. 2009;6:171Y179. 37. Thorpe S, Salkovskis PM, Dittner A. Claustrophobia in MRI: the role of cognitions. Magn Reson Imaging. 2008;26:1081Y1088. 38. Berg WA, Blume JD, Adams AM, et al. Reasons women at elevated risk of breast cancer refuse breast MR imaging screening: ACRIN 6666. Radiology. 2010;254:79Y87. 39. Niendorf HP, Dinger JC, Haustein J, et al. Tolerance data of Gd-DTPA: a review. Eur J Radiol. 1991;13:15Y20. 40. Thomsen HS, Morcos SK, Almen T, et al. Nephrogenic systemic fibrosis and gadolinium-based contrast media: updated ESUR Contrast Medium Safety Committee guidelines. Eur Radiol. 2013;23:307Y318. 41. Delille JP, Slanetz PJ, Yeh ED, et al. Physiologic changes in breast magnetic resonance imaging during the menstrual cycle: perfusion imaging, signal enhancement, and influence of the T1 relaxation time of breast tissue. Breast J. 2005;11:236Y241. 42. Kuhl CK, Bieling HB, Gieseke J, et al. Healthy premenopausal breast parenchyma in dynamic contrast-enhanced MR imaging of the breast: normal contrast medium enhancement and cyclical-phase dependency. Radiology. 1997;203:137Y144. 43. Schnur JB, Montgomery GH, Hallquist MN, et al. Anticipatory psychological distress in women scheduled for diagnostic and curative breast cancer surgery. Int J Behav Med. 2008;15:21Y28. 44. Brett J, Bankhead C, Henderson B, et al. The psychological impact of mammographic screening: a systematic review. Psychooncology. 2005;14:917Y938. 45. Pediconi F, Miglio E, Telesca M, et al. Effect of preoperative breast magnetic resonance imaging on surgical decision making and cancer recurrence rates. Invest Radiol. 2012;47:128Y135. 46. Taylor JS, Reddick WE. Evolution from empirical dynamic contrast-enhanced magnetic resonance imaging to pharmacokinetic MRI. Adv Drug Deliv Rev. 2000;41:91Y110. 47. Tofts PS, Berkowitz B, Schnall MD. Quantitative analysis of dynamic Gd-DTPA enhancement in breast tumors using a permeability model. Magn Reson Med. 1995;33:564Y568. 48. Gibbs P, Liney GP, Lowry M, et al. Differentiation of benign and malignant sub-1 cm breast lesions using dynamic contrast enhanced MRI. Breast. 2004;13: 115Y121. 49. Hoffmann U, Brix G, Knopp MV, et al. Pharmacokinetic mapping of the breast: a new method for dynamic MR mammography. Magn Reson Med. 1995;33:506Y514. 50. Huang W, Tudorica LA, Li X, et al. Discrimination of benign and malignant breast lesions by using shutter-speed dynamic contrast-enhanced MR imaging. Radiology. 2011;261:394Y403. 51. Renz DM, Diekmann F, Schmitzberger FF, et al. Pharmacokinetic approach for dynamic breast MRI to indicate signal intensity time curves of benign and malignant lesions by using the tumor flow residence time. Invest Radiol. 2013;48:69Y78. 52. Port RE, Knopp MV, Brix G. Dynamic contrast-enhanced MRI using GdDTPA: interindividual variability of the arterial input function and consequences for the assessment of kinetics in tumors. Magn Reson Med. 2001;45: 1030Y1038. 53. Boetes C, Barentsz JO, Mus RD, et al. MR characterization of suspicious breast lesions with a gadolinium-enhanced TurboFLASH subtraction technique. Radiology. 1994;193:777Y781. 54. Tudorica LA, Oh KY, Roy N, et al. A feasible high spatiotemporal resolution breast DCE-MRI protocol for clinical settings. Magn Reson Imaging. 2012;30: 1257Y1267. 55. Le Y, Kroeker R, Kipfer HD, et al. Development and evaluation of TWIST Dixon for dynamic contrast-enhanced (DCE) MRI with improved acquisition efficiency and fat suppression. J Magn Reson Imaging. 2012;36:483Y491. 56. Dromain C, Boyer B, Ferre R, et al. Computed-aided diagnosis (CAD) in the detection of breast cancer. Eur J Radiol. 2013;82:417Y423. 57. Mann RM, Veltman J, Huisman H, et al. Comparison of enhancement characteristics between invasive lobular carcinoma and invasive ductal carcinoma. J Magn Reson Imaging. 2011;34:293Y300. 58. Rosen EL, Smith-Foley SA, DeMartini WB, et al. BI-RADS MRI enhancement characteristics of ductal carcinoma in situ. Breast J. 2007;13:545Y550.
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A Novel Approach to Contrast-Enhanced Breast Magnetic Resonance Imaging for Screening High-Resolution Ultrafast Dynamic Imaging Ritse M. Mann, MD, PhD,* Roel D. Mus, MD,* Jan van Zelst, MD,* Christian Geppert, PhD,Þ Nico Karssemeijer, PhD,*þ and Bram Platel, PhD* Objectives: The use of breast magnetic resonance imaging (MRI) as screening tool has been stalled by high examination costs. Scan protocols have lengthened to optimize specificity. Modern view-sharing sequences now enable ultrafast dynamic whole-breast MRI, allowing much shorter and more cost-effective procedures. This study evaluates whether dynamic information from ultrafast breast MRI can be used to replace standard dynamic information to preserve accuracy. Materials and Methods: We interleaved 20 ultrafast time-resolved angiography with stochastic trajectory (TWIST) acquisitions (0.9 1 2.5 mm, temporal resolution, 4.3 seconds) during contrast inflow in a regular highresolution dynamic MRI protocol. A total of 160 consecutive patients with 199 enhancing abnormalities (95 benign and 104 malignant) were included. The maximum slope of the relative enhancement versus time curve (MS) obtained from the TWIST and curve type obtained from the regular dynamic sequence as defined in the breast imaging reporting and data system (BIRADS) lexicon were recorded. Diagnostic performance was compared using receiver operating characteristic analysis. Results: All lesions were visible on both the TWIST and standard series. Maximum slope allows discrimination between benign and malignant disease with high accuracy (area under the curve, 0.829). Types of MS were defined in analogy to BIRADS curve types: MS type 3 implies a high risk of malignancy (MS 913.3%/s; specificity, 85%), MS type 2 yields intermediate risk (MS G13.3%/s and 96.4%/s), and MS type 1 implies a low risk (MS G6.4%/s; sensitivity, 90%). This simplification provides a much higher accuracy than the much lengthier BIRADS curve type analysis does (area under the curve, 0.812 vs 0.692; P = 0.0061). Conclusions: Ultrafast dynamic breast MRI allows detection of breast lesions and classification with high accuracy using MS. This allows substantial shortening of scan protocols and hence reduces imaging costs, which is beneficial especially for screening. Key Words: breast cancer, dynamic contrast-enhanced (DCE) breast MRI, contrast enhancement versus time curve, ultrafast dynamic MRI, MRI protocol length reduction, screening, costs (Invest Radiol 2014;49: 579Y585)
D
ynamic contrast-enhanced (DCE) breast magnetic resonance imaging (MRI) is the most sensitive method for the detection of breast cancer currently available. Recent evaluations have shown that
Received for publication January 2, 2014; and accepted for publication, after revision, February 17, 2014. From the *Radboud University Nijmegen Medical Centre, Department of Radiology, Nijmegen, the Netherlands; †Siemens Medical Solutions, New York, NY; and ‡FraunHofer MEVIS, Bremen, Germany. Conflicts of interest and sources of funding: This work was supported by the European Unions Seventh Framework Programme FP7 under grant agreement 306088. Supplemental digital contents are available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.investigativeradiology.com) Reprints: Ritse M. Mann, MD, PhD, Radboud University Nijmegen Medical Centre, Department of Radiology (766), PO Box 9101, 6500 HB Nijmegen, the Netherlands. E-mail: [email protected]. Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 0020-9996/14/4909Y0579
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MRI is superior to mammography and ultrasound not only in the detection of invasive breast cancer but also in the detection of ductal carcinoma in situ (DCIS), the noninvasive precursor of breast cancer.1 In meta-analysis, an overall sensitivity of 90% has been reported.2 The potential of breast MRI is likely even higher because expert centers worldwide consistently report sensitivities of greater than 95%, for example, by introducing 3-T MRI and high-relaxivity contrast agents, which have been associated with an increase in sensitivity.3Y5 Based on these evaluations, it has been concluded that breast MRI should be regarded as an independent modality for the early detection of breast cancer.6 Despite its excellent performance, the use of MRI for breast cancer screening has thus far been restricted to patients at very high risk for the development of breast cancer. In terms of cancer detection, MRI has been shown superior to mammography also for women at intermediate risk. Nevertheless, recent cost-effectiveness evaluations have clearly shown that costs in non-BRCA mutation carriers may exceed $100,000 per life year gained, especially in women younger than 50 years.7 The need for cost reduction of MRI scanning itself is evident from the fact that costs in MRI screening are most influenced by the actual price of the MRI.8,9 In recent years, most research in breast MRI addressed the less than perfect specificity of the technique, because breast MRI has a high sensitivity for both malignant and benign disease. Standard DCE breast MRI consists of 3 bilateral T1-weighted spoiled gradient echo acquisitions. These are respectively obtained before contrast administration, at the peak of contrast enhancement around 90 seconds after administration, and in the late phase 5 to 7 minutes after contrast administration.10,11 Structured reporting according to the breast imaging reporting and data system (BIRADS) lexicon, which takes lesion shape, margin, internal enhancement, and shape of the contrast enhancement versus time curve into account,12 improves lesion classification. The dynamic evaluation relies mainly on the contrast washout phase. To further improve specificity, this protocol has been expanded with a highresolution T2 sequence and diffusion-weighted imaging (DWI).13Y17 An up-to-date breast MRI protocol takes between 12 and 20 minutes, and in most centers, no more than 2 breast MRI examinations per hour are performed on a single MRI scanner.5 The task to increase the specificity of breast MRI has therefore reduced its feasibility as a screening tool, lengthening both the examination and the time needed for interpretation and thus increasing the costs. However, the positive predictive value of an MRI finding at DCE-MRI only is at approximately 40%, already as high as the positive predictive value for mammographic abnormalities in screening.18,19 Therefore, there is uncertainty whether further additions in a screening setting are justified. To increase the usefulness of breast MRI as a screening tool, Kuhl et al20 recently proposed a streamlined protocol that reduces imaging time to approximately 3 minutes. The proposed protocol acquires only the precontrast and first postcontrast acquisition and evaluates lesions on the maximum-intensity projections and subtraction series. All dynamic information, the T2, and DWI are discarded. This yields a negative predictive value of 99.8% in screening. However, especially for the classification of small mass-like lesions, the typical finding in screening,21,22 additional dynamic information is important.5,21,23,24 www.investigativeradiology.com
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This implies the need for a dynamic scan protocol, while imaging time should not be extended. Recently, new k-space acquisition strategies have been introduced for dynamic breast MRI. These ultrafast sequences, such as time-resolved angiography with stochastic trajectories (TWIST), 4-dimensional timeresolved magnetic resonance angiography with keyhole, time-resolved imaging of contrast kinetics, and switch on the fly technique, can be used to capture the inflow of contrast in breast lesions.25Y29 All techniques heavily undersample the outer part of k-space but share data points between successive time points (aptly named view sharing) to increase the obtained spatial resolution to diagnostic quality. Sophisticated sampling patterns are used to minimize the disadvantages of view sharing. The rate of enhancement can still be accurately measured for each individual time point as the contrast in an image is determined by the center of k-space that is fully acquired.30 This is also visually highly attractive because successive maximum-intensity projections now can be presented as a high-quality movie of contrast inflow (Fig. 1, Supplemental Movie 1 [Supplemental Digital Content 1, which shows the typical enhancement pattern of an invasive ductal carcinoma in the right breast. Note that after the heart, but before anything else, the tumor enhances in a further nearly black breast. This ‘‘light bulb’’ effect greatly facilitates lesion detection. The vessels often observed on MIP projections of subtraction images from breast MRI are usually venous in origin, as is shown by the enhancement of the draining vessel after the enhancement of the tumor; http://links.lww.com/RLI/A147] and Supplemental Movie 2 [Supplemental Digital Content 2, which shows an multifocal invasive lobular cancer in the right breast. Dorsal a larger invasive mass is seen. More anteriorly an area of non-mass like enhancement enhances somewhat slower. This area consists mainly of lobular carcinoma in situ with microinvasion. Nonetheless, based upon morphology also the anterior lesion is easily classified as suspicious; http://links.lww.com/RLI/A148]. The potential of these new breast MRI techniques for screening has not yet been explored. In this work, we used a TWIST technique to obtain images of both breasts with diagnostic spatial resolution while simultaneously capturing the inflow of contrast in breast lesions. The total duration of this sequence is only 102 seconds. We assessed lesion visibility on these images and evaluated the maximum slope of the contrast enhancement versus time curve (MS) as a novel dynamic parameter to differentiate between benign and malignant breast disease. The aim of our study was to compare MS with the classic dynamic parameter in conventional DCE-MRI: the curve type as defined by the BIRADS lexicon.
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used for acquisition of inflow kinetics.31,32 Patients were positioned in the prone position with their arms down. The coil was adjusted to the breast size, but no compression was applied. Contrast administration (0.1 mmol/kg Dotarem [gadoteric acid 0.5 mmol/mL]; Guerbet, Villepinte, France) was performed through an intravenous (IV) cannula placed in the cubital vein. The power injector (Medrad, Warrendale, PA) was started immediately after completion of the first population of k-space in the TWIST sequence at a rate of 2.5 mL/s. The contrast bolus was followed by a 20 mL saline flush. Figure 2 provides a schematic drawing of the protocol with the dynamic data that can be extracted from the contrast-enhanced sequences, and specific scan parameters are listed in Table 1.
Image Evaluation All breast MRI scans were reported for clinical use by dedicated breast radiologists with at least 5 years of experience in breast MRI. A commercially available dedicated breast MRI workstation was used (DynaCAD, Invivo, Philips, Best, the Netherlands). For this study, the dynamic sequences of all enhancing lesions were reevaluated by 1 of 2 independent readers with more than 7 years’ experience in breast MRI. They were blinded to patient history and any information on the lesion except for its location. When the lesion was visible, relative enhancement versus time curves were created from both the TWIST series and the volumetric interpolated breath-hold examination (VIBE) series. For the TWISTacquisitions, the strongest enhancing voxels were regarded as being the most representative for the lesion. Consequently, the curve that was taken to represent the lesion was obtained from a 3 3 1 voxel region that showed the highest peak enhancement, which was determined with the aid of a color map of peak enhancement generated by DynaCAD. The most suspicious BIRADS curve was extracted from the VIBE acquisitions with the aid of a color-coded washout overlay. Both curves were extracted independently. Curves from the TWIST data were printed and presented in random order to 2 readers who determined MS in consensus. At this stage, no images of the tumor were provided. The MS was determined by drawing a tangent along the steepest (usually first) part of the curve. The slope of the tangent (percentage relative enhancement/second [%/s]) was then calculated (Fig. 3). The BIRADS curve types were determined by another independent reader.
Pathology MATERIALS AND METHODS Patients From January 2011, all patients were scanned using an institutional review boardYapproved breast MRI protocol that incorporated ultrafast TWIST acquisitions during the inflow of the contrast agent. The need for informed consent was waived by the institutional review board. We retrospectively evaluated the prospectively acquired database for all patients who presented with abnormalities between January 2011 and December 2011. In this period, 1031 patients were scanned. All patients with enhancing lesions that were histopathologically assessed (either benign or malignant) were included, as well as all patients with lesions that were at least 2 years stable (regarded as benign). Consequently, 160 consecutive patients who presented with 199 enhancing lesions were included.
Imaging We performed a bitemporal breast MRI protocol on 3-T MRI scanners (Siemens Magnetom Trio/Siemens Skyra) using a 16channel bilateral breast coil (Siemens, Erlangen, Germany). The protocol is an improvement of earlier published protocols that can be 580
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Information on histopathology of biopsied lesions was extracted from the pathology reports created at the time of treatment. These reports were created by 1 of 2 dedicated breast pathologists with at least 10 years of experience in breast pathology. For benign lesions, results of histopathological biopsy were considered conclusive. Lesions stable for more than 2 years were also regarded as benign. For malignant lesions, histopathological reports of the surgical specimen were retrieved.
Statistics We performed an receiver operating characteristic (ROC) analysis of the discriminating power of the MS, using histopathology or follow-up as ground truth. We subsequently defined cutoff values of the slope to classify lesions as low risk (MS 1, G15% chance of being malignant), intermediate risk (MS 2, 915% and G85% chance of being malignant), and high risk (MS 3, 985% chance of being malignant) in analogy to the classic washout analysis. Subsequently, we compared the predictive value of these thus created MS types with the conventional BIRADS curve types using ROC analysis. The areas under the curve (Az) were compared using the method of DeLong et al.33 Calculations were performed in SPSS * 2014 Lippincott Williams & Wilkins
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FIGURE 1. Selected stills (maximum intensity projections) from a movie of contrast inflow. In A, only the pulmonary artery enhances. In B, the contrast has reached the aorta. In C, the tumor in the right breast starts to enhance, just as the overlying infiltrated skin. In D, the tumor stands out like a light bulb in a further empty breast. In E, the draining veins become visible, and in F, minimal normal glandular tissue enhancement is seen.
statistics 20 (IBM SPSS, Hong Kong, China) and Medcalc 12.3 (Medcalc software, Mariakerke, Belgium). P values less than than 0.05 were considered significant.
RESULTS Lesions In total, 199 enhancing lesions were evaluated; 95 proved to be benign and 104 were malignant. The specifications of the lesions are * 2014 Lippincott Williams & Wilkins
presented in Table 2. All lesions were visible on the TWIST and VIBE acquisitions (relative sensitivity, 100%).
Maximum Slope Discriminating between benign and malignant lesions using MS achieves an Az of 0.829. The discriminating power of the MS is significantly better than that of the BIRADS curve types, which achieved an Az of 0.692 (P = 0.0036). www.investigativeradiology.com
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FIGURE 2. Schematic drawing of the breast MRI scan protocol: The TWIST acquisitions allow evaluation of the contrast inflow in the lesion, whereas the VIBE acquisitions are used for 3 time point analysis, creating the classic contrast enhancement versus time curve.
Specific Cutoff Values Based upon the ROC curve, a sensitivity of 90% can be achieved at a specificity of 67% when regarding all lesions with a maximum slope higher than 6.4%/s to be malignant. Similarly, 85% specificity is achieved at 65% sensitivity when regarding lesions with a maximum slope of more than 13.3%/s to be malignant. Consequently, we propose the use of cutoff values of 6.4%/s to differentiate low-risk from intermediate-risk lesions and 13.3%/s to differentiate intermediate-risk from high-risk lesions. This yields 3 MS types analogue to the classic curve types (Table 3). This can also be depicted graphically. When the ratio between the x- and y-axis of a grid of relative enhancement versus time is kept constant, the curve type can be appreciated by evaluation of the angle from the baseline as depicted in Figure 4. By clustering the data in MS types, only minimal discriminating power is lost. The Az of the MS type is 0.812, and significantly
outperforms BIRADS curve type analysis (P = 0.012). Figure 5 depicts the ROC curves.
DISCUSSION Maximum slope as a dynamic parameter achieves a much higher accuracy in the differentiation between benign and malignant breast lesions than BIRADS curve type analysis does. Thus, MS can replace conventional dynamic information in streamlined breast MRI protocols aimed at screening and can also be used for lesion classification in state-of-the-art breast MRI protocols. We did not evaluate the value of TWIST for evaluation of morphological parameters that are normally also used for lesion classification as that was not the focus of the study. The high spatial resolution that is achieved nevertheless meets the requirements of all breast MRI guidelines.10,11 This explains why, in our study, the relative sensitivity of TWIST when compared with that of VIBE for the
TABLE 1. Specific Scan Parameters of the Bitemporal Breast MRI Protocol
Spatial resolution, mm Number of time points Temporal resolution (per time point), s FOV TE/TR, ms FA b values Parallel imaging factor (GRAPPA) Reordering Central zone Sampling density outer zone
DWI
VIBE (T1)
TWIST (T1)
T2
1.5 1.5 4.0 1 186 340 60/6400 NA 50, 800 2 Standard NA NA
0.9 0.8 1.0 5 (1 pre, 4 post) 80 360 1.71/5.50 20 NA 3 3D centric NA NA
1.0 0.9 2.5 20 (1 pre, 19 post) 4.32 360 2.02/3.96 20 NA 3 Standard 15% 10%
1.3 1.1 2.5 1 88 340 143/3220 80 NA 3 Standard NA NA
High-resolution VIBE acquisitions are obtained before and 4 times after contrast administration. They are interleaved with a series of 20 ultrafast TWIST acquisitions before and during the inflow of the contrast agent. The first TWIST acquisition populates the entire k-space and lasts 17 seconds; subsequent acquisitions sample the central zone and replace 10% of the outer k-space data per time point in a stochastic filling pattern. The dynamic sequences are preceded by a diffusion-weighted series and followed by a T2-weighted TSE acquisition. DWI indicates diffusion-weighted imaging; FA, flip angle; FOV, field of view; GRAPPA, generalized autocalibrating partially parallel acquisition; MRI, magnetic resonance imaging; NA, not applicable; TE/TR, echo time/repetition time; TSE, turbo spin echo; TWIST, time-resolved angiography with stochastic trajectories.
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TABLE 3. Clinical Meaning of MS Types MS Type 1 2 3
MS, %/s
Clinical Meaning
G6.4 Q6.4, G13.3 Q13.3
Cancer unlikely (G15%) Cancer equivocal Cancer likely (985%)
MS indicates maximum slope of the relative enhancement versus time curve.
FIGURE 3. Determining the MS. A tangent is drawn along the steepest part of the curve. The slope of the tangent is calculated by dividing the relative enhancement over time.
detection of the index lesion was 100%. The different approach in image acquisition using TWIST does not seem to influence the sensitivity of the technique, at least in retrospection. Because of the high spatial resolution, morphological information is preserved and reporting of the TWIST images according to the BI-RADS lexicon is possible. In computer-aided analysis of morphological parameters, identical diagnostic value for TWIST and VIBE acquisitions was found.34 Whether this holds also true for human readers remains to be investigated in prospective clinical trials, possibly opening the possibility of a TWIST-only screening protocol with an unprecedented total acquisition time of 102 seconds. The fact that breast MRI is not as far introduced in breast screening as could be expected based on the high gain in sensitivity over mammography is probably mainly cost based. The exact costs of breast MRI are highly variable. This depends on standards of specific countries. However, in literature, estimated costs for cost-effectiveness analysis range between $277 and $965 and average around $500 (€369) for a 30-minute scan.7Y9,35,36 Using ultrafast MRI, a total ‘‘inroom time’’ of 10 minutes including 8 minutes for the positioning of women on the MRI table should be feasible, allowing up to 6 women per hour and thus saving more than $300 per woman scanned. Because patients are required to lie motionless in a narrow tube during the procedure, a substantial shortening of the acquisition time also makes the examination more acceptable to women with slight symptoms of claustrophobia.37,38
Some drawbacks of breast MRI as a screening tool remain present: (1) the need for IV gadolinium-based contrast administration, which implies the need for placement of an IV cannula; (2) the risks associated with contrast administration, including allergic reactions (usually mild) and (rarely) nephrogenic systemic fibrosis in women with severely impaired renal function39,40; and (3) the need to evaluate premenopausal women in the right period of the menstrual cycle, as enhancing glandular tissue may otherwise obscure lesions.41,42 When using breast MRI for screening, the preservation of specificity is still a major issue. The high sensitivity of MRI for both benign and malignant disease implies detection of many benign lesions that would otherwise remain occult. Benign lesions may easily mimic early breast cancer as both often present as a relatively indistinct small mass. The following need to biopsy many benign lesions places a high emotional burden on women screened and adds substantial additional costs to screening.9,36,43,44 This is the reason that a high-resolution T2 sequence that provides detailed morphological information and may show necrosis and edema in and around breast lesions is added to state-of-the-art breast MRI protocols.13,14 Furthermore, DWI has also been added because cellular density is generally high in breast cancers, and consequently, diffusion is restricted, thus allowing some further differentiation.15Y17 However, these techniques are additional to DCE-MRI and cannot replace the dynamic
TABLE 2. Histopathology of Included Lesions Malignant
Benign
Lesion Type
n
IDC ILC DCIS Pathologic Lymph nodes Other
104 70 18 10 3 3
Lesion Type
n
Stable lesion (no pathology) Fibroadenoma Lymph node Inflamed cyst Microcysts Adenosis Other
95 32 29 7 6 5 5 11
IDC indicates invasive ductal carcinoma; ILC, invasive lobular carcinoma; DCIS, ductal carcinoma in situ.
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FIGURE 4. Evaluation of inflow curve types by upslope angle from the baseline. In the proposed grid (relative enhancement of 1000% on the y-axis equals 90 seconds on the x-axis), an angle of 50- or more classifies a lesion as probably malignant. An angle of 30- or less classifies a lesion as probably benign. An exemplary curve of a probably malignant lesion is drawn in gray. The white line corresponds to the actual slope. www.investigativeradiology.com
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FIGURE 5. ROC curves of MS as continuous variable, MS type using the specific cutoffs described above, and the BIRADS curve type.
information that is in small mass lesions of vital importance to differentiate between benign and malignant disease.45 Nevertheless, T2 and DWI may still provide additional information on top of morphology and MS, although the magnitude is unknown. Whether subsequent full state-of-the-art breast MRI after abnormal streamlined screening breast MRI examinations can further reduce unnecessary biopsies thus remains to be investigated. The underlying pathophysiology of MS is not easily explained. In empirical studies, MS is governed by the first pass of the contrast agent through the lesion and hence shows perfusion.46 Nevertheless, the temporal resolution applied in this study (4.32 seconds) is not sufficiently high to capture only perfusion effects. Consequently, the curve shape is strongly influenced by early leakage of contrast from the vessels into the extravascular extracellular space, a process that is governed by the transfer constant (or Ktrans), which is dependent on the permeability surface area of the vessels in the tumor.47 Studies that modeled dynamic information obtained from fast acquisitions at a much lower spatial resolution than applied in this study showed that Ktrans values, or variations thereof, are indeed a very strong discriminators between benign and malignant disease.31,48Y51 Nevertheless, these techniques have so far not surfaced in clinical practice because of the difficulties associated with this modeling, which include the determination of an arterial input function that is often not robust.52 Moreover, modeling techniques for breast imaging are not commercially available and therefore not accessible outside research facilities. In contrast, MS can be used instantaneously as no dedicated software is required. The use of a TWIST sequence for breast MRI has been described before. Herrmann et al26 showed in a small pilot study in 14 patients (of which 4 had an abnormality) that TWIST can be used to obtain dynamic images at a very high temporal resolution. The first part of the contrast enhancement versus time curve could only be fully appreciated with very fast sequences (5.7 seconds in their protocol). They also showed that benign lesions enhance later than malignant ones, which is in line with older studies that used single slice techniques to capture contrast inflow in breast lesions.53 A further 584
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advantage of the TWIST sequence is that, because of the data sharing between successive time points, the sequence proved robust against motion artifacts. Tudorica et al54 recently also described the use of TWIST for breast MRI. Although they did not reduce the temporal resolution further than 18 seconds, they showed that the resulting images are very comparable with images from conventional sequences. Furthermore, they showed that the dynamic data from the TWIST sequences are also well suited for quantitative pharmacokinetic analysis, yielding a maximum specificity of 91% at a sensitivity of 100% using the $Ktrans technique.50 Le et al55 recently showed that TWIST can be combined with a DIXON technique, allowing fatsuppressed imaging at high speed. Our study has limitations. The proposed cutoff values for MS are probably dependent on many technical parameters such as contrast agent, contrast dose, and specific scan protocol settings and need to be verified. However, the simple observation that the steeper MS, the higher the likelihood of malignancy is likely holds true regardless of these factors, which allows fast implementation in clinical practice. Although evaluation of MS can be performed without dedicated software, the use of a dedicated breast MRI workstation is still recommended for image registration, the creation of subtraction series, and simple color-coded overlays.56 It is already possible to create a colorcoded overlay of MS on several commercially available software tools. Despite the good classification properties of MS, it remains essential to evaluate morphology, although this was outside the scope of the current investigation.5,10,11 By definition, 10% of malignant lesions has an MS type 1, and these should not be missed. Some cancer types, most notoriously DCIS and low-grade invasive lobular carcinoma, enhance less because of the relative paucity of neovascularization and the maturation of the new formed vessels.57,58 Morphologically, these lesions often present as non-mass-like enhancement. It is therefore not surprising that in our study, the group of malignancies with an MS type 1 consists of 4 pure DCIS cases, 2 DCIS cases with small invasive foci, 1 diffuse growing invasive lobular carcinoma, 1 tubular carcinoma, 1 pathological lymph node, and only 1 mass-like invasive ductal carcinoma. Before screening regimens can be converted to ultrafast breast MRI, a prospective study in a screening setting comparing the performance of TWIST-only imaging with that of a full state-of-the-art breast MRI protocol is still mandatory. However, it does not require a whole new learning curve for reporting radiologists, as most of the evaluation techniques are identical to current clinical practice. In conclusion, we present a novel approach to dynamic breast MRI that combines common morphologic evaluation with dynamic information from the contrast wash-in phase rather than washout phase. The accuracy of MS is significantly higher than that of conventional BIRADS curve type analysis, which implies that the washout phase no longer needs to be imaged, while specificity may be improved. The substantial shortening of breast MRI protocols thus achieved may allow cost-effective breast MRI screening in a much larger population than is currently possible, including women with an intermediate lifetime risk based on family history and women with very dense breasts. REFERENCES 1. Kuhl CK, Schrading S, Bieling HB, et al. MRI for diagnosis of pure ductal carcinoma in situ: a prospective observational study. Lancet. 2007;370: 485Y492. 2. Peters NH, Borel Rinkes I, Zuithoff NP, et al. Meta-analysis of MR imaging in the diagnosis of breast lesions. Radiology. 2008;246:116Y124. 3. Carbonaro LA, Pediconi F, Verardi N, et al. Breast MRI using a high-relaxivity contrast agent: an overview. AJR Am J Roentgenol. 2011;196:942Y955. 4. Kuhl CK. Breast MR imaging at 3 T. Magn Reson Imaging Clin North Am. 2007;15:315Y320, vi. 5. Pinker-Domenig K, Bogner W, Gruber S, et al. High resolution MRI of the breast at 3 T: which BI-RADS(R) descriptors are most strongly associated with the diagnosis of breast cancer? Eur Radiol. 2012;22:322Y330.
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