Diffusion Magnetic Resonance Imaging of the Breast

Fernanda Philadelpho Arantes Pereira, MDa,b,*, Gabriela Martins, MDa,c, Raquel de Vasconcellos Carvalhaes de Oliveira, MScd

KEYWORDS  Breast cancer  Breast tumor  Magnetic resonance imaging (MRI)  -weighted imaging (DWI)  Apparent diffusion coefficient (ADC)  b-value  Chemotherapy  Diffusion imaging (DTI)

Magnetic resonance (MR) imaging has been results related to the menstrual cycle, hormonal increasingly used for accurate diagnosis of both therapy, proliferative alterations, fibroadenomas, primary and recurrent breast cancers, particularly and papillomas. As a result of this confounding in cases in which and breast overlap, in some cases it is not possible to make sonography are inconclusive or yield discrep- a differential diagnosis between benign and malig- ancies. In addition, MR imaging may improve the nant lesions from conventional MR imaging analysis of the local extent of breast cancer by features.10,11 In addition to morphologic and kinetic revealing multifocal and multicenter tumor growth analyses, molecular characterization has been ex- in patients scheduled for conservative breast pected to be useful for the diagnosis of breast surgery. Although the high sensitivity of breast disease. Hence, several studies have investigated MR imaging has proved to be advantageous for the role of advanced MR imaging techniques, preoperative patients, the limited specificity of such as diffusion-weighted imaging (DWI), in this imaging method continues to be a significant improvement of the specificity of MR imaging for problem, particularly in patients referred for further the evaluation of breast lesions.10,12e18 clarification and delineation of inconclusive find- DWI has been used in neurologic imaging for ings obtained using conventional breast imaging some time, but has only recently been applied to techniques.1 breast imaging.8,12e14,19,20 However, recent devel- MR imaging has high sensitivity (89%e100%), opments in MR imaging technology have enabled but lacks specificity for characterization of breast the clinical application of DWI to the entire body, tumors.2e6 An overlap between MR imaging find- which has shown great promise for the detection ings for benign and malignant lesions persists, re- and characterization of most tumor types. Through sulting in variable specificity (50%e90%).4,7e9 imaging of alterations in the microscopic motion of This phenomenon can be caused by false-positive water molecules, DWI can yield novel quantitative

The authors have nothing to disclose. a Department of Breast Imaging, Clı´nica de Diagno´ stico por Imagem (CDPI), Av. Ataulfo de Paiva 669, Leblon, Rio de Janeiro 22440-032, Brazil b Department of , Federal University of Rio de Janeiro, Rua Professor Rodolpho Paulo Rocco 255, Cidade Universita´ ria, Rio de Janeiro 21941-913, Brazil c Department of Breast MR Imaging, Multi-imagem Ressonaˆ ncia Magne´ tica, Rua Saddock de Sa 266, Ipanema, Rio de Janeiro 22411-040, Brazil d Clinic Epidemiology Department, Instituto de Pesquisa Evandro Chagas (IPEC), Fundac¸a˜ o Oswaldo Cruz (Fiocruz), Av. Brasil 4365, Manguinhos, Rio de Janeiro 21040-900, Brazil * Corresponding author. Rua Corcovado 57/502, Jardim Botaˆ nico, Rio de Janeiro 22460-050, Brazil. E-mail address: [email protected]

Magn Reson Imaging Clin N Am 19 (2011) 95–110 doi:10.1016/j.mric.2010.09.001

1064-9689/11/$ e see front matter Ó 2011 Elsevier Inc. All rights reserved. mri.theclinics.com 96 Pereira et al

and qualitative information reflecting cellular increased ADC during the week before menstrua- changes that can provide unique insights into tion has been attributed to increases in secretion tumor cellularity.21 With respect to breast DWI, activity, stromal , and water volume in the a potential role for the apparent diffusion coeffi- extracellular . Normal breast ADC values cient (ADC), a quantitative measure that is directly seem to vary by only 5.5% across the different proportional to the diffusion of water and inversely menstrual phases.27 However, no statistically proportional to the tumor cellular density,22 has significant influence of the menstrual cycle on the been reported to be useful for characterizing ADC values for the breast has been reported. breast tumors and distinguishing malignant Because contrast-enhanced breast MR imaging is tissues from benign tissues.13,17,18,23 recommended to be performed in the second week of the menstrual cycle,28 a similar recommen- CLINICAL APPLICATIONS OF DIFFUSION dation may be optimal for DWI. In women with less IMAGING dense breasts, the ADC values for breast tissue may be artificially reduced as a result of partial Despite improvements in the detection of breast volume effects of fat tissue.20 The mean ADC values cancer as a result of the widespread application in normal breast tissue vary from 1.51 Â 10À3 to of mammography and ultrasound, breast lesions 2.37 Â 10À3 mm2/s for sequences acquired with remain difficult to diagnose and characterize. The b-values ranging from 0 to 1074 s/mm2.14,16,23,29e32 primary advantage of MR imaging of the breast is improvement of the detection and characteriza- Diffusion of Water in Malignant and Benign tion of multiple and/or small lesions, even in dense Tissues fibroglandular breast tissue. However, the low specificity of MR imaging remains a significant In biologic tissues, microscopic water molecular problem.24 motion is induced by both intravascular water DWI has been increasingly recognized as movement (flow) and an extravascular component a promising quantitative method for use in differ- (diffusion).33 With respect to the extravascular ential diagnosis of enhancing lesions in breast component, the state of the extracellular space is MR imaging.25 Based on the principles of DWI, the most important factor that regulates diffusion. visualization and quantification of the random If a tissue is made up of tightly packed cells, as motions of molecules, this technique can be occurs in a malignant tumor, the extracellular used to analyze tissue microstructure in vivo. space is reduced, and diffusion of water is Compared with contrast-enhanced techniques, decreased. This phenomenon results in a higher which can reveal the vasculature and perfusion, DWI signal intensity, restricted signal intensity on this new approach to assess tissue characteristics the ADC map, and a lower ADC value (Fig. 1). In can provide additional diagnostic information to contrast, in benign lesions in which the cells are improve differential diagnosis. In general, the more separated, the extracellular space is larger, DWI technique is faster than dynamic contrast- diffusion of water is less restricted, and the ADC enhanced MR imaging. Consequently, this value is higher.20,34 Tumor cellularity is inversely imaging method can easily be added to a standard correlated with the ADC value, and malignant breast MR imaging protocol. breast tumors exhibit higher cellularity and lower ADC values than benign breast tumors. DWI of Normal Breast Tissue Specificity and Sensitivity of DWI In diffusion-weighted images, the normal breast gland has a high signal in images acquired with There seems to be a consensus in the literature low b-values and low signal in images acquired regarding the ability of DWI of the breast to differen- with high b-values. Ideally, the background signal tiate between malignant and benign breast lesions. for the breast gland should be suppressed to Many studies have shown that lower ADC values emphasize the tumor signal and to avoid the T2 are associated with breast cancer tissues compared shine-through effect.26 with normal breast tissues or benign A trend toward a decreased ADC has been tumors.7,10,12,13,15,16,19,25,29,31,34,35 A meta-analysis observed during the second week of the menstrual of 12 articles reported that the ADC values for cycle, and an increased ADC during the final week benign breast tumors ranged from 1.41 Â 10À3 to before menstruation.27 Variations in the ADC occur 2.01 Â 10À3 mm2/s, and those of malignant breast in the breast as a result of normal hormonal fluctua- tumors ranged from 0.9 Â 10À3 to 1.61 Â 10À3 tions associated with the menstrual cycle. The mm2/s. Variations in ADC values may be present reduced ADC in the second week is correlated across different studies as a result of technical with reduced water content in the breast, and the differences. For example, studies analyzed in the Diffusion MR Imaging of the Breast 97

Fig. 1. 49-year-old woman with IDC of the right breast. (A) Axial maximum intensity projection of a contrast- enhanced T1-weighted three-dimensional spoiled gradient-echo image, first phase, subjected to subtraction technique. (B) Axial diffusion-weighted image. (C) Axial black-and-white and (D) colored ADC maps obtained using b-values of 0 and 750 s/mm2 show enhancement of a highly suspicious mass, evident as increased loss of signal on the ADC black-and-white map and blue on the ADC colored map, which indicate restricted diffusion. meta-analysis used different b-values, varying from values for the noninvasive malignant lesion, ductal 0to1074s/mm2, yet a significant difference in the carcinoma in situ (DCIS), were found to be signifi- ADC values was identified between malignant and cantly higher than those of invasive cancer, but benign lesions, with a pooled sensitivity of 89.1% lower than those of benign lesions, consistent with (range, 85%e91%) and a pooled specificity of the less aggressive, but malignant, nature of these 77% (range, 69%e84%) for an ADC cutoff of 1.1 lesions.25 In another study, high-grade DCIS was to 1.6 Â 10À3 mm2/s.34 shown to be associated with a significantly lower The literature also shows that increased positive ADC value than low-grade DCIS.23 These and other predictive value (PPV) can be achieved by incor- results suggest that there is a significant correlation porating an ADC threshold into breast MR imaging between tumor ADC values and tumor assessment. In a study by Partridge and histology.12,14,35e37 Conversely, others investiga- colleagues,18 in which DWI was acquired using tors have found that no correlation exists between b-values of 0 and 600 s/mm2, application of an the ADC and breast cancer histology and that no ADC threshold of 1.8 Â 10À3 mm2/s for 100% statistically significant difference is present sensitivity produced a PPV of 47%, compared between the ADC values associated with invasive with 37% for MR imaging alone. This methodology ductal carcinoma (IDC) and DCIS.32,38 Therefore, would have avoided biopsy for 33% of benign further studies are needed to critically evaluate lesions without missing any cancers. the clinical usefulness of the mean ADC for tumor grading.

Correlation of the ADC with Tumor Histology False-positive and False-negative Results Several investigators have described an inverse of DWI correlation between tumor cellularity and ADC values, and have suggested that further asso- Several benign lesion subgroups exhibit a remark- ciations with the proliferation rate and tumor able overlap with malignant lesions. According to aggressiveness may be assumed.12,25,32,35 ADC previous reports,12,21,39 the diffusion of water 98 Pereira et al

molecules is not only restricted in environments is necessary to achieve uniform results and to containing high cellularity but also in cases of intra- make interstudy comparisons on the diagnostic cellular and extracellular edema, high viscosity accuracy of DWI for breast cancer possible. regions in abscesses and hematomas, coagulated blood or proteinaceous debris within ducts and Effects of the magnetic strength on DWI cysts, and areas with a high degree of fibrosis. MR imaging scanners operating at 3 T are widely Similar to decreases in extracellular space, these used in the clinic and provide higher signal-to- conditions can impede the movement of water noise ratio (SNR) and greater spatial resolution molecules. Inflammatory changes also favor high than 1.5-T scanners. Small cancers are more cellularity, granulomatous inflammatory elements, clearly visible by DWI at 3 T compared with 1.5 T. fibrous components, and hemosiderin capabil- However, higher magnetic strengths are also ities.38 These benign conditions can also lead to accompanied by an increase in susceptibility arti- low diffusion of water and low ADC values. facts and nonuniformity of the , which Fibroadenomas would be expected to have high can cause image distortions. With the application rates of diffusion and ADC values as a result of of parallel imaging techniques, these artifacts can stromal myxoid changes and consequently be reduced, and the image quality is markedly 37,40,41 increased mobility of water.16,38 However, fibroa- improved. denomas with a predominant fibrous component Diffusion-weighted techniques have lower ADC values. In addition, fibrocystic No consensus exists among different research disease, which is characterized by varying groups regarding the optimal diffusion-weighted degrees of fibrosis and proliferation, can be asso- technique for the breast. Most groups perform ciated with ADC values in the range of malignant DWI by an echo-planar imaging (EPI) ap- 25,35,39 lesions. proach.10,12e14,29,35,39,40,42,43 However, other With respect to false-negative results, the groups apply fast spin-echo technique. Although mucinous colloid carcinoma, which is character- EPI is fast and has a high SNR, results using this ized by the presence of extracellular mucus in technique can be distorted by susceptibility and the absence of increased cellularity, has been re- chemical shift artifacts, as well as by breathing 17,25,35,39 ported to have high ADC values. For this and other motion artifacts.11,36,37 Distortion can reason, further information, such as irregular be decreased by improving the homogeneity of margins, is required for reliable diagnosis. the magnetic field using manual shimming or Occasionally, DCIS and malignant phyllodes parallel imaging. However, EPI remains limited by tumor with bleeding present with high ADC values noise, and thicker slices are generally used as a result of the strong effects of magnetic suscep- compared with contrast-enhanced T1 imaging. tibility.31,36 Malignant phyllodes tumor can have high ADC values as a result of cystic areas inside the Determination of the optimum b-value tumor.17 Similarly, scirrhous carcinomas may be For clinical MR imaging scanners, the diffusion associated with high ADC values and may, conse- sensitivity can easily be altered by changing the quently, be misdiagnosed as benign in nature. parameter known as the b-value. Diffusion images Papillary cancer has a mean ADC value similar to are produced using at least 2 different b-values, that of papilloma, a reflection of the similarity and the loss of signal between these images is between benign and malignant papillary lesions, proportional to the amount of diffusion. Images and it is speculated that hemorrhage is the differen- acquired with low b-values are less diffusion- tiating factor between malignant and benign intra- weighted because they use less of a gradient. ductal papillomas.31,36 Papillomas can also have The diffusion sensitivity is also more affected by low ADC values as a result of high cellularity.17,25,36 microperfusion when low b-values are used, which leads to higher ADC values.23 On the other hand, high b-value images are strongly diffusion- Technical Issues Associated with DWI weighted, highlighting signals from malignant Initial results from studies characterizing DWI tumors and eliminating signals from normal seem promising, but the considerable heteroge- tissues, but have a lower SNR and, consequently, neity between studies and the lack of a complete more image distortion.26 understanding of the factors that influence this The presence of the T2 shine-through effect, in heterogeneity represent significant obstacles in which molecules with long T2 relaxation times the use of this diagnostic tool. For example, varia- produce high signal intensities on diffusion-weighted tions between studies could be caused by the use images, and the high signal intensity of the of different protocols. Therefore, standardization surrounding normal breast parenchyma can limit of DWI parameters and postprocessing methods lesion visibility on imagesobtainedusinglower Diffusion MR Imaging of the Breast 99 b-values. For a given level of a basic T2-dependent hand, Rubesova and colleagues13 and Baltzer signal, a lesion with a lower ADC value requires and colleagues25 did not find a significant differ- a higher b-value than a lesion with a higher ADC value ence in ADC values obtained before and after to compensate for the T2-dependent signal and contrast injection. avoid T2 shine-through.26 DWI is typically performed using at least 2 Postprocessing b-values to enable meaningful interpretation of The placement of the regionof interest (ROI) is crucial 10,13 the results. In theory, the inherent error of ADC for proper analysis of DWI results. First, it is calculations can be reduced by the use of more important to localize the lesion on diffusion- b-values. However, the more b-values used, the weighted images and on the ADC map and to deter- longer time the DWI sequence requires.17 More- mine the location at which the lesion is best over, no consensus exists as to how many and visualized. In most previous studies, the ROI was which b-values should be used for breast DWI. placed directly on the ADC map. The subtracted Pereira and colleagues17 found no statistically images of the dynamic contrast-enhanced significant difference between the ADC values sequence can also be referenced to the ROI place- obtained using different b-value combinations for ment. The ROI should cover the tumor, avoiding differentiation of benign and malignant lesions. areas of hemorrhage or necrosis. In previous studies, However, the ADC values calculated using ROIs of variable areas have been used, ranging from 2 2 19,29,35,44 b-values of 0 and 750 s/mm2 were slightly better 8mm to more than 100 mm . The optimal than the other combinations analyzed. These find- number and type of ROIs remain to be determined. ings suggest that higher b-values are useful for Further studies are needed to characterize the distinguishing benign from malignant lesions, and optimal ROI parameters for measurement of ADC that the use of multiple b-values in the DWI values that best reflect the characteristics of tumors. sequence is unnecessary, saving examination time. Consistent with these results, a study by DWI Limitations 23 Bogner and colleagues found that a combined Movement artifacts 2 b-value protocol of 50 and 850 s/mm resulted in Application of DWI to the breast has previously optimum ADC determination and DWI quality at been limited by movement artifacts. Patient move- 3.0 T. ADC calculations performed using multiple ment during the acquisition of the diffusion- b-values were not significantly more precise than weighted sequences can lead to inaccurate ADC those performed with only two. values.10 In addition, longer acquisition times caused by the use of a greater number of b-values Effect of the contrast medium can lead to patient motion. Therefore, improvement DWI is generally performed before contrast admin- of patient comfort to reduce motion, respiratory istration, but it has been reported that it can also gating, and the use of alternative pulse sequences be performed after contrast. When DWI is per- or postprocessing techniques to reduce eddy formed after contrast, a reduction in the ADC value current-based distortions may help to improve the 33 is usually expected. Yuen and colleagues re- quality of clinical breast DWI data.18,45 ported a mean ADC value reduction of 23% for performance after contrast, and this reduction Lesion visibility and size was generally higher in tumors with relatively Even under optimal circumstances, DWI can fail to high ADC values (>1.3 Â 10À3 mm2/s).44 Investiga- categorize breast lesions because of the limited tors have postulated that the contrast causes spatial resolution and capability of recognizing suppression of the microperfusion effect, leading some lesions on ADC maps, particularly lesions to a reduction in the ADC value. smaller than 1 cm.7 When lesions cannot be visual- Pathologic studies have revealed that microves- ized on diffusion-weighted images, the precise sel counts are higher for malignant tumors localization of the ROI on the ADC map cannot be compared with benign tumors,33 representing determined. Studies focused on lesion visibility in a factor that could potentially increase the ADC DWI compared with contrast-enhanced breast MR values of malignant breast tumors.23 This phenom- imaging detected 89% to 100% of all enon is referred to as the microperfusion effect. lesions,10,12,25,29,42 and good visibility was obtained Considering the suppressive effect of contrast on for 89% to 95.3% of lesions.10,25,42 However, less microperfusion, postcontrast ADC values may visible lesions were reported being either small or purely reflect tumor cellularity in these cases. benign. Another recent study compared the lesion Thus, postcontrast ADC may be a more reliable visibility in DWI results with those of subtrac- indicator than precontrast ADC for reflection of ted contrast-enhanced images.42 Approximately the malignant potential of tumors. On the other 68.9% of lesions showed the same level of visibility 100 Pereira et al

on DWI as on subtraction images, 20.3% of lesions addition, this study revealed no significant statis- showed good, but inferior, visibility, and 10.8% of tical difference between ADC values obtained lesions showed poor visibility. All lesions were de- using different b-value combinations, although b- picted on diffusion-weighted images. values of 0 and 750 s/mm2 performed slightly The critical problem is that breast lesions must better at differentiating between benign and malig- be detected as a prerequisite for differential diag- nant breast lesions than the other combinations nosis. However, current studies have reported analyzed. However, a further study using a larger a lower to equal lesion detection rate for DWI population was needed to improve the statistical compared with dynamic contrast-enhanced MR power and to fortify the previous results. imaging.10,12,25,29,42 These findings may be at least partially a result of the DWI technique used, Study Population because the distortion of EPI remains a major problem for accurate measurement of the ADC, From August 2007 to March 2010, 156 women particularly for small lesions.11,34,36,37 with 178 breast mass-type lesions were prospec- tively enrolled in the study. The study was Nonmasslike enhancement approved by our institutional review board, and Another factor that can affect ADC values is the all patients provided informed consent. Exclusion architecture of tumors. According to the American criteria included benign cysts, patient movement, College of Radiology Breast Imaging Reporting sequences with susceptibility and chemical shift and Data System (BI-RADS) lexicon, pathologic artifacts, lesions not visible on the DWI sequence, growth conditions in the breast can be described and neoadjuvant treatment before MR imaging. as mass or nonmasslike enhancement.46 Guo From these criteria, 40 lesions from 34 patients and colleagues12 and Sinha and colleagues16 were excluded. As a result, the study included found that the mean ADC value is inversely propor- 122 patients (age range, 22e86 years; mean age, tional to the cell density. Therefore, as nonmass- 46.9 years) with 138 breast lesions. like enhancement lesions can form large and On histopathologic examination, 81 malignant noncompact lesions, with normal parenchyma in lesions were identified, including IDC (n 5 64), the center of the tumor, a lesser restriction of the invasive lobular carcinoma (ILC; n 5 6), DCIS diffusion processes may occur in these tumors (n 5 4), tubular carcinoma (n 5 2), mucinous compared with mass lesions (Fig. 2). This colloid carcinoma (n 5 2), medullary carcinoma phenomenon has been reported for several patho- (n 5 1), adenoid cystic carcinoma (n 5 1), and logic and normal states, including noninvasive malignant phyllodes tumor (n 5 1). The median ductal carcinomas, lobular carcinoma in situ, atyp- size of the malignant lesions was 2.1 cm (range, ical ductal hyperplasia, papillomas, hormonal 0.8e11.2 cm). changes, and fibrocystic disease.47 A total of 57 benign lesions were identified, 19 of These results indicate that ADC measurements which showed histopathologic results, which have a limited ability to differentiate between included fibroadenoma (n 5 14), papilloma benign and malignant nonmasslike enhancement (n 5 2), epidermoid cyst (n 5 1), nodular adenosis lesions. ADC values for malignant lesions may be (n 5 1), and ductal ectasia with stroma fibrosis in the range of benign lesions in these cases.25 (n 5 1). The authors also included 38 lesions clas- Therefore, a higher ADC value cutoff may be sified as BI-RADS 46 category 2 by MR imaging to required for nonmasslike enhancement lesions increase the number of samples of benign lesions compared with mass lesions. Yabuuchi and for use in identification of more reliable and repre- colleagues47 suggested that an ADC value of sentative ADC values. The diagnoses were defined À less than 1.3 Â 10 3 mm2/s was a significant factor by the consensus of 2 experienced breast radiolo- for indication of malignancy for nonmasslike gists with 12 and 9 years of experience, respec- enhancement lesions. In contrast, Baltzer and tively. Benign lesions were followed up for at colleagues42 found that ADC measurements failed least 1 year by mammography, sonography, or to be of diagnostic value for these lesions. Further MR imaging, with no significant modifications in investigation is needed to analyze the precise the imaging patterns. The median size of benign diagnostic potential of DWI for diagnosis of non- lesions was 1.2 cm (range, 0.6e11.4 cm). masslike enhancement lesions.

ANALYSIS OF DWI AT OUR INSTITUTION MR Imaging Acquisition, Analysis and Data Collection A preliminary study in our institution17 confirmed the usefulness of DWI for the differential diagnosis All MR imaging examinations, including DWI, were of benign and malignant breast lesions. In performed on a 1.5-T MR System with a bilateral Diffusion MR Imaging of the Breast 101

Fig. 2. 62-year-old woman with nonmasslike enhancement of the left breast. (A) Axial contrast-enhanced T1-weighted three-dimensional spoiled gradient-echo image, first phase, subjected to subtraction technique. (B) Axial diffusion-weighted image. (C) Axial colored ADC map obtained using b-values of 0 and 750 s/mm2. (D) Fusion axial contrast-enhanced T1-weighted subjected to subtraction technique and axial colored ADC map reveal a nonmasslike enhancement lesion classified as highly suspicious by conventional MR imaging. Because nonmasslike enhancement lesions form large but noncompact lesions, a lesser restriction of the diffusion processes may occur, evident as yellow, and not blue, on the ADC colored map. Note that even using the sub- tracted image as reference to the ROI placement, there are still no enhancing areas, which may not represent tumor inside the ROIs (white arrows).

8-channel breast coil. DWI was performed using and color ADC maps. Color maps used a color an axial single-shot EPI sequence centered on scheme, ranging from blue (diffusion restriction) the lesion (Table 1). Standard sequences, to red (no diffusion restriction). The ADC maps of including pre- and postcontrast sequences, were each lesion were calculated using 5 b-values (0, acquired before DWI. 250, 500, 750, and 1000 s/mm2) and also using All images were transferred to a workstation, the b 0 s/mm2 value in combination with the other and the DWI sequence was postprocessed using b-values (0 and 250 s/mm2, 0 and 500 s/mm2, commercial software to obtain black-and-white 0 and 750 s/mm2, 0 and 1000 s/mm2). 102 Pereira et al

Table 1 Protocol used for the DWI study at our institution

Parameter Value Sequence DWI single-shot EPI TR/TE 1800 ms/93.8 ms (minimum TE) FOV 360 mm Matrix 160 Â 192 Slice thickness/interval 5 mm/0 mm NEX 16 rBW 25 kHz b-values 0, 250, 500, 750, 1000 s/mm2 Scan time 224 s Scan time for b-value 56 s

Abbreviations: FOV, field of view; NEX, number of excitations; rBW, receive band width; TE, echo time; TR, repetition time.

DWI and ADC maps are typically noisy and were combinations was for the combination of b 0 and therefore viewed in conjunction with contrast- 250 s/mm2, which exhibited a significantly lower enhanced images. To achieve standardized condi- area under the curve (AUC) compared with the tions for analysis and to avoid contamination of the other combinations (P 5 .019). No significant data by adjacent structures, 2 similar circular ROIs differences were observed between the other with a median area of 49 mm2 (range, 16e536 b-value combinations (P>.05). Consistent with mm2) were individually placed within the target previous findings, the ADC values calculated using lesion in the same location for the 5 ADC maps b-values of 0 and 750 s/mm2 were still slightly described earlier, and the average ADC was better than the other b-value combinations. Based acquired for each b-value combination. Apparent on a cutoff value of 1.24 Â 10À3 mm2/s for ADCs necrotic or cystic components were avoided by calculated using b-values of 0 and 750 s/mm2,4 referring to conventional MR images. of 57 benign lesions (two fibroadenomas, one The median ADC values were correlated with papilloma, and one nodular adenosis) and 7 of imaging findings and histopathologic diagnoses. 81 malignant lesions (3 IDC, one ILC, 2 mucinous The cutoff ADC value and the sensitivity and spec- colloid carcinomas, and one malignant phyllodes ificity of DWI to differentiate between benign and tumor) were misdiagnosed, resulting in a sensitivity malignant lesions were calculated for all b-value of 91.4% and a specificity of 93%. The ADC values combinations. Comparisons between the median calculated using b-values of 0 and 250 s/mm2 ADC values for noninvasive ductal carcinoma yielded the poorest differentiation between benign and different grades of IDC were also performed and malignant lesions, resulting in a sensitivity of for all b-value combinations. P-values less than .05 81.5% and a specificity of 87.7%, based on were considered statistically significant. a cutoff value of 1.47 Â 10À3 mm2/s. With respect to the different benign histologic types, for the b-value combination of 0 and 750 Results s/mm2, the median ADC values for fibroadenoma, The median ADC values obtained using 5 b-values papilloma, epidermoid cyst, nodular adenosis, and and b 0 s/mm2 value in combination with the other ductal ectasia with stroma fibrosis were 1.46 Â b-values were significantly lower for malignant 10À3 mm2/s, 1.22 Â 10À3 mm2/s, 1.32 Â 10À3 breast lesions (median, 0.82e1.19; interquartile mm2/s, 0.99 Â 10À3 mm2/s, and 1.99 Â 10À3 range [IQR] 0.72e1.4 Â 10À3 mm2/s) than for mm2/s, respectively. With respect to the different benign lesions (median, 1.38e1.71; IQR malignant histologic types, for the b-value combina- 1.22e1.93 Â 10À3 mm2/s) (P<.001, Table 2). tion of 0 and 750 s/mm2, the median ADC values for All of the b-value combinations used to calculate IDC, ILC, DCIS, tubular carcinoma, mucinous the ADC resulted in high sensitivity and specificity colloid carcinoma, medullary carcinoma, adenoid for the differentiation of benign and malignant cystic carcinoma, and malignant phyllodes tumor lesions (Table 3). The only significant difference were 0.91 Â 10À3 mm2/s, 0.94 Â 10À3 mm2/s, that occurred between the different b-value 0.91 Â 10À3 mm2/s, 0.84 Â 10À3 mm2/s, 1.59 Â 10À3 Diffusion MR Imaging of the Breast 103

Table 2 ADC values by b-value combination for benign and malignant lesions

ADC values (310L3 mm2/s) Benign Lesions Malignant Lesions (n 5 57) (n 5 81) b-Value Combinations (s/mm2) Median IQR Median IQR P-value 0, 250, 500, 750, and 1000 1.45 1.30e1.58 0.907 0.76e1.01 <0.001 0 and 250 1.71 1.56e1.93 1.190 1.04e1.40 <0.001 0 and 500 1.59 1.44e1.77 1.010 0.90e1.19 <0.001 0 and 750 1.51 1.34e1.64 0.931 0.83e1.03 <0.001 0 and 1000 1.38 1.22e1.55 0.820 0.72e0.94 <0.001 mm2/s, 0.86 Â 10À3 mm2/s, 0.93 Â 10À3 mm2/s, and was slightly better than the others. These findings 1.84 Â 10À3 mm2/s, respectively. suggest that higher b-values can be useful for dis- No statistically significant difference was evident tinguishing benign from malignant lesions and between the median ADC values for noninvasive that use of multiple b-values in DWI sequences is ductal carcinoma and the different grades of IDC unnecessary. using any of the b-value combinations. For the Based on the diagnostic criteria used in this b-value combinationof 0 and 750s/mm2,themedian study, only two fibroadenomas (14.2%) and 4 ADC value for DCIS was 0.91 Â 10À3 mm2/s, and the invasive carcinomas (5.7%) were not appropriately median ADC values for IDC grades I, II, and III were classified using the ADC. These results indicate 0.92 Â 10À3 mm2/s, 0.88 Â 10À3 mm2/s, and that DWI can effectively discriminate between 1.02 Â 10À3 mm2/s, respectively (P 5 .426). fibroadenomas and invasive carcinomas (Figs. 3 and 4). This capability could likely prove to be useful for lesion characterization, because fi- Comments broadenomas have characteristics that overlap The present results confirmed the findings of our with malignant lesions in both sonography previous study.17 Both studies showed that the and dynamic contrast-enhanced MR imaging median ADC value for benign lesions was signifi- studies.16,48,49 In our series, 5 fibroadenomas cantly lower than that of malignant lesions for all were misdiagnosed as suspect by MR imaging, b-value combinations analyzed. Moreover, no but 3 of these lesions were correctly diagnosed statistically significant difference was observed as benign by DWI. between ADC values calculated using most of the The primary limitations of our study were similar b-value combinations analyzed, although the ADC to those reported in the literature, including poor calculated using b-values of 0 and 750 s/mm2 quality data as a result of patient movement and

Table 3 Sensitivity and specificity of the ADC in differentiation of benign from malignant lesions for each b-value combination

b-Value Combinations Cutoff Sensitivity Specificity (s/mm2) (310L3 mm2/s)a (%) 95% CIb (%) 95% CIb AUCc 0, 250, 500, 750, and 1.17 90.1 (73/81) 81.4e95.6 94.7 (54/57) 85.4e98.9 0.929 1000 0 and 250 1.47 81.5 (66/81) 73.0e90.0 87.7 (50/57) 79.2e96.2 0.891 0 and 500 1.34 91.4 (74/81) 85.3e97.5 91.2 (52/57) 83.8e98.6 0.928 0 and 750 1.24 91.4 (74/81) 85.3e97.5 93.0 (53/57) 86.4e99.6 0.941 0 and 1000 1.12 91.4 (74/81) 85.3e97.5 91.2 (52/57) 83.8e98.6 0.943

Numbers in parentheses indicate number of lesions. a ADC cutoff value. b Confidence interval. c Area under the curve, represents the probability that the ADC value accurately characterizes a breast lesion as malig- nant or benign according to the cutoff value. 104 Pereira et al

Fig. 3. 35-year-old woman with IDC of the left breast. (A) Axial contrast-enhanced T1-weighted three- dimensional spoiled gradient-echo image, in late phase. (B) Axial diffusion-weighted image. (C) Axial black- and-white and (D) colored ADC maps obtained using b-values of 0 and 750 s/mm2 reveal a 1.1-cm mass (white arrows) classified as probably benign by conventional MR imaging. Note the low signal on the ADC black-and- white map and the blue on the ADC colored map, which indicates a malignant lesion.

difficulty visualizing some lesions on DWI, particu- accuracy of MR imaging, reducing the number of larly small lesions. Limited ADC value measure- unnecessary invasive procedures. In our study, ments resulting from motion artifacts (10.1%) or the overall specificity of MR imaging increased from lack of visibility of the lesion on DWI, even after from 82.4% to 93% with the use of DWI. correlation with contrast-enhanced images (7.9%), resulted in exclusion of these cases. However, POTENTIAL APPLICATIONS OF DIFFUSION generally, good lesion visibility (92.1%) was ob- IMAGING tained in the present study, and 8 of the 14 nonvisi- ble lesions (57.1%) were smaller than 1 cm. Our results indicate that DWI can serve as a power- Despite these limitations, our results and the ful tool for differentiating benign from malignant results of others suggest that DWI of the breast breast lesions. In addition to this use, DWI also can provide additional information for the charac- shows potential for use in several additional diag- terization of mass breast lesions in a rapid and nostic and therapeutic applications, including straightforward manner. Furthermore, combina- monitoring of neoadjuvant chemotherapy (NAC), tion of ADC measurements with dynamic studies evaluation of peritumor tissues, and assessment that interpret enhancement patterns, which of axillary lymph nodes. These promising novel exhibit good sensitivity but variable specificity applications of DWI are discussed in the following for characterizing lesions, can increase the overall sections. Diffusion MR Imaging of the Breast 105

Fig. 4. 43-year-old woman with fibroadenoma of the left breast. (A) Axial contrast-enhanced T1-weighted three- dimensional spoiled gradient-echo image, first phase, subjected to subtraction technique. (B) Axial diffusion- weighted image. (C) Axial black-and-white and (D) colored ADC maps obtained using b-values of 0 and 750 s/mm2 reveal a 1.3-cm mass (white arrows) classified as suspicious by conventional MR imaging. Note the high signal on the ADC black-and-white map and the red on the ADC colored map, which suggest that the lesion is benign.

Application of DWI to Monitoring of NAC chemotherapy. Identification of surrogate biomarkers able to predict therapeutic outcomes NAC is used to achieve tumor shrinkage, allowing earlier or more accurately than the current methods breast conservation surgery for a proportion of would be valuable for individualized tailoring of patients with locally advanced breast cancer. treatment and would allow for more cost-effective Large clinical trials assume that the degree of use of resources.51 response of the primary tumor to NAC is correlated Imaging modalities can be used to track tumor with patient survival.50 However, 20% to 25% of all changes in response to a particular chemotherapy patients with breast cancer do not respond to 106 Pereira et al

regimen. Several imaging modalities have been tumor-free margins and to reduce the risk of local used to assess the extent of response to primary recurrence without compromising the cosmetic breast cancer treatment. MR imaging is considered outcome. Therefore, accurate determination of the to be the best available choice for evaluating the transition boundary between the tumor and normal tumor and its response to the administered treat- tissue is critical for deciding the surgical scope. ment as a result of the higher accuracy of this tech- A previous study was designed to analyze changes nique compared with the traditional methods of in ADC values in peritumor tissues using DWI.55 This physical examination and mammography.52 study was based on the hypothesis that genetic and A role for DWI in monitoring and predicting early molecular alterations precede phenotypic changes in breast tumor responses to NAC has previously peritumor tissues. Therefore, DWI may be able to been described.21,30,51,53 Chemotherapy treatment detect alterations earlier than conventional MR results in cell lysis and loss of integ- imaging. These investigators revealed that the ADC rity, which results in an increase in extracellular value of malignant lesions was statistically lower space and a concomitant increase in diffusion of than that of peritumor tissues. They also found that water. Based on these effects, interest is growing the ADC values increased gradually from the inner- in the measurement of changes in diffusion to most to the outermost layers of peritumor tissues. detect tumor responses. Therefore, DWI may prove These results suggest that DWI can be used to to be valuable for monitoring the effectiveness of predict the involvement of peritumor tissues, which treatment and for assessing changes caused by could be highly beneficial for surgery preparation. cell swelling and apoptosis rather than the applica- tion of conventional radiologic response indicators. Application of DWI to Assessment Pickles and colleagues53 reported that a signifi- of Axillary Lymph Nodes cantincreaseintheADCoccurredbeforeadecrease Preliminary studies have shown that diffusion can be in tumor size measured by MR imaging in a cohort of used to detect lymph nodes affected by malignant patients with invasive breast cancer examined cells after the nodes have undergone changes and before and after the first and second NAC cycles. increases in cellularity that lead to diffusion restric- The increase in the ADC value at the first cycle tion and low ADC values.21 In a retrospective feasi- time point was significant, but the decrease in the bility study, DWI was evaluated as a potential tool for longest diameter at the second cycle time point characterization of pelvic lymph nodes in patients was only of borderline significance. Sharma and with prostate cancer.56 The results from this study colleagues30 found a statistically significantly larger showed that there was a highly significant difference increase in the ADC after the first chemotherapy between the mean ADC values of malignant versus cycle in responders compared with nonresponders, benign lymph nodes. Use of a cutoff of 1.30 Â 10À3 indicating the potential of this method for assess- mm2/s resulted in good accuracy (85.6%), sensi- ment of early responses. At this time point, no tivity (86.0%), and specificity (85.3%) for differentia- change in tumor size was evident for either group. tion between malignant and benign lymph nodes These results underscore the potential usefulness using ADC values. These findings indicate that of DWI for assessing treatment responses at early DWI is an accurate technique for the analysis of time points, before changes in tumor size. pelvic lymph nodes. A comparison between the ability of MR imaging One could predict that metastasis to lymph no- and DWI to detect residual tumors revealed accu- des present in the axilla should result in similar racy rates of 89% and 96%, respectively, which effects on the ADC, specifically restricted diffusion were not found to be statistically significant.54 and corresponding low ADC values. However, DWI exhibited, at minimum, equivalent accuracy further studies are necessary to investigate the levels to contrast-enhanced MR imaging for moni- usefulness of DWI for characterization of malig- toring NAC. Therefore, use of DWI to visualize nant axillary lymph nodes. In addition, character- residual breast cancer without the need for ization of the necessary lymph nodal invasion contrast medium could be advantageous. level required to restrict diffusion and reduce the ADC value is needed for clinical applications. It Application of DWI to Evaluation also remains unclear whether DWI can accurately of Peritumor Tissues diagnose small metastases. Conservative surgery has become a well- Use of DWI for Cancer Screening in Clinical established alternative to mastectomy for treatment Practice of breast cancer. However, for conservative surgery to be successful, it is necessary to remove an The usefulness of DWI in clinical practice remains adequate volume of breast tissue to achieve to be determined. DWI is often used as a supportive Diffusion MR Imaging of the Breast 107 tool when results from conventional MR imaging useful for detecting disease and assessing local are unclear. Applications using DWI for assessment invasion. of the response to NAC are also under develop- In the brain, diffusion measures have ment. Therefore, DWI has primarily been used for been useful for elucidating organization and devel- diagnostic purposes. However, the power of DWI opment of and for identifying abnor- for evaluation of high-risk patients who undergo malities.57 With recent advancements in MR screening MR imaging remains unknown. imaging technology, DTI has also enabled unique The objectives of cancer screening are to improve microstructural characterization of normal and the prognosis of patients with cancer and to reduce abnormal tissues in other areas of the body. The mortality. The accurate and timely detection of general assumption in previous studies has been cancer is crucial to decreasing cancer-related that water diffusion in breast tissue is isotropic, mortality. High-risk groups are likely to be given with equal mobility in all directions. However, in priority for screening. Insufficient objective data more organized breast tissues, such as the paren- are available to evaluate the effectiveness of DWI chyma, which has a network of branching ducts for cancer screening, and future studies in this and associated periductal fibrous stroma that areaare needed. DWI can bepredicted tobe auseful extends radially and posteriorly from the nipple, it screening tool because of its short scan time, cost- is possible that water molecules tend to follow effectiveness, and high sensitivity.36,37 a less restricted path and diffuse preferentially along or parallel to the ducts.57 This phenomenon Use of DWI as a Stand-alone Technique may result in anisotropic diffusion in normal breast tissue that can be detected by DTI. Because DWI does not require the injection of any Partridge and colleagues57 found low to contrast agent, it could possibly be of value as moderate diffusion anisotropy in normal fibro- a stand-alone technique in severely ill patients, glandular tissue. Fractional anisotropy (FA) who cannot tolerate extended examinations. measurements differed between breast regions Furthermore, in patients with impaired renal func- and were generally higher in the outer posterior tion, the risk of nephrogenic systemic fibrosis is region. This observation may reflect microstruc- avoided using this technique.25 tural differences in the fibroglandular tissue. A An initial investigation focused exclusively on higher concentration of smaller tapering ducts malignant lesions showed a high rate of sensitivity and terminal ductolobular units in the peripheral for a contrast-free diagnostic approach combining breast could influence diffusion directionality and DWI and short T1 inversion recovery imaging.25,43 increase posterior FA measurements in this region. However, before such an approach could be intro- Characterization of these influences on DTI duced into the clinical routine, a possible incre- measurements may be important for clinical inter- mental increase in value of contrast-free breast pretation of DTI results and standardization of MR imaging over conventional methods must be techniques. Future studies are necessary to validated. Knowledge regarding the diagnostic assess the clinical usefulness of DTI for breast usefulness of ADC values compared with standard imaging by comparing diffusion anisotropy in morphologic and dynamic descriptors remains breast tumors and normal tissue. DTI may be limited. In a recent investigation, quantitative diffu- able to detect disruptions in the normal anisotropy sivity measurements resulted in high, but nonethe- of water diffusion in the breast caused by cancer less clearly inferior, diagnostic parameters growth and may lead to new indices for identifica- compared with routine breast MR imaging.25,42 tion of breast cancer. Therefore, further studies are needed to quantita- tively compare the accuracy of contrast-free and contrast-enhanced MR imaging of the breast. SUMMARY Diffusion sequences can be used for characteriza- Diffusion Tensor Imaging: An Extension tion and differentiation of malignant and benign of DWI breast lesions. Use of DWI as a diagnostic tool can Diffusion tensor imaging (DTI) extends standard increase the specificity of breast MR imaging and DWI, characterizing diffusion in at least 6 direc- can reduce the number of false-positive results tions, to measure the full diffusion tensor and to and associated unnecessary biopsies. In addition, characterize the motion of water in greater detail. DWI can be performed without significantly In addition to the ADC value, DTI enables calcula- increasing examination time and can easily be intro- tion of the degree of diffusion anisotropy (or direc- duced into the standard breast MR imaging tionality).57 Therefore, information obtained by DTI protocol. Furthermore, novel applications for DWI for normal and altered breast tissue may also be are under development, including monitoring of 108 Pereira et al

the response to NAC, evaluation of peritumor 10. Wenkel E, Geppert C, Schulz-Wendtland R, et al. tissues, assessment of axillary lymph nodes, and Diffusion weighted imaging in breast MRI: compar- characterization of the advanced DTI technique. ison of two different pulse sequences. Acad Radiol Although DWI is not currently recommended as 2007;14(9):1077e83. a stand-alone diagnostic tool, future studies without 11. Sinha S, Sinha U. Functional magnetic resonance of injection of contrast agents may support the use of human breast tumors: diffusion and perfusion DWI in this capacity. imaging. Ann N Y Acad Sci 2002;980:95e115. The performance of DWI under different condi- 12. Guo Y, Cai YQ, Cai ZL, et al. Differentiation of clini- tions and at different field strengths must be better cally benign and malignant breast lesions using characterized to define a universal protocol. In addi- diffusion-weighted imaging. J Magn Reson Imaging tion, determination of the diagnostic criteria is also 2002;16(2):172e8. important, such as the threshold ADC value for 13. Rubesova E, Grell AS, De Maertelaer V, et al. Quan- quantitative diagnosis and the signal intensity for titative diffusion imaging in breast cancer: a clinical qualitative diagnosis. Potential pitfalls related to the prospective study. J Magn Reson Imaging 2006; diagnosis of nonmass-type enhancement lesions 24(2):319e24. and small mass-type lesions, as well as movement 14. Woodhams R, Matsunaga K, Iwabuchi K, et al. Diffu- artifacts, should be taken into consideration. sion-weighted imaging of malignant breast tumors: the usefulness of apparent diffusion coefficient (ADC) value and ADC map for the detection of REFERENCES malignant breast tumors and evaluation of cancer extension. J Comput Assist Tomogr 2005;29(5): 1. Kuhl CK. Current status of breast MR imaging. Part 644e9. II. Clinical applications. Radiology 2007;244(3): 15. Kuroki Y, Nasu K, Kuroki S, et al. Diffusion-weighted 672e91. imaging of breast cancer with the sensitivity encod- 2. Kuhl CK. The current status of breast MR imaging. ing technique: analysis of the apparent diffusion Part I. Choice of technique, image interpretation, coefficient value. Magn Reson Med Sci 2004;3(2): diagnostic accuracy, and transfer to clinical prac- 79e85. tice. Radiology 2007;244(2):356e78. 16. Sinha S, Lucas-Quesada FA, Sinha U, et al. In vivo 3. Schnall MD, Blume J, Bluemke DA, et al. Diagnostic diffusion-weighted MRI of the breast: potential for architectural and dynamic features at breast MR lesion characterization. J Magn Reson Imaging imaging: multicenter study. Radiology 2006;238(1): 2002;15(6):693e704. 42e53. 17. Pereira FPA, Martins G, Figueiredo E, et al. Assess- 4. Macura KJ, Ouwerkerk R, Jacobs MA, et al. Patterns ment of breast lesions with diffusion-weighted MRI: of enhancement on breast MR images: interpretation comparing the use of different b values. AJR Am J and imaging pitfalls. Radiographics 2006;26(6): Roentgenol 2009;193(4):1030e5. 1719e34. 18. Partridge SC, De Martini WB, Kurland BF, et al. 5. Wierner JI, Schilling KJ, Adami C, et al. Assessment Quantitative diffusion-weighted imaging as an of suspected breast cancer by MRI: a prospective adjunct to conventional breast MRI for improved clinical trial using a combined kinetic and morpho- positive predictive value. AJR Am J Roentgenol logic analysis. AJR Am J Roentgenol 2005;184(3): 2009;193(6):1716e22. 878e86. 19. Yabuuchi H, Matsuo Y, Okafuji T, et al. Enhanced 6. Bedrosian I, Mick R, Orel SG, et al. Changes in the mass on contrast-enhanced breast MR imaging: surgical management of patients with breast carci- lesion characterization using combination of noma based on preoperative magnetic resonance dynamic contrast-enhanced and diffusion-weighted imaging. Cancer 2003;98(3):468e73. MR images. J Magn Reson Imaging 2008;28(5): 7. Marini C, Iacconi C, Giannelli M, et al. Quantitative 1157e65. diffusion-weighted MR imaging in the differential 20. Kelcz F. Diffusion weighted imaging of breast e prom- diagnosis of breast lesion. Eur Radiol 2007;17(10): ises and problems. Eur Radiol 2009;19(Suppl 4): 2646e55. S856e8. 8. Kuhl CK, Mielcareck P, Klaschik S, et al. Dynamic 21. Koh DM, Collins DJ. Diffusion-weighted MRI in the breast MR imaging: are signal intensity time course body: applications and challenges in . data useful for differential diagnosis of enhancing AJR Am J Roentgenol 2007;188(6):1622e35. lesions? Radiology 1999;211(1):101e10. 22. Paran Y, Bendel P, Margalit R, et al. Water diffusion 9. Fischer U, Kopka L, Grabbe E. Breast carcinoma: in the different microenvironments of breast cancer. effect of preoperative contrast-enhanced MR NMR Biomed 2004;17(4):170e80. imaging on the therapeutic approach. Radiology 23. Bogner W, Gruber S, Pinker K, et al. Diffusion- 1999;213(3):881e8. weighted MR for differentiation of breast lesions at Diffusion MR Imaging of the Breast 109

3.0 T: how does selection of diffusion protocols 37. Kuroki Y, Nasu K. Advances in breast MRI: diffusion- affect diagnosis? Radiology 2009;253(2):341e51. weighted imaging of the breast. Breast Cancer 24. Kuhl CK. Concepts for differential diagnosis in 2008;15(3):212e7. breast MR imaging. Magn Reson Imaging Clin N 38. Belli P, Constantini M, Bufi E, et al. Diffusion- Am 2006;14(3):305e28. weighted imaging in breast lesion evaluation. Radiol 25. Baltzer PAT, Dietzal M, Vag T, et al. Diffusion Med 2010;115(1):51e69. weighted imaging e useful in all kinds of lesions? 39. Woodhams R, Kakita S, Hata H, et al. Diffusion- A systematic review. Eur Radiol 2009;19(Suppl 4): weighted imaging of mucinous carcinoma of the S765e9. breast: evaluation of apparent diffusion coefficient 26. Geijer B, Sundgren PC, Lindgren A, et al. The value and signal intensity in correlation with histologic find- of b required to avoid T2 shine-through from old ings. AJR Am J Roentgenol 2009;193(1):260e6. lacunar infarcts in diffusion-weighted imaging. 40. Matsuoka A, Minato M, Harada M, et al. Comparison Neuroradiology 2001;43(7):511e7. of 3.0 and 1.5-tesla diffusion-weighted imaging in 27. Partridge SC, McKinnon GC, Henry RG, et al. the visibility of breast cancer. Radiat Med 2008; Menstrual cycle variation of apparent diffusion coef- 26(1):15e20. ficients measured in the normal breast using MRI. 41. Lo GG, Ai V, Chan JK, et al. Diffusion-weighted J Magn Reson Imaging 2001;14(4):433e8. magnetic resonance imaging of breast lesions: first 28. Kuhl CK, Bieling HB, Gieseke J, et al. Healthy experiences at 3.0T. J Comput Assist Tomogr premenopausal breast parenchyma in dynamic 2009;33(1):63e9. contrast-enhanced MR imaging of the breast: 42. Baltzer PA, Renz DM, Herrmann KH, et al. Diffusion- normal contrast medium enhancement and weighted imaging (DWI), in MR mammography cyclical-phase dependency. Radiology 1997; (MRM): clinical comparison of echo planar imaging 203(1):137e44. (EPI) and half-Fourier single-shot turbo spin echo 29. Park MJ, Cha ES, Kang BJ, et al. The role of (HASTE) diffusion techniques. Eur Radiol 2009; diffusion-weighted imaging and the apparent diffu- 19(7):1612e20. sion coefficient (ADC) values for breast tumors. 43. Kuroki-Suzuki S, Kuroki Y, Nasu K, et al. Detecting Korean J Radiol 2007;8(5):390e6. breast cancer with non-contrast MR-imaging: 30. Sharma U, Danishad KK, Seenu V, et al. Longitudinal combining diffusion-weighted and STIR imaging. study of the assessment by MRI and diffusion- Magn Reson Med Sci 2007;6(1):21e7. weighted imaging of tumor response in patients 44. Kim SH, Cha ES, Kim HS, et al. Diffusion-weighted with locally advanced breast cancer undergoing imaging of breast cancer: correlation of the neoadjuvant chemotherapy. NMR Biomed 2009; apparent diffusion coefficient value with prognostic 22(1):104e13. factors. J Magn Reson Imaging 2009;30(3):615e20. 31. Woodhams R, Matsunaga K, Kan S, et al. ADC 45. Le Bihan D, Poupon C, Amadon A, et al. Artifacts mapping of benign and malignant breast tumors. and pitfalls in diffusion MRI. J Magn Reson Imaging Magn Reson Med Sci 2005;4(1):35e42. 2006;24(3):478e88. 32. Yoshikawa MI, Ohsumi O, Sugata S, et al. 46. American College of Radiology (ACR). ACR Comparison of breast cancer detection by BIRADS: magnetic resonance imaging. In: diffusion-weighted magnetic resonance imaging Ikeda DM, Hylton NM, editors. ACR breast imaging and mammography. Radiat Med 2007;25(5): reporting and data system, breast imaging atlas. 218e23. Reston (VA): American College of Radiology; 2003. 33. Yuen S, Yamada K, Goto M, et al. Microperfusion- p. 111e4. induced elevation of ADC is suppressed after 47. Yabuuchi H, Matsuo Y, Kamitani T, et al. Non-mass- contrast in breast carcinoma. J Magn Reson like enhancement on contrast-enhanced breast MR Imaging 2009;29(5):1080e4. imaging: lesion characterization using combination 34. Tsushima Y, Takahashi-Taketomi A, Endo K. of dynamic contrast-enhanced and diffusion- Magnetic resonance (MR) differential diagnosis of weighted MR images. Eur J Radiol 2010;75(1): breast tumors using apparent diffusion coefficient 126e32. (ADC) on 1.5-T. J Magn Reson Imaging 2009; 48. Stomper PC, Winston JS, Herman S, et al. Angio- 30(2):249e55. genesis and dynamic MR imaging gadolinium 35. Hatakenaka M, Soeda H, Yabuuchi H, et al. enhancement of malignant and benign breast Apparent diffusion coefficients of breast tumors: lesions. Breast Cancer Res Treat 1997;45(1): clinical application. Magn Reson Med Sci 2008;7: 39e46. 23e9. 49. Hochman MG, Orel SG, Powell CM, et al. Fibroade- 36. Razek AA, Gaballa G, Denewer A, et al. Diffusion- nomas: MR imaging appearances with radiologice weighted MR imaging of the breast. Acad Radiol histopathologic correlation. Radiology 1997;204(1): 2010;17(3):382e6. 123e9. 110 Pereira et al

50. Ma B, Meyer CR, Pickles MD, et al. -by-voxel 54. Woodhams R, Kakita S, Hata H, et al. Identifica- functional diffusion mapping for early evaluation of tion of residual breast carcinoma following breast cancer treatment. Inf Process Med Imaging neoadjuvant chemotherapy: diffusion-weighted 2009;21:276e87. imagingecomparison with contrast-enhanced MR 51. Turnbull LW, Ma B, Meyer CR, et al. Diffusion imaging and pathologic findings. Radiology 2010; changes in chemotherapy of breast cancer: the 254(2):357e66. earliest sign? Eur Radiol 2009;19(Suppl 4): 55. Yili Z, Xiaoyan H, Hongwen D, et al. The value of S948e9. diffusion-weighted imaging in assessing the ADC 52. Iacconi C, Giannelli M, Marini C, et al. The role of changes of tissues adjacent to breast carcinoma. mean diffusivity (MD) as a predictive index of the BMC Cancer 2009;9:18. response to chemotherapy in locally advanced 56. Eiber M, Beer AJ, Holzapfel K, et al. Preliminary breast cancer: a preliminary study. Eur Radiol results for characterization of pelvic lymph nodes in 2010;20(2):303e8. patients with prostate cancer by diffusion-weighted 53. Pickles MD, Gibbs P, Lowry M, et al. Diffusion MR-imaging. Invest Radiol 2010;45(1):15e23. changes precede size reduction in neoadjuvant 57. Partridge SC, Murthy RS, Ziadloo A, et al. Diffusion treatment of breast cancer. Magn Reson Imaging tensor magnetic resonance imaging of the breast. 2006;24(7):843e7. Magn Reson Imaging 2010;28(3):320e8.