Breast magnetic resonance imaging performance: safety, techniques, and updates on diffusion-weighted imaging and magnetic resonance spectroscopy.

REVIEW ARTICLE

Breast Magnetic Resonance Imaging Performance Safety, Techniques, and Updates on Diffusion-Weighted Imaging and Magnetic Resonance Spectroscopy Amy Melsaether, MD, and Anjali Gudi, MD Abstract: Dynamic contrast-enhanced breast magnetic resonance imaging (MRI) is a well-established, highly sensitive technique for the detection and evaluation of breast cancer. Optimal performance of breast MRI continues to evolve. This article addresses breast MRI applications, covers emerging breast MRI safety concerns; outlines the technical aspects of breast MRI, including equipment and protocols at 3 T and 1.5 T; and describes current promising areas of research including diffusionweighted imaging and magnetic resonance spectroscopy. Key Words: breast MRI, MRI safety, 3 T, diffusion-weighted imaging, magnetic resonance spectroscopy (Top Magn Reson Imaging 2014;23: 373–384)

D

ynamic contrast-enhanced (DCE) breast magnetic resonance imaging (MRI) was first described almost 30 years ago1 and is today a highly sensitive technique for breast cancer screening, for imaging the extent of disease, and for evaluating response to treatment. Magnetic resonance imaging–guided breast biopsies allow for diagnoses of minimal breast cancers before many of these same lesions can be detected with mammogram or ultrasound. Recently, the multicenter prospective American College of Radiology Imaging Network (ACRIN) 6666 trial by Berg et al,2 which included women with increased breast cancer risk and dense breasts, demonstrated 100% sensitivity for MRI as compared with 52% for mammography alone and 76% for combined mammography and screening ultrasound. Similarly, the 2010 Evaluation of the Efficacy of Diagnostic Methods (Mammography, Ultrasound, MRI) in the secondary and tertiary prevention of familial breast cancer (EVA) trial, a multicenter prospective study by Kuhl et al,3 demonstrated cancer yields (per 1000 women years) of 14.9/1000 with MRI, 6.0/1000 with ultrasound, 5.4/1000 with mammogram, and 7.7/1000 with mammogram and ultrasound combined. In 2003, the first-edition Breast Imaging Reporting and Data System (BI-RADS) lexicon for MRI was published.4 In 2008, The American College of Radiology (ACR) issued standardized practice guidelines for performing MRI.5 In 2013, the ACR released revised practice guidelines6 and, as part of the fifth edition of the BI-RADS lexicon, the second edition of the BIRADS MRI lexicon,7,8 which allows for increased standardization of MRI interpretation. Although breast MRI is undoubtedly successful, there is still room for improvement. Approximately 7% to 11% of cancers in high-risk women are not seen on MRI but detected with mammogram.3,9 Moreover, MRI still suffers from variable specificity. In the ACRIN 6666 trial, MRI decreased specificity to 65% as compared with 84% for mammography and ultrasound combined.2 Similarly, a study of high-risk women by Riedl et al9 demonstrated a false-positive rate of 81% for MRI. Overall, breast MRI specificity From the School of Medicine, New York University, New York, NY. Reprints: Amy Melsaether, MD, Breast Imaging Section, 160 E 34th St, 3rd Floor, New York, NY 10016 (e‐mail: [email protected]). The authors declare no conflict of interest. Copyright ©2014 by Lippincott Williams & Wilkins

is approximately 75%,10,11 well below that of mammography. Challenges to breast MRI and barriers to broader implementation include this decreased specificity, which yields false-positive results often requiring expensive and relatively time-consuming MRIguided biopsies; the time and expense of examinations as compared with mammography and ultrasound; and the requirement for injection of intravenous gadolinium. Like mammography and breast ultrasound, breast MRI is useful in both screening and diagnostic settings. Specific indications for breast MRI are discussed in a separate chapter. In the screening setting, MRI has been validated in many clinical trials as an important tool in diagnosing clinically, mammographically, and sonographically occult breast malignancies in patients with an elevated risk for breast cancer.2,3,12–15 Although no clinical trials have demonstrated a mortality benefit as has been demonstrated for mammography, it is thought that prognostic variables including the smaller sizes and earlier stages of cancers seen at the time of MRI diagnosis positively impact patient outcome. Please note that screening MRI is recommended in conjunction with and not as a replacement for annual mammography because neither MRI nor mammography alone will detect all cancers.3,6,9 When screening MRI is performed, additional screening ultrasound may not provide incremental value.2,3 In patients with newly diagnosed breast cancer, several studies show that MRI detects additional occult ipsilateral disease in approximately 12% to 27% of cases16–22 and occult contralateral disease in approximately 3% to 5%.16,17,23,24 A single study suggests a preoperative MRI reduces the rate of metachronous contralateral breast cancer.25 There is contention, however, as to whether this improved detection leads to improved patient care. Reexcision and recurrence rates are not necessarily reduced,26,27 and mastectomy rates in patients who undergo preoperative breast MRI seem to be increased.18,26,27 Magnetic resonance imaging has also been shown to be useful in assessing response to chemotherapy,28,29 in determining the presence of fascial and muscular involvement,30 and in assessing for residual disease in cases of close margins.31 Additional diagnostic indications are discussed in a separate chapter. In this chapter on the performance of breast MRI, we address MRI safety, describe how to perform a breast MRI, and look at current areas of research including diffusion-weighted imaging (DWI) and magnetic resonance spectroscopy (MRS).

PATIENT SAFETY Although DCE breast MRI is in general a very safe procedure, both the intravenous gadolinium injection and the magnetic field may pose risks to some patients.

Gadolinium In patients with renal impairment, gadolinium administration may precipitate the development of nephrogenic systemic fibrosis (NSF), a syndrome that involves fibrosis of the skin, joints, eyes, and internal organs.32 Apart from screening for silicone implant integrity, breast MRI cannot be performed without gadolinium. Therefore, at the authors' institution, a review of patient records

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for evidence of renal impairment including glomerular filtration rate less than 30 mL/min per 1.73 m2 is performed at the time of scheduling. Creatinine testing is recommended in patients older than 60 years and in those with a personal or family history of renal disease, diabetes, hypertension, multiple myeloma, or solid organ transplantation. Dialysis after gadolinium administration will not protect against NSF and cannot stand in for adequate renal function.33 Gadolinium can also cause allergic and even severe anaphylactic reactions.34,35 From 2004 to 2009, the Food and Drug Administration received reports of 40 gadolinium-based contrast agent deaths in the United States, unrelated to NSF, with an incidence per million doses of 0.15 to 2.7. The lowest incidence was reported for gadodiamide (Omniscan; GE Healthcare, Little Chalfont, United Kingdom), and the highest was reported for gadobenate dimeglumine (Multi-hance; Bracco Imaging, Milan, Italy).34 The overall rate of any hypersensitivity reaction is approximately 0.1%, with urticaria and hives accounting for 90% of these and anaphylaxis for 10%. Rates of hypersensitivity reactions are higher in women, in patients with a history of allergies or asthma, and in patients with a previous hypersensitivity reaction to gadolinium or iodinated contrast media.34,35 Although these rates are low, they are high enough that a radiologist is likely to encounter a gadolinium-based contrast reaction at some point during their career. Radiologists should therefore be aware of allergy risk with gadolinium and be familiar with how to manage anaphylactic reactions in an MRI setting, with attention to moving the patient out of the scanning room and immediate area (MRI zones 3 and 4) and into a space where staff and paramedics who are less familiar with MRI safety will not complicate management with metallic objects or non–MRI-compatible oxygen tanks. Currently, there are no set guidelines for managing patients at an elevated risk for gadolinium reaction. According to the ACR, patients who have reacted to one agent can be injected with another gadolinium-based contrast agent if they are restudied, and at-risk patients can be premedicated with corticosteroids and, occasionally, with antihistamines.36 All patients with asthma, allergies, or previous contrast reactions should be closely monitored.36

Pregnancy and Lactation Gadolinium has not been expressly tested in pregnant or lactating women, and in general, contrast-enhanced breast MRI is not recommended. The ACR states that MR contrast agents should not be routinely provided to pregnant patients.36 In lactating

women, the ACR estimates that the amount of maternally injected gadolinium absorbed by the infant is less than 0.0004%.37 The likelihood of an adverse reaction from such a low dose is thought to be remote, and no such adverse reaction has been reported. The ACR states, “we believe that the available data suggest that it is safe for the mother and infant to continue breast-feeding after receiving such an agent.” If the mother remains concerned about any potential ill effects to the infant, the ACR notes that she may abstain from breast-feeding (while pumping and discarding) for 12 to 24 hours and that there is no value to stop breast-feeding beyond 24 hours.37 The use of gadolinium contrast media in pregnant and women has also been addressed by the European Society of Uroradiology Contrast Medium Safety Committee.38 Their recommendation follows and is based on agent stability (Table 1), which is related to the risk of NSF but not necessarily to the risk of allergic reaction: When there is a very strong indication for enhanced MR, the smallest possible dose of one of the most stable gadolinium contrast agents may be given to the pregnant female.

In cases where MRI would be requested for an extent of disease examination, bilateral whole breast ultrasound with attention to the ipsilateral axilla can be performed. In elevated risk screening patients, a bilateral screening ultrasound can be substituted during pregnancy. Finally, for patients being screened with noncontrast MRI for silent implant ruptures, the authors' institution prefers to hold the examination until after delivery. Although there is currently no evidence that noncontrast MRI produces harmful effects to a fetus, long-term safety regarding radiofrequency fields and the loud acoustic environment continues to be studied.40,41

Magnetic Field Because metallic objects can move in strong magnetic fields, all patients are questioned before imaging as to whether they have indwelling metal, tattoos, or medical devices that may pose safety issues. In breast imaging, it is of particular note that almost all tissue expanders, which are often placed before reconstructive surgery, are not MRI compatible.42,43 MRIsafety.com is an excellent resource for verifying safety of medical devices. Please note that MRI safety is based on field strength and devices proven safe at 1.5 T, such as copper intrauterine devices, some sorts of aneurysm

TABLE 1. Gadolinium-Based Contrast Agents Categorized According to Risk of NSF, the Criterion Used to Stratify Risk to Pregnant and Lactating Women39 Risk Level Lowest (most stable)

Gadolinium-Based Agent

Trade Name(s)

Gadobutrol

Gadovist (Bayer HealthCare, Whippany, NJ) Gadavist (Bayer HealthCare) Dotarem (Guerbet, Paris, France) Magnescope (Terumo, Tokyo, Japan) Prohance(Bracco Imaging)

Gadoterate meglumine Gadoteridol Intermediate

Higher (least stable)

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Gadobenate dimeglumine Gadofosveset trisodium

Multihance (Bracco Imaging) Vasovist (Bayer HealthCare) Ablavar (Lantheus Medical Imaging, North Billerica, MA)

Gadodiamide Gadopentetate dimeglumine Gadoversetamide

Omniscan (GE Healthcare, Little Chalfont, United Kingdom) Magnevist (Bayer HealthCare) Optimark (Mallinckrodt Pharmaceuticals, St. Louis, MO)

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Update on Breast MRI Performance and Safety

first day of the last menstrual period) is important because this week is when background parenchymal enhancement, a confounding factor that may increase recommendations for follow-up examinations and biopsies,39,44 is lowest.45 At the author's institution, documentation of the last menstrual period date is kept, together with the MRI safety questionnaire, in our Picture Archiving and Communication System. Although screening examinations are almost always scheduled within this window, examinations evaluating the extent of disease, response to therapy, and margins may be performed outside this window because of clinical concerns. Noncontrast examinations assessing silicone implant integrity can be performed at any time of the cycle.

Positioning

FIGURE 1. A ripple effect artifact in the head-to-toe phase encoding direction is seen on the fat-saturated precontrast T1-weighted radial 3D gradient echo sequence. This artifact is occasionally seen when the patient's arms are overhead and can be solved by placing the patient's arms at her sides.

clips, and orthopedic hardware, cannot be assumed to be safe at 3 T. Patients with these devices should be scanned at 1.5 T.

BREAST MRI TECHNIQUE Exam Timing In premenopausal patients, scheduling MRI examinations during week 2 of the menstrual cycle (days 8–14, with day 1 as the

Every attempt should be made to ensure the patient is comfortable. In addition to making the MRI experience more pleasant, patient comfort will also reduce motion and allow for better image quality. Patients should be scanned in the prone position with arms up over the head or at the side of the body. Occasionally, arms overhead can cause artifact in the phase encoding direction, which can be solved by positioning the arms at the patient's side (Fig. 1). Vitamin E markers are recommended over scars, biopsy sites, and areas of palpable concern. Both breasts should be properly centered as deeply as possible within the breast coil with the nipples pointing downward. For patients with large breasts, pulling the abdominal fat out of the coil may be helpful. For patients with small breasts, it may be helpful to use thin padding or to place arms at the side of the body rather than at the patient's head.46,47 At the authors' institution, mild compression is applied in the medial-lateral direction to reduce motion artifact (Fig. 2) and to decrease the number of slices needed to image each breast. Finally,

FIGURE 2. A, Motion artifact is seen in the head-to-toe phase encoding direction as parallel lines superior and inferior to the breast (thin arrows) on a fat-saturated postcontrast T1-weighted radial 3D gradient echo subtraction sequence. In addition, motion contributes to decreased signal intensity of the background parenchyma and to blurring of the margins of a possible mass in the upper breast (open arrow). B, Mild medial-to-lateral compression is applied, resulting in reduced motion with resolution of the lines outside the breast and clearer representation of background parenchymal enhancement. The possible mass in the upper breast now demonstrates smooth concave margins and is most consistent with background parenchymal enhancement. ©2014 Lippincott Williams & Wilkins

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TABLE 2. A Suggested, ACR-Compliant, 3-T Breast MRI Protocol, as Performed at the Authors' Institution

Parameter Repetition time, ms Echo time, ms Chemical fat saturation Flip angle Field of view, mm Matrix Slice thickness, mm No. sections Voxel size, mm Bandwidth, Hz/pixel Imaging time, min:s

Sagittal T2-Weighted

Sagittal T1-Weighted GRE

4470 84 Yes 130 270 163 320 3 80 1.2 0.8 3.0 252 6:17

3.57 1.08 Yes 12 270 235 384 1 320 1.0 0.7 1.0 450 1:59, first set

before initiating diagnostic sequences, scout images are taken and reviewed by the technologist to ensure that both breasts are entirely included and centered. At this point, repositioning can be performed as needed.

Equipment Dedicated bilateral breast coils and high field strength magnets are essential to performing high-quality breast MRI. Breast coils with 4, 8, and 16 channels are commercially available and provide good signal-to-noise ratio (SNR) and signal homogeneity. With the breast coil as the receiver coil, a standard body coil can be use as the transmit coil. Typically, multichannel bilateral breast coils are matched to maximize parallel imaging techniques. Parallel imaging uses multiple receiver coils to derive spatial localization and thereby allows for the simultaneous acquisition of multiple channels of data without loss of spatial resolution.48 Acquisition time with parallel imaging is decreased by the acceleration factor, which in unidirectional parallel imaging is recommended to be kept between 2 and 3 to prevent artifacts and loss of SNR. Encouragingly, recent work with a 16-channel coil on a 3-T scanner demonstrates high-quality images obtained with a bidirectional (left/ right and superior/inferior) acceleration factor of 6.3.49 Additional considerations in coil selection include interventional capability for MR-guided biopsy and localization and adequate padding for patient comfort. Although unilateral breast coils are available, bilateral simultaneous imaging is recommended by the ACR.6 Bilateral imaging provides an internal standard for comparison of background parenchymal enhancement and, as noted previously, in patients with a newly diagnosed breast cancer, has been shown to detect an unsuspected contralateral cancer in 3% to 5%.16,17,23,24 Breast MRI is usually performed on 1.5-T or 3-T field strength magnets, although some lower field strength dedicated breast magnets are available. The ACR notes that both high spatial and temporal resolutions are needed to characterize small abnormalities.6 High field strength can provide several advantages. At 3 T compared with 1.5 T, the increased magnetic field strength provides an increase in SNR of approximately a factor of 2, which can be used to decrease scan time, to increase spatial resolution, or to improve visualization of subtle lesions requiring increased SNR.47,48,50–52 In addition, the homogeneity of chemical fat suppression can be improved at 3 T as the separation between fat and water resonant frequencies is doubled as compared with 1.5 T.47,48,50 In theory, these increased capabilities of MRI at 3 T could provide

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increased accuracy. In practice, Kuhl et al52 demonstrated increased diagnostic confidence at 3 T with increased sensitivity, which was attributed to patient motion on 1.5 T scans. Although the patient motion may have been incidental, shorter scan times at 3 T can make motion degradation less likely. In general, direct comparisons between magnet strengths are difficult because of nonstandardized protocol modifications. Higher magnetic field strengths also have disadvantages such as stronger susceptibility effects, longer T1 relaxation times, and higher radiofrequency deposition. These effects can result in increased chemical shift and susceptibility, especially on the gradient echo pulse sequences commonly used in breast MRI, which can lead to artifacts and nonuniformity.47,50,51 Radiofrequency homogeneity becomes more difficult to achieve as field strength increases. Resultant inhomogeneity can lead to nonuniform signal intensity across an image.47,50,51 Moreover, radiofrequency energy deposition increases exponentially with field strength, for example quadrupling between 1.5 T and 3 T. This energy deposition may cause tissue heating and causes specific absorption rate limits to be reached sooner at 3 T. For this reason, devices proven to be safe at 1.5 T are not necessarily safe at 3 T.

Protocol Suggested DCE breast MR protocols at 3 T and 1.5 T are presented in Tables 2 and 3. Effects of changing various MRI parameters on SNR, resolution, and scan time are presented in Table 4. These protocols are guidelines and may need adaptation on a case-by-case basis. For all protocols, homogeneity of both magnetic field and fat suppression are necessary as is correct selection of the phase encoding direction (discussed later). Slice thicknesses of no more than 3 mm (1 mm preferred), high (1 1 mm) in plane resolution, and high SNR per pixel are also essential for high-quality breast MRI. At the authors' institution, a breast MR examination begins with scout images to evaluate positioning and to ensure full coverage of both breasts. After review, diagnostic sequences including (1) sagittal non–fatsaturated, noncontrast T1-weighted sequence, (2) sagittal fatsaturated T2-weighted fast spin echo sequence, (3) sagittal precontrast fat-saturated T1-weighted radial 3D gradient echo sequence, (4) 3 consecutive sagittal postcontrast fat-saturated T1-weighted radial 3D gradient echo sequence, and (5) axial fatsaturated postcontrast T1-weighted radial 3D gradient echo sequence are acquired. When imaging for silicone implant integrity,

TABLE 3. A Suggested 1.5-T Breast MRI Protocol, as Performed at the Authors' Institution

Parameter Repetition time, ms Echo time, ms Chemical fat saturation Flip angle Field of view, mm Matrix Slice thickness, mm No. sections Voxel size, mm Bandwidth, Hz/pixel Imaging time, min:s

Sagittal T2-Weighted

Sagittal T1-Weighted GRE

5410 72 Yes 130 270 182 320 4 70 1.3 0.8 4.0 203 5:42

5.18 2.38 Yes 10 280 189 320 1.8 176 1.3 0.9 1.8 380 1:59, first set





TABLE 4. Effect of Changing Various MRI Parameters on SNR, Resolution, and Scan Time Parameter

SNR

Resolution

Scan Time

Other

+ + + − −* + −

− − No change No change + No change No change

No change − + No change + + −

Decrease aliasing artifact Volume averaging in slice select direction Decreased T1 weighting Increased T2 weighting

Increasing field of view Increasing slice thickness Increasing repetition time Increasing echo time Increasing matrix Increasing no. excitations Increasing bandwidth

Decreased minimum echo time, reduced chemical shift

*

If pixel size decreases.

intracapsular ruptures can easily be missed with routine sequences (Fig. 3A). Dedicated turbo spin echo T2-weighted short-time inversion recovery silicone-excited and silicone-saturated sequences are recommended (Fig. 3B, C). As a reminder, tissues with short T1 relaxation times such as fat and gadolinium-enhanced lesions appear bright on T1-weighted imaging, whereas those with long relaxation times such as cysts and normal fibroglandular tissue appear dark. The noncontrast non–fat-saturated T1-weighted sequence is therefore particularly useful for general anatomy and to confirm fat in fat necrosis and benign lymph nodes (Fig. 4A, B). Architectural distortion and metallic signal void may also be best seen on gradient echo sequences, with or without fat suppression47,53 (Fig. 4C, D). On T2-weighted imaging, tissues with long T2 relaxation times, such as cysts, appear bright, whereas those with short T2 relaxation times, such as fibroglandular tissue, appear dark. The noncontrast fat-saturated T2-weighted fast spin echo sequence is useful for identifying and determining the internal architecture of fluid containing structures such as cysts and seromas (Fig. 5A, B). Lymph nodes and many fibroadenomas also demonstrate high T2 signal intensity,54 whereas malignancies often demonstrate low T2 signal intensity (Fig. 5C, D). The pregadolinium and 3 sequential postgadolinium fatsuppressed T1-weighted radial 3D gradient echo sequences are the workhorses of this protocol and are the images on which enhancing lesions are identified. Chelated gadolinium, a paramagnetic contrast agent, is administered by intravenous injection of 0.1 mmol/kg at 2 mL/s followed by a 20 to 30 mL of saline flush. Because many cancers reach peak enhancement within 2 minutes of gadolinium injection,55 the first postcontrast sequence should be obtained within 120 seconds of gadolinium administration, and subsequent sequences should be acquired within 240 and 360 seconds. Although there is no universally agreed upon protocol, at least 2 postcontrast image sets are necessary,46,47 and a third or even fourth may be useful for identifying slowly enhancing lesions such as ductal carcinoma in situ (DCIS) or lobular cancers.56,57 These serial image sets allow for the evaluation of the kinetics of enhancing lesions, discussed later in this article. Enhancing lesions are often most conspicuous and easily separable from blood and proteinaceous material on the subtraction set of postcontrast images. Although fat suppression can be achieved through subtraction, the ACR guidelines recommend chemical fat suppression in addition to subtraction for this image set.6 As with any set of subtracted imaged, avoiding motion artifact is crucial. In cases where there is complicating motion artifact, protocols relying on subtraction for fat suppression may have variable, inhomogeneous fat suppression, which can (1) obscure enhancing lesions and (2) create pseudolesions. Chemically fat-suppressed ©2014 Lippincott Williams & Wilkins

FIGURE 3. A, On the routine fat-saturated postcontrast T1weighted radial 3D gradient echo sequence, there is a suggestion of intracapsular rupture involving the left silicone implant (arrow). The right silicone implant appears intact. B, The dedicated silicone-excited turbo spin echo T2-weighted short-time inversion recovery sequence clearly demonstrates bilateral “linguini signs,” consistent with bilateral intracapsular rupture (arrows). C, A silicone-saturated turbo spin echo T2-weighted short-time inversion recovery sequence is most useful for confirming extracapsular rupture by suppressing high extracapsular signal seen on the silicone-excited sequence. www.topicsinmri.com


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FIGURE 4. A, A rim enhancing irregular mass (arrow) appears suspicious for malignancy on this subtracted fat-saturated postcontrast T1-weighted radial 3D gradient echo image. B, Comparison with the non–fat-saturated T1-weighted sequence demonstrates central fat (arrow), consistent with benign fat necrosis. Gradient echo T1-weighted images may also accentuate susceptibility artifact caused by metallic objects disrupting local magnetic field homogeneity as seen caused by a mediport (C, arrow) and a biopsy clip (D, arrow).

unsubtracted images are often helpful in cases of motion artifact and allow for differentiation between fat and enhancing lesions. At the authors' institution, a fourth postcontrast fat-suppressed T1-weighted radial 3D gradient echo sequence is obtained in

the axial plane. This image set offers an internal standard for comparison and is especially useful for differentiating between bilateral symmetric background parenchymal enhancement and suspicious asymmetric nonmass enhancement.

FIGURE 5. A cluster of palpable masses (arrows on A and B). A does not enhance on the fat-saturated postcontrast T1-weighted radial 3D gradient echo subtraction image, and B demonstrates high signal intensity on the fat-saturated T2-weighted image, consistent with benign cysts. The open arrow points to a marker over the palpable area of concern. Conversely, and invasive ductal carcinoma (arrows on C and D) demonstrates C, robust enhancement on the fat-saturated post contrast T1-weighted radial 3D gradient echo subtracted image and D, the low signal intensity typical of malignancies on the fat-saturated T2-weighted image.

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FIGURE 6. A, DynaCAD (InVivo) color-mapped image demonstrates clumped nonmass enhancement with a persistent, type I kinetic curve. B, The graph corresponding to the pixel selected by crosshairs in A demonstrates greater than 60% wash-in at the first time point, the cutoff for color mapping at the authors' institution, and increasing enhancement at the next 2 time points. C, The corresponding fat-saturated postcontrast T1-weighted radial 3D gradient echo subtraction image demonstrates clumped nonmass enhancement in a segmental distribution. D, The corresponding postbiopsy mammogram demonstrates pleomorphic calcifications in the same distribution. Biopsy results yielded DCIS and emphasized that kinetics alone are insufficient for lesion evaluation.

Imaging Plane Breast MR images are acquired in the sagittal plane at the authors' institution but can be obtained in the axial and coronal planes as well. The sagittal plane allows for a smaller field of view, higher spatial resolution, and improved fat suppression. The axial plane allows for half the number of slices and offers an internal standard for comparison at all time points. Coronal acquisition may minimize artifacts caused by cardiac motion but is more susceptible to respiratory motion and is not as easily correlated with mammography.58,59 In any case, if isotropic voxel size is acquired, multiplanar 3D tools can be used to render the other planes.47 The correct phase encoding direction is dependent on the plane of imaging. For patients scanned in the sagittal plane, ©2014 Lippincott Williams & Wilkins

phase encoding should be superior to inferior; for patients scanned in the axial plane, phase encoding should be left to right; and for patients scanned in the coronal plane, phase encoding should be anterior to posterior. Artifacts related to patient motion, including flow-related ghosting artifacts, occur in the phase encoding direction (Fig. 2).60,61

Gadolinium, Signal Enhancement Time Curves, and Computer-Automated Detection Gadolinium is the chemical element Gd with anatomic weight of 64 and is essential to breast MRI for accurate lesion detection and characterization. In its free form, gadolinium is toxic to mammals, but chelation to a conjugate base allows for renal www.topicsinmri.com


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excretion (half-life is approximately 90 minutes) before free gadolinium is released. In this chelated form, gadolinium can be injected intravenously, and its paramagnetic properties, which cause T1 > T2 relaxation, render hypervascular tissues brighter than surrounding tissues on T1-weighted images. Because breast cancers stimulate blood vessel growth via angiogenesis and often these new vessels are different from normal vessels in that they are larger and leaky, the kinetics of gadolinium uptake can help differentiate benign from malignant lesions.62,63 A time-signal intensity curve depicts the kinetics of lesion contrast enhancement and can be generated from continuous imaging of both breasts with a temporal resolution of 1 to 2 minutes during a time span of approximately 6 to 7 minutes after contrast administration (Fig. 6). Commercially available MRI computer-aided detection (CAD) software such as DynaCAD (InVivo, Cambridge, MA), CADstream (Merge Healthcare, Chicago, IL), and Aegis (Hologic, Bedford, MA) generates a semiquantitative analysis of the percent change in signal intensity from the precontrast value, plotted as a function of time. This time curve is divided into 2 phases: the early or initial wash in phase, which includes the first postcontrast sequence at 60 to 120 seconds, and the late or delayed phase, which occurs after 120 seconds. According to the fifth edition BI-RADS lexicon, the initial phase is categorized as slow, medium, or fast, where slow is less than 50% increase over baseline, medium is 50% to 100% over baseline, and rapid is greater than 100% over baseline in the first postcontrast series (approximately 90 seconds).8 The delayed patterns of enhancement are defined as (1) persistent, in which signal intensity continues to increase by 10% or greater from the first time point over the span of imaging; (2) plateau, in which signal intensity reaches a peak at the first time point and flattens for the remainder of the examination; and (3) washout, in which signal intensity peaks at the first time point and decreases by 10% or greater during the remainder of the examination.8 For kinetic mapping, an enhancement threshold is set (typically 50% at the first postcontrast sequence), and all areas that enhance greater than that threshold are color coded according to their delayed phase. Lesions that do not demonstrate at least threshold enhancement are not colored. Although there is significant overlap, breast cancers characteristically demonstrate rapid contrast uptake that peaks within the first 2 minutes after injection and similarly rapid washout,55,62,63 whereas benign enhancing lesions and normal enhancing breast parenchyma will demonstrate lower peak enhancement and longer time to peak enhancement than is seen in breast

malignancies.64 Kuhl et al65 addressed both initial wash-in and delayed phase lesion kinetics in 266 enhancing lesions, 98 of which were primary breast cancers, 3 were other malignancies, and 165 were benign. The authors found that when using delayed phase type II and III patterns as criteria for malignancy and the type I pattern as criterion for benignity, they arrived at 91% sensitivity, 83% specificity, and 86% diagnostic accuracy. Six percent of malignancies demonstrated type I delayed curves. Although these numbers are encouraging, they also show that a type I curve cannot definitively exclude malignancy just as a type III curve cannot definitively diagnose malignancy. Similarly, although there was a significant difference in mean wash in between malignancies (104%) and benign lesions (72%), broad SDs led to considerable overlap in rates of initial rise, which also cannot be used definitively to categorize lesions as benign or malignant. Similar work by Schnall et al62 included 995 lesions and demonstrated that marked and moderate enhancement and washout and plateau kinetics were more likely to be associated with cancers than benign lesions (odds ratio, 9.4–26.1, 3.8–6.2, 2.1–2.3, and 1.7, respectively). However, in this study, 45% of type I kinetic curves were found in cancers. Although markedly enhancing lesions and lesions with washout kinetic patterns should be viewed with high suspicion, evaluation of morphologic features in conjunction with kinetics is important both to avoid classifying atypical or early malignancies as benign lesions and, conversely, to avoid overcalling benign lesions.

DIFFUSION-WEIGHTED IMAGING Diffusion-weighted imaging is a noncontrast functional MRI technique that evaluates microscopic displacements of water in tissues. The MRI signal obtained from diffusion in tissue is reduced proportionally as compared with diffusion in water and is quantified via apparent diffusion coefficient (ADC) values. Apparent diffusion coefficient measurements are typically reduced in cancers because proliferating cells reduce the extracellular space for free diffusion and replace it with viscous intracellular fluid. The characteristic MRI appearance of malignant lesions is therefore that of restricted diffusion, with high signal intensity on DWI and low ADC values66 (Fig. 7). It is important to note that ADC values and, consequently, suggested cutoff values between benign malignant lesions are dependent on the b values (discussed later) used in DWI scanning protocols. In part because DWI techniques and interpretation are not yet standardized, they are not widely used in clinical breast MRI.

FIGURE 7. Diffusion-weighted imaging of an invasive ductal carcinoma. There is a spiculated mass (circled on all images), which demonstrates high signal intensity on the b700 diffusion-weighted image (A) and low signal intensity on the corresponding ADC map (B), consistent with restricted diffusion. C, This mass demonstrates increased 18 fluorodeoxyglucose (18FDG) uptake on a corresponding 18FDG-positron emission tomography image. D is well seen on the routine fat-saturated T1-weighted radial 3D gradient echo image as a spiculated mass. This patient stopped her examination before gadolinium administration, so image D is a noncontrast image.

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Apparent diffusion coefficient measurements have been shown in several studies to help differentiate benign from malignant breast lesions.67–70 In particular, DWI has the potential to increase DCE-MRI specificity.68,71–73 In a recent study by Spick et al,72 DWI was performed before MRI-guided biopsy of 104 lesions seen only on MRI. Mean ADC values were significantly different between malignant and benign lesions, and receiver operating characteristic curve analysis demonstrated only benign lesions at mean ADC values greater than 1.58 10−3 mm2/s. Setting this ADC value as the upper limit for biopsy would have reduced false-positive examination results by approximately one third (34.5%). In another recent study, 44 lesions were imaged at 3 T. The sensitivity of DCE-MRI alone was 100%, with a specificity of 66.7%. When DCE-MRI was combined with DWI, specificity rose to 100%, whereas sensitivity fell to 90.6%.73 Diffusion-weighted imaging has been also investigated as part of a method for stratifying high- and low-grade DCIS in vivo74 and has been shown to be helpful in identifying early response in tumors undergoing neoadjuvant chemotherapy.75–77 In cancers that are responding to chemotherapy, ADC values may increase before a change in tumor volume is measureable.75,77 Finally, DWI has been investigated as a noncontrast screening tool.78–80 In small enriched studies, noncontrast MRI has outperformed mammography in patients with breast cancer.78,79 In this setting, DWI sensitivity as compared with DCE-MRI has been reported at 86%.80 To further examine and potentially standardize DWI in breast MRI, ACRIN trial 6702 “A Multi-Center Study Evaluating the Utility of Diffusion Weighted Imaging for Detection and Diagnosis of Breast Cancer” has recently been opened. The main goals of this study are to determine whether the application of ADC values to DCE-MRI can reduce biopsy rates without sacrificing sensitivity and to determine whether an ADC threshold can be set for distinguishing benign from malignant lesions.81 Incorporating DWI into a DCE breast MRI protocol requires 2 to 5 extra minutes of imaging time either before or after the routine protocol. Often, DWI sequences are performed after DCE-MRI in


case the examination cannot be completed as the DCE-MRI sequences are considered most important. Whether and how the adminstration of gadolinium affects ADC values is controversial.82–84 The DW sequence typically involves a fat-saturated T2-weighted spin echo prepared echo planar image sequence with an extra pair of motion sensitizing gradient pulses. Diffusion gradients should be applied in at least 3 orthogonal directions to obtain rotationally invariant measures.85 Images are acquired at at least 2 b values, typically between b = 0 and b = 1000, where b describes the degree of diffusion weighting. Apparent diffusion coefficient is then calculated from these acquisitions using the formula ADC = ln (S1 / S2) / (b2 − b1), where S1 is the signal at b1, the minimum b value (often 0 in breast imaging), and S2 is the signal at b2, which ranges. Adequate SNR is important for lesion detection and ADC measurement. For normal breast tissue, a b value of 600 s/mm2 has been shown to provide the best SNR.86 Higher b values provide increased contrast resolution at the expense of SNR.87

MAGNETIC RESONANCE SPECTROSCOPY Like DWI, proton MRS, also called Hydrogen-1 or 1H MRS, is a noninvasive functional imaging technique, which may complement DCE-MRI by increasing specificity. Magnetic resonance spectroscopy, specifically 1H MRS, uses 1H signals to determine the presence and concentration of various metabolites in tissue. Magnetic resonance spectroscopy of the breast evaluates for a resonance peak at 3.2 parts per million; this peak signifies increased levels of choline metabolites including choline, phosphocholine, and glycerophosphocholine, referred to together as total choline (tCho).88 Total choline is a marker for increased cell membrane turnover and, in breast imaging, is detected not only primarily in malignant lesions85,89,90 (Fig. 8) but also at lower levels in benign lesions and normal fibroglandular tissue.91 Baltzer and Dietzel88 performed a meta-analysis of 19 breast MRS studies, which showed a pooled sensitivity of 73% and a pooled specificity of 88%; sensitivities in the included studies ranged from 42% to 100% and specificities from 67% to 100%. At 3 T, metabolite

FIGURE 8. 1H MRS. A, A known invasive ductal carcinoma presents as a microlobulated enhancing mass (arrow) seen on the fat-saturated T1-weighted radial 3D gradient echo postcontrast subtracted image. B, A choline peak, typical of breast cancers, at 3.2 parts per million. ©2014 Lippincott Williams & Wilkins

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peaks are more widely separated than at 1.5 T, so although no significant difference in diagnostic performance has been shown to date,88 there is conjecture that MRS at 3 T may improve sensitivity over that at 1.5 T, especially for smaller lesions. Magnetic resonance spectroscopy has also been investigated in the evaluation of neoadjuvant chemotherapy response, with mixed results. Several studies have demonstrated decreased tCho in responders as compared with nonresponders after the first or second round of chemotherapy.92–95 In the studies that compare changes in tumor measurements with changes in tCho, tCho does not seem to predict response before change in tumor size on DCE-MRI.92,93 Magnetic resonance spectroscopy acquisition, like DWI acquisition, is nonstandardized. Water suppression is critical as signal from water will overwhelm spectra of all other metabolites. Detailed techniques including single-voxel spectroscopy and chemical shift or MR spectroscopic imaging are well described by Bolan in his recent review.96 Single-voxel spectroscopy produces a single spectrum from a single voxel, whereas MR spectroscopic imaging excites a larger volume and produces a spatially resolved grid of spectra. Single-voxel spectroscopy regions of interest must be prospectively assigned, which can limit integration into clinical workflow. As MR spectroscopic imaging images a larger area, regions of interest can be retrospectively assigned, and additional evaluations, such as peak tCho over the total volume, tumor heterogeneity, and comparison with background, can be performed.

SUMMARY Dynamic contrast-enhanced breast MRI has become a highly sensitive imaging tool, useful both in screening for occult breast cancers in high-risk patients and in several diagnostic indications. When performing MRI, patient safety must remain a top priority, and as such, awareness of potential hazards such as allergic reactions to gadolinium, NSF, and complications of magnetic fields is imperative for radiologists. Technically, breast MRI requires a high field strength magnet, a dedicated multichannel breast coil, and an optimized protocol, which allows for the acquisition of images that provide both high spatial and high temporal resolution. New directions in breast MRI include DWI and MRS, noninvasive functional imaging techniques, which have demonstrated, among other things, initial promise for improving the specificity of DCE-MRI. REFERENCES 1. Heywang SH, Hahn D, Schmidt H, et al. MR imaging of the breast using gadolinium-DTPA. J Comput Assist Tomogr. 1986;10:199–204. 2. Berg WA, Zhang Z, Lehrer D, et al. Detection of breast cancer with addition of annual screening ultrasound or a single screening MRI to mammography in women with elevated breast cancer risk. JAMA. 2012;307:1394–1404. 3. 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;28:1450–1457. 4. Ikeda D, Hylton M, Kuhl C, et al. Breast Imaging Reporting and Data System, BI-RADS: Magnetic Resonance Imaging (BI-RADS: MRI). Reston, VA: American College of Radiology; 2003. 5. American College of Radiology. ACR Practice Guideline for the Performance of Magnetic Resonance Imaging (MRI) of the Breast. Practice Guidelines and Technical Standards. Reston, VA: American College of Radiology; 2008. 6. American College of Radiology. ACR Practice Guideline for the Performance of Magnetic Resonance Imaging (MRI) of the Breast. Practice Guidelines and Technical Standards. Reston, VA: American College of Radiology; 2013.

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Magnetic resonance imaging safety in cardiothoracic imaging.

Breast magnetic resonance imaging indications.

Breast magnetic resonance imaging for the interventionalist: magnetic resonance imaging-guided vacuum-assisted breast biopsy.

Statistical normalization techniques for magnetic resonance imaging.

Brain magnetic resonance imaging and magnetic resonance spectroscopy findings of children with kernicterus.

Combining Magnetic Resonance Spectroscopy and Magnetic Resonance Imaging in Diagnosing Focal Brain Lesions in Children.

Magnetic resonance imaging in breast disease.

Breast magnetic resonance imaging incidental findings.

Diagnostic magnetic resonance imaging of the breast.

foci.

Breast magnetic resonance imaging: kinetic curve assessment.

Approach to breast magnetic resonance imaging interpretation.

Magnetic resonance imaging of breast implants.

[Magnetic resonance imaging].

Pelvic magnetic resonance imaging.

Gynecologic magnetic resonance imaging.

Intracranial magnetic resonance imaging.

Shoulder magnetic resonance imaging.

Magnetic resonance imaging.

An atypical meningioma demystified and advanced magnetic resonance imaging techniques.

Magnetic Resonance Imaging and Spectroscopy: Application to Experimental Neuro-Oncology.

Magnetic resonance imaging and spectroscopy in hepatic encephalopathy.

Magnetic resonance chemical shift imaging and spectroscopy of atherosclerotic plaque.

Cardiovascular applications of magnetic resonance imaging and phosphorus-31 spectroscopy.