BREAST IMAGING The potential of Diffusion- Weighted MRI as an unenhanced breast cancer screening tool by Dr. N Amornsiripanitch and Dr. SC Partridge This article provides an overview of the potential publication [8]. Summary of evidence role of diffusion-weighted magnetic resonance to date of DW-MRI in cancer detection, imaging (DW-MRI) as a breast scancer screening optimal approaches, and future consid- tool independent of dynamic contrast-enhance- erations are presented. ment. The article aims to summarize evidence to CURRENT EVIDENCE FOR DW-MRI IN date of DW-MRI in cancer detection and present BREAST CANCER The following equation describes optimal approaches and future considerations. DW-MRI signal intensity in rela- tion to water mobility within a voxel: Due to well-documented limita- Considering the constraints of SD=S0e-b*ADC, where SD is defined tions of mammography in the settings contrast-enhanced breast MRI, there as diffusion weighted signal intensity, of women with dense breasts and high- is great clinical value in identifying an S0 the signal intensity without diffusion risk women [1], there has been great unenhanced MRI modality. Diffusion- weighting, b or ‘b-value’ the diffusion interest in identifying imaging tech- weighted (DW) MRI is a technique sensitization factor, which is dependent niques to supplement mammography that does not require external contrast on applied gradient’s strength and tim- in breast cancer screening. Dynamic administration—instead, image con- ing (s/mm2), and the apparent diffusion contrast-enhanced (DCE) MRI is trast is generated from endogenous coefficient (ADC) the rate of diffusion endorsed by multinational organiza- water movement, reflecting multiple or average area occupied by a water tions as a supplemental screening tool tissue factors such as cellular mem- molecule per unit time (mm2/s) [9]. for women at high risk for breast can- brane integrity, density, and organiza- Compared to normal surround- cer [2, 3] due to high sensitivity and tion. DW-MRI has been investigated ing tissue, breast malignancies typi- cancer detection rate [4, 5]. Screening for a variety of breast imaging applica- cally exhibit impeded water diffusion, with DCE-MRI has also been shown tions, most commonly as an adjunct appearing dark on ADC map and to decrease incidental cancer rate in tool for lesion assessment in multipa- bright on DW-MRI sequences [10] women with extremely dense breast [6]. rametric breast MRI examinations and [Figure 1]. A meta-analysis of 73 stud- However, widespread implementation for evaluating response to neoadjuvant ies demonstrated that, using only ADC of DCE-MRI is limited by cost. And chemotherapy. However, a growing measurements, DW-MRI could differ- given the unknown long-term effects number of studies are evaluating the entiate benign versus malignant lesions of gadolinium retention after admin- role of DW-MRI as a stand-alone tool with comparable sensitivity and speci- istration for contrast-enhanced MRI for breast cancer detection. ficity to DCE-MRI (sensitivity=89% [7], caution may be warranted against The goal of this article is to provide vs. 93% and specificity=82% vs. 71%, repeated administrations in a healthy an overview of DW-MRI’s potential as respectively) [11]. In another study, 89% population such as women undergoing a breast cancer screening tool, which of mammographically occult cancers breast cancer screening. is outlined in greater detail in a recent were visually detected on DW-MRI, The Authors ABBREVIATIONS 1 2,3 Nita Amornsiripanitch, MD and Savannah C Partridge, PhD ADC – apparent diffusion coefficient 1. Department of Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA DCE – dynamic contrast-enhanced 2. Department of Radiology, University of Washington, Seattle, Washington, USA DCIS – ductal carcinoma in situ 3. Breast Imaging, Seattle Cancer Care Alliance, Seattle, Washington, USA DW – diffusion-weighted Corresponding Author Dr SC Partridge EPI – echo planar imaging email : [email protected] MIP – maximum intensity projection 40 DI EUROPE FEB/MARCH 2020 Figure 1. 52-year-old woman with invasive ductal carcinoma in the right breast detected on DCE-MRI (left). On DW-MRI, the lesion is not visible on the (T2-weighted) b=0 image but is hyperintense to normal breast tissue on the diffusion-sensitized b=800 s/mm2 image (arrow). The lesion shows lower diffusivity (dark) on corresponding ADC map (right, mean ADC=0.89x10-3 mm2/s) compared to normal tissue (mean ADC=2.21x10-3 mm2/s). (Reprinted, with permission, from [7].) suggesting that DW-MRI may be superior sensitivity included only mammographi- imaging modalities was reported in some to mammogram in cancer detection [12]. cally occult cancer and did not exclude of the studies [13-18]. Compared to mam- However, readers in these studies were not studies with suboptimal image quality [15], mography, one study found DW-MRI to blinded to DCE-MRI images when iden- whereas the study with the highest sensi- be more accurate and sensitive in cancer tifying cancers with DW-MRI. Therefore, tivity performed double reading [19]. A detection (area under the receiver oper- these study designs do not approximate a variety of imaging acquisition techniques ating characteristic curve=0.73 vs. 0.64 clinical setting where DW-MRI is poten- were also used. and sensitivity=69% vs. 40%) [18], and tially used as a stand-alone unenhanced Performance of DW-MRI versus other all malignancies detected by DW-MRI in modality to supplement mammogram in screening for breast cancer. BLINDED DW-MRI READER STUDIES Several studies to-date have explored the use of DW-MRI in study designs simu- lating a clinical screening setting [13-19]. Readers in these studies retrospectively reviewed only DW-MRI and other unen- hanced MRI sequences without access to contrast-enhanced sequences. Readers assessed exams for level of suspicion for malignancy (assigning a numeric score or positive versus negative assessment). Study designs ranged from inclusion of only asymptomatic intermediate-to-high risk patients (cancer prevalence 1.4-2.5%) [13, 19], enriched asymptomatic cancer population (prevalence 25-67%) [15, 18], to inclusion of symptomatic and/or known cancer patients [14, 16, 17]. However, to simulate a screening experience, readers in the latter study design did not have access to clinical history and other imaging modalities, and, therefore, were not privy to prevalence of cancer in the study popula- tions (prevalence 27-46%) [14, 16, 17]. DW-MRI performances in these seven studies are summarized in Table 1. Briefly, mean sensitivity was 76% (range 45-100%) and mean specificity 90% (range 79–95%). Variation in reported sensitivities is likely due to inclusion criteria and interpreta- tion protocol: the study with the lowest Table 1: Blinded reader studies evaluating DW-MRI performance for breast cancer screening. FEB/MARCH 2020 DI EUROPE 41 BREAST IMAGING GE Healthcare SEE DIFFERENTLY SEE IN CONTRAST Figure 2. Two examples of DCIS appearance on DW-MRI. (a) 49-year-old woman with left DCIS identified on DCE as 5.2 cm non-mass enhancement and DW-MRI at b = 1000 s/mm2 (arrows, left). (b) 60-year-old woman with DCIS detected on DCE as a 36 mm non-mass enhancement but not detectable on DW-MRI at b = 800 s/mm2. A bright susceptibility-based artifact was also present at the nipple (arrowhead). (Reprinted, with permission, from [7].) McDonald et al were missed on mammog- missed [14, 19], which is to be expected to optimize both diagnostic specificity and raphy [15]. Compared to DCE-MRI, three given that typical DW-MRI voxel sizes are image quality (i.e., signal-to-noise ratio). studies reported lower mean sensitivity for larger than that of DCE-MRI, therefore cre- Standardization of optimal diagnostic ADC ™ DW-MRI (78.9%, range 50–94%) compared ating partial volume effect for small lesions. cut-offs is also warranted. A recent multi- Seno HD to that of DCE-MRI (93.4%, range 86-98%) Notable false positives included com- center trial suggested that an ADC cutoff Bright [13, 16, 18], suggesting that DW-MRI may plicated/proteinaceous cysts, fibroadeno- of 1.68 ×10-3 mm2/s using a maximum Contrast Enhanced Spectral Mammography not be as sensitive in detecting cancer com- mas, and artifactual “lesions” [14-17]. In b-value of 800 s/mm2 could avoid 21% of pared to DCE-MRI. None of the above stud- one study, all seven DW-MRI false positives unnecessary breast biopsies prompted by ies directly compared blinded DW-MRI were found to represent complicated cysts DCE-MRI without compromising sensitiv- performance with that of screening whole [16]. Fibroadenomas can present with a ity [24]. Specific to screening applications breast US. However, a non-blinded study wide range of ADC values; a study reported where both sensitivity and specificity are a of 60 mammographically occult cancers that 37% of fibroadenomas exhibited ADCs major consideration, there is also benefit in showed that more cancers were detectable in the same range as those of malignancies acquiring an additional very high b-value on DW-MRI than MRI-guided focused US (all below an ADC cut-off of 1.81 ×10-3 (1200 – 1500 s/mm2) as lesion conspicu- (78% vs 63% respectively) [20]. mm2/s) [22]. Examples of a complicated ity increases with b-value [8]. High diffu- Notable false negatives in these cyst and fibroadenoma on DW-MRI are sion-weighting can also be achieved with DW-MRI studies included ductal carci- shown in Figure 3. Figure 2b also demon- computed DW-MRI, a technique that uses noma in situ (DCIS), malignant lesions with strates an example of artifactual lesion at images acquired at low b-values to synthe- high ADC values, and small cancers. DCIS, the nipple from field inhomogeneity-related size ones at higher b-values.