Dynamic contrast-enhanced (DCE) magnetic resonance imaging

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1 ORIGINAL ARTICLE Improved Diagnostic Accuracy With Multiparametric Magnetic Resonance Imaging of the Breast Using Dynamic Contrast-Enhanced Magnetic Resonance Imaging, Diffusion-Weighted Imaging, and 3-Dimensional Proton Magnetic Resonance Spectroscopic Imaging Katja Pinker, MD,* Wolfgang Bogner, PhD,Þ Pascal Baltzer, MD,* Stephan Gruber, PhD,Þ Hubert Bickel, MD,* Benedikt Brueck, MD,* Siegfried Trattnig, MD,Þ Michael Weber, PhD,* Peter Dubsky, MD,þ Zsuzsanna Bago-Horvath, MD, Rupert Bartsch, MD, and Thomas H. Helbich, MD* Introduction: The purpose of this study was to compare the diagnostic accuracy of dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) as a single parameter to multiparametric (MP) MRI with 2 (DCE MRI and diffusionweighted imaging [DWI]) and 3 (DCE MRI, DWI, and 3-dimensional proton magnetic resonance spectroscopic imaging [3D 1 H-MRSI]) parameters in breast cancer diagnosis. Materials and Methods: This prospective study was approved by the institutional review board. Written informed consent was obtained in all patients. One hundred thirteen female patients (mean age, 52 years; range, 22Y86 years) with an imaging abnormality (Breast Imaging Reporting and Data System 0, 4Y5) were included in this study. Multiparametric MRI of the breast at 3 Twith DCE MRI, DWI, and 3D 1 H-MRSI was performed. The likelihood of malignancy was assessed for DCE MRI and MP MRI with 2 (DCE MRI and DWI) and 3 (DCE MRI, DWI, and 3D 1 H-MRSI) parameters separately. Histopathology was used as the standard of reference. Appropriate statistical tests were used to assess sensitivity, specificity, and diagnostic accuracy for each assessment combination. Results: There were 74 malignant and 39 benign breast lesions. Multiparametric MRI with 3 MRI parameters yielded significantly higher areas under the curve (0.936) in comparison with DCE MRI alone (0.814) (P G 0.001). Multiparametric MRI with just 2 parameters at 3 T did not yield higher areas under the curve (0.808) than did DCE MRI alone (0.814). Multiparametric MRI with 3 parameters resulted in elimination of false-negative lesions and significantly reduced the false-positives ones (P = 0.002). Conclusions: Multiparametric MRI with 3 parameters increases the diagnostic accuracy of breast cancer in comparison with DCE-MRI alone and MP MRI with 2 parameters. Key Words: breast cancer diagnosis, multiparametric MRI, dynamic contrast-enhanced magnetic resonance imaging, diffusion-weighted imaging, 3D proton MR spectroscopic imaging (Invest Radiol 2014;49: 421Y430) Dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) of the breast has been the mainstay of breast MRI with an Received for publication October 9, 2013; and accepted for publication, after revision, November 25, From the Departments of *Biomedical Imaging and Image-guided Therapy, Division of Molecular and Gender Imaging, Biomedical Imaging and Image-guided Therapy, MR Centre of Excellence, Surgery, Pathology, and Internal Medicine, Division of Oncology, Medical University of Vienna, Vienna, Austria. Conflicts of interest and sources of funding: Supported by the Austrian National Bank Jubiläumsfond Project nos and The authors report no conflicts of interest. Reprints: Thomas H. Helbich, MD, Department of Biomedical Imaging and Imageguided Therapy, Division of Molecular and Gender Imaging, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria. thomas.helbich@ meduniwien.ac.at. Copyright * 2014 by Lippincott Williams & Wilkins ISSN: /14/4906Y0421 excellent sensitivity. 1Y5 However, it is limited by a low specificity. 6,7 Dynamic contrast-enhanced MRI of the breast provides morphologic information and limited functional information regarding angiogenesis and tumor vascularity. Available data suggest that the use of other functional MRI parameters such as diffusion-weighted imaging (DWI) with quantitative apparent diffusion coefficient (ADC) mapping and proton magnetic resonance (MR) spectroscopic imaging ( 1 H-MRSI) may provide additional specificity. 8Y15 Diffusion-weighted imaging reflects the diffusivity of water molecules in tissue. Typically, the movement of water is restricted in malignant cells. 16,17 Proton MR spectroscopic imaging reflects tumor metabolism. Choline (Cho), a marker of cell turnover, is increased in breast cancer. 12,18Y20 To date, research groups have investigated multiparametric (MP) MRI of the breast using combinations of DCE-MRI with one additional functional MRI parameter, for example, DWI or 1 H-MRSI. The results obtained with MP MRI of the breast using 2 parameters were promising. 9Y13,21,22 However, to our knowledge, the diagnostic accuracy of a combination of 3 parameters (DCE MRI, DWI, and 3- dimensional [3D] 1 H-MRSI) has not been performed. The number of parameters necessary to significantly improve the accuracy of breast cancer diagnosis is unknown. In this study, we aimed to assess the diagnostic accuracy of 3 parameters (DCE MRI, DWI, and 3D 1 H-MRSI) in comparison with dual-parameter (DCE MRI and DWI) and single-parameter DCE MRI. MATERIALS AND METHODS Patients This prospective; single-institution study was approved by the institutional review board of the Medical University of Vienna. Written informed consent was obtained from all patients before their MRI examination. From September 2008 to December 2012, a total of 133 consecutive female patients were enrolled in this study. They underwent MP MRI of the breast with DCE-MRI, DWI, and 3D 1 H-MRSI. The inclusion criteria were as follows: age of 18 years or older and an abnormality at mammography or breast ultrasound (asymmetric density, architectural distortion, suspicious microcalcifications, or breast mass; Breast Imaging Reporting and Data System (BI-RADS) category 0 or 4Y5). The exclusion criteria were pregnancy, lactation, prior treatment (eg, breast biopsy before MRI, neoadjuvant chemotherapy), and contraindications to MRI or contrast agents. 1 In addition to the previously mentioned criteria, 12 patients were excluded because of the technical failure of 3D 1 H-MRSI (frequency shift 91 ppm resulting in insufficient water and/or fat suppression) and 8 patients were excluded because of insufficient data quality because of motion artifacts, resulting in a total of 113 (mean age, 52 years; range, 22Y86 years) patients to be included in the study. Regardless of the results of MP MRI, histopathological verification of the lesion in question was performed. The initial BI-RADS category Investigative Radiology & Volume 49, Number 6, June

2 Pinker et al Investigative Radiology & Volume 49, Number 6, June 2014 distributions of the lesions before MRI were the following: BI-RADS 0 for 43, BI-RADS 4 for 38, and BI-RADS 5 for 32 lesions. MR Imaging All patients underwent MP MRI of the breast. All MR examinations were performed in the prone position using a 3-T MR scanner (Tim Trio; Siemens, Erlangen, Germany) and a dedicated 4-channel breast coil (InVivo, Orlando, FL). In premenopausal women, MRI was performed in the second week of the menstrual cycle. 1 The MRI sequence protocol was acquired in the following order: a) T2-weighted turbo spin echo sequence with fat suppression (repetition time [TR]/echo time [TE]/inversion time [TI], 4800/61/230 milliseconds; field of view (FOV), 340 mm; 34 slices at 4 mm; matrix, ; 1 average; time of acquisition (TA) 2 minutes 26 seconds); b) Diffusion-weighted, double-refocused, single-shot echo-planar imaging with inversion recovery fat suppression (TR/TE/inversion time, 13700/83/220 milliseconds; FOV, mm; 40 slices at 3.5 mm; matrix [50% oversampling]; 2 averages; b values, 50 and 850 s/mm 2 ; TA, 3 minutes 19 seconds) 8 ; c) Point-resolved spectroscopic sequence with spectral water and fat suppression and spatial outer volume suppression (TR/TE, 750/ 145 milliseconds; FOV, cm 3 ; matrix, ; interpolated voxel size, mm 3 ; 5 averages; TA, 11 minutes 17 seconds) before the application of contrast agent application to avoid an influence of the contrast agent on the Cho signal 12 ; d) A split dynamics protocol combining high-spatial and high-temporal resolution was used. Parameters applied were as follows: T1- weighted volume interpolated breathhold examination sequences (TR/TE, 3.61/1.4 milliseconds; FOV, 320 mm; 72 slices; 1.7-mm isotropic; matrix, ; 1 average; 13.2 seconds per volume) with a total TA of 15 minutes 20 seconds and T1-weighted turbo fast low-angle shot 3D sequences with selective water excitation (TR/TE, 877/3.82 milliseconds; FOV, 320 mm; 96 slices; 1-mm isotropic; matrix, ; 1 average; 2 minutes). 23 All patients were injected with a single dose of the contrast agent. Gadoterate meglumine (Dotarem; Guerbet, Roissy, France) was injected intravenously as a bolus (0.1 mmol/kg of body weight) at 4 ml/s, followed by a 20-mL saline flush using a power injector (Spectris Solaris EP; Medrad, Pittsburgh, PA). Application of the contrast agent was started at 75 seconds after starting the first coronal T1-weighted volume interpolated breathhold examination. The total examination time for the MP MRI protocol was approximately 34 minutes. Data Analysis Multiparametric MRI data were prospectively evaluated by 2 experienced breast radiologists (K.P., 7 years of experience in breast MRI; T.H., 16 years of experience in breast MRI) in consensus as previous studies have shown very good intraobserver and interobserver agreement by using the following evaluation of each MRI parameter. 8,14 The readers were aware that the patients had a breast lesion, but they were not provided with the previous mammographic and sonographic imaging data or histopathological results. MRI Parameters DCE-MRI of the Breast To distinguish between benign and malignant contrastenhancing lesions descriptors according to the American College of Radiology, BI-RADS lexicon was used. 24,25 Lesions were classified as masses or nonymass like enhancing lesions (NMLEs). According to the American College of Radiology MRI BI-RADS lexicon, the following descriptors were assessed for masses: shape (round, oval, lobulated, irregular), margin (smooth, irregular, spiculated), enhancement pattern (homogenous, heterogeneous), and enhancement kinetics (persistent enhancement [type I], initial strong enhancement and plateau phase [type II], initial strong enhancement and wash-out [type III]). 26 For NMLE, the distribution (focal, regional, mutiple regions; segmental, ductal, linear, and diffuse), the pattern of enhancement (homogenous, heterogeneous, clumped, and stippled), and the symmetry were assessed. Lesion enhancement kinetics were used to assess functional information. Regions of interest (ROIs) were manually drawn in the most enhancing part of a lesion, and intensity courses were plotted against time. For NMLE, the enhancements kinetics were not taken into account. The probability of malignancy was determined by assigning a final BI-RADS category. 6,7,24 In addition, the lesion size measuring the largest diameter in 1 plane was assessed. Diffusion-Weighted Imaging When assessing water diffusivity, highyb value (ie, 850 s/mm 2 ) images were visually evaluated for hyperintense regions that corresponded to enhancing lesions on DCE MRI. Three-dimensional ROIs were drawn manually on ADC maps in all lesions. Partial volume effects due to normal parenchyma at the border of the lesion and areas of necrotic tissue identified in the morphological and contrast-enhanced images were avoided. The ROIs were defined as slightly smaller than the actual lesions to avoid partial-volume effects. Bogner et al 8 evaluated the diagnostic quality of DWI regarding apparent ADC accuracy. On the basis of receiver operating characteristic (ROC) curves, the optimal ADC threshold of j3 mm 2 /s for the differentiation between benign and malignant breast lesions was determined. This ADC threshold was applied in the current study. Lesions were classified as benign if ADC values were equal to or greater than j3 mm 2 /s and malignant if less than j3 mm 2 /s. 3D 1 H-MRSI An experienced spectroscopist (S.G., more than 10 years of experience) evaluated the 3D 1 H-MRSI data. For the assessment of metabolic information, all 3D 1 H-MRSI voxels in the lesion volume as detected with DCE MRI were evaluated for elevated levels of Cho. The voxel with the maximum Cho signal-to-noise ratio (SNR) was determined. Gruber et al 12 evaluated the diagnostic accuracy of 3D 1 H-MRSI for the differentiation of benign and malignant breast lesions, on the basis of Cho SNR threshold levels, defining a threshold of 2.6. Choline SNR measurements are a commonly accepted approach in MR spectroscopy of the breast. 20 This Cho SNR threshold level was applied in the current study. A lesion was classified as malignant if SNR was equal to or greater than 2.6 and benign if SNR was lower than 2.6. MP MRI With 2 Parameters Dynamic Contrast-Enhanced MRI and DWI Multiparametric MRI with DCE MRI and DWI was considered positive if one or more MRI parameter was indicative of malignancy. Dynamic Contrast-Enhanced MRI and 3D 1 H-MRSI Multiparametric MRI with DCE MRI and 3D 1 H-MRSI was considered positive if one or more MR imaging parameter was indicative of malignancy. DWI and 3D 1 H-MRSI In the current study, interpretation of DWI and 3D 1 H-MRSI data was always performed after identification of lesions on DCE MR images. Therefore, these 2 parameters were not assessed individually or in combination without the information provided by DCE MRI * 2014 Lippincott Williams & Wilkins

3 Investigative Radiology & Volume 49, Number 6, June 2014 Diagnostic Accuracy of Multiparametric Breast MRI MP MRI With 3 Parameters For the assessment of MP MRI with all 3 parameters (DCE MRI, DWI, and 3D 1 H-MRSI), the following reading scheme was used: If the results of DCE MRI, DWI, and 1 H-MRSI of the breast were positive, MP MRI was considered positive for malignancy (Fig. 1). If the results of DCE MRI, DWI, and 1 H-MRSI of the breast were negative, MP MRI was considered negative for malignancy. If 2 of 3 parameters were positive, MP MRI was considered positive for malignancy (Figs. 2, 3). If 2 of the 3 parameters were negative, MP MRI was considered negative for malignancy. Histopathology The final diagnosis was established through histopathology. All cases were read by 1 pathologist (Z.B-H, 6 years of experience in breast pathology). FIGURE 1. Invasive ductal carcinoma G3 in a 67-year-old woman retroareolar in the left breast. A to D, The indistinct irregular mass lesion (large arrow) demonstrates heterogeneous initial strong enhancement followed by a wash-out and is classified as BI-RADS 5 (suspicious finding) through DCE MRI of the breast. Note the clumped NMLE in the anterior aspect of the lesions representing an extensive intraductal component (small arrow) (E). The mass demonstrates low ADC values ( j3 mm 2 /s). F, In 3D 1 H-MRSI, the lesion presents with a Cho peak at 3.23 ppm (SNR, 7.45). Multiparametric MRI with 3 parameters accurately classifies the tumor as malignant. * 2014 Lippincott Williams & Wilkins 423

4 Pinker et al Investigative Radiology & Volume 49, Number 6, June 2014 FIGURE 2. Melanoma metastasis in a 39-year-old woman in the left breast retroareolar. A to D, The oval smooth mass (arrow) shows a persistent homogenous enhancement and is classified through DCE MRI of the breast as BI-RADS 2 (benign). E, The lesion demonstrates decreased ADC values ( j3 mm 2 /s). F, In 3D 1 H-MRSI, elevated Cho is observed at 3.23 ppm (SNR, 10.2). Multiparametric MRI with 3 parameters accurately classifies the tumor as malignant. All patients underwent image-guided needle biopsy, 27 surgical biopsy, mastectomy, or lumpectomy. In case of a benign histopathological diagnosis at image-guided needle biopsy, the final diagnosis was benign (n = 31). In case of discordant findings between histopathological diagnosis and imaging findings, the final diagnosis was established with open surgery (n = 4). In case of a high-risk lesion, which has an uncertain potential for malignancy, the final diagnosis was established with open surgery (n = 4). 27,28 Statistical Methods Statistical analysis was performed by a statistician (M.W.), using Statistical Package for the Social Sciences 19.0 and CIA All calculations were performed on a per-lesion basis. To calculate the sensitivity and specificity of DCE MRI of the breast, the assigned BI-RADS classifications for MRI data were dichotomized. Magnetic resonance imaging BI-RADS 1, 2, and 3 were considered as benign. Magnetic resonance imaging BI-RADS 4 and 5 were considered as malignant. Sensitivity, specificity, accuracy, negative predictive value (NPV), positive predictive value (PPV), and their 95% confidence intervals for DCE MRI of the breast and MP MRI with 2 and 3 parameters were calculated. Histopathology was used as the criterion standard. Significant differences in sensitivity, specificity, NPV, PPV, and diagnostic accuracy were assessed through logistic regression for multiple measures * 2014 Lippincott Williams & Wilkins

5 Investigative Radiology & Volume 49, Number 6, June 2014 Diagnostic Accuracy of Multiparametric Breast MRI FIGURE 3. Fibroadenoma in a 48-year-old woman in the 2-o clock position of the right breast. A to D, The slightly irregular partly indistinct mass (arrow) with a heterogeneous initial strong enhancement and plateau curve is classified through DCE MRI of the breast as BI-RADS 4 (probably malignant). E, The mass lesion shows high ADC values ( j3 mm 2 /s). F, There is no Cho peak depicted at 3.23 ppm in 3D 1 H-MRSI. The lesion is false positive in DCE MRI but true negative in DWI and 3D 1 H-MRSI. Therefore, MP MRI with 3 parameters accurately classifies the tumor as benign. (generalized estimating equations). Receiver operating characteristic curves were plotted, and the area under the curve (AUC) was determined. Statistical differences between the AUCs were assessed using the method proposed by DeLong et al. 29 A P value of less than or equal to 0.05 was considered a significant result. RESULTS There were 113 lesions with a lesion size ranging from 5 to 98 mm (mean, 29 mm). Histopathologic diagnosis revealed 74 lesions to be malignant and 39 to be benign (Table 1). There were 98 enhancing masses (size range, 5Y98 mm; mean, 28.1 mm) and 15 NMLE (size range, 5Y89 mm; mean, 36.8 mm) at DCE MRI of the breast. Dynamic contrast-enhanced MRI classified 87 lesions as malignant (MRI BI-RADS 4 and 5) and 26 lesions as benign (MRI BI- RADS 2 and 3). The benign mass lesions showed type 1 curve in 15 (46.9%) of 32, type 2 curve in 13 (40.6%) of 32, and type 3 curve in 4 (12.5%) of 32. Curve types in the malignant mass lesions were distributed as follows: type 1 in 14 (21.2%) of 66, type 2 in 22 (33.3%) of 66, and type 3 in 30 (45.5%) of 66. * 2014 Lippincott Williams & Wilkins 425

6 Pinker et al Investigative Radiology & Volume 49, Number 6, June 2014 TABLE 1. Detailed Histopathological Diagnoses of all Malignant (n = 74) and Benign (n = 39) Breast Lesions Malignant n % Histopathological subtype IDC ILC Mucinous carcinoma Papillary carcinoma Phylloid high grade Metastasis DCIS Benign n % High risk (complex sclerosing lesion, FEA, CCC with focal atypia) FA/FAH Papilloma DH, CCC, FCC, focal fibrosis, nodular sclerosing adenosis Miscellaneous (chronic abscess, gynecomastia, fat necrosis, pseudoangiomatosis) CCC indicates columnar cell changes; DCIS, ductal carcinoma in situ; DH, ductal hyperplasia; FA, fibroadenoma; FAH, fibroadenomatous hyperplasia; FCC, fibrocystic changes; FEA, flat epithelial atypia; IDC, invasive ductal carcinoma; ILC, invasive lobular carcinoma. The ADC values of the benign lesions ranged from 0.98 to j3 mm 2 /s (mean, j3 mm 2 /s); those of the malignant lesions, from 0.4 to 1.62 (mean, j3 mm 2 /s). Choline SNR values of the benign lesions ranged from 0 to 5.6 (mean, 0.89); those of the malignant lesions, from 0 to 56.1(mean, 9.98). Sensitivities, specificities, PPV, NPV, diagnostic accuracies, and the AUCs for DCE MRI and MP MRI with 2 or 3 MRI parameters are summarized in Table 2. Diagnostic Accuracy: ROC Analysis Diagnostic accuracy was significantly higher with MP MRI using 3 parameters, that is, DCE MRI, DWI, and 3D 1 H-MRSI, with an AUC of compared with DCE MRI alone with an AUC of (P G 0.001) (Fig. 4). Multiparametric MRI with 2 parameters, that is, DCE MRI and DWI or 3D 1 H-MRSI, did not improve diagnostic accuracy (AUC, 0.808) compared with DCE MRI alone (P = 0.323). Diagnostic accuracy of MP MRI with 3 parameters was significantly higher compared with MP MRI with 2 parameters (P G 0.001). Sensitivity, Specificity, NPV, and PPV Multiparametric MRI with 3 parameters, that is, DCE MRI, DWI, and 3D 1 H-MRSI, yielded the highest sensitivity (), which was maximized compared with DCE MRI with 98.6%. Multiparametric MRI with 3 parameters significantly increased specificity to 87.2% compared with DCE-MRI with 64.1% (P G 0.001). Multiparametric MRI with 2 parameters also maximized sensitivity to but showed a decrease in specificity of 61.5%. Positive predictive values of DCE MRI alone and MP MRI with 2 or 3 parameters for breast cancer diagnosis are summarized in Figure 5. The PPV was significantly higher with MP MRI with 3 parameters at 93.7% compared with DCE MRI alone at 83.9% (P G 0.001). Multiparametric MRI with 2 parameters demonstrated lower PPVs of 83.1% compared with DCE MRI alone. The NPV of MP MRI with either 2 or 3 parameters was increased to compared with DCE MRI at 96.2%. Multiparametric MRI with all 3 parameters allowed the elimination of the false-negative finding and a significant reduction in false-positive findings from 14 with DCE MRI and 15 with MP MRI with 2 parameters to 5 with 3 parameters (P = 0.002). Detailed histopathological results for all false-positive and false-negative lesions for DCE MRI and MP MRI are listed in Table 3. DISCUSSION The results of our study show that the highest diagnostic accuracy for breast cancer diagnosis is achieved with MP MRI using 3 parameters, that is, DCE MRI, DWI, and 3D 1 H-MRSI,withanAUCof0.936 compared with DCE MRI with an AUC of (P G 0.001). Multiparametric MRI with 2 parameters does improve diagnostic accuracy in comparison with DCE-MRI alone. As demonstrated in our study, each MRI parameter has an incremental value, 8,12,23,30 but only MP MRI with 3 parameters allows an increase in both sensitivity and particularly specificity, resulting in a significantly improved diagnostic accuracy. With MP MRI using parameters, there were no false negatives and there was a significant reduction in false-positive lesions compared with DCE MRI and MP MRI with 2 parameters. In addition, MP MRI with 3 parameters has the potential to eliminate almost two thirds of unnecessary breast biopsies recommended by DCE MRI alone. The results are in agreement with TABLE 2. Sensitivities, Specificities, PPV, NPV, Diagnostic Accuracy, AUC, and 95% Confidence Intervals (in Brackets) for DCE-MRI and MP MRI Sensitivity Specificity PPV NPV Accuracy AUC DCE-MRI (1 parameter) 98.6% (92.7%Y99.8%) 64.1% (48.4%Y77.3%) 83.9% (74.8%Y90.2%) 96.2% (81.1%Y99.3%) 86.7% (79.2%Y91.8%) (0.72Y0.91) MP MRI with DCE MRI and DWI (2 parameters) (93.6%Y) 61.5% (44.7%Y76.2%) 83.1% (74%Y89.5%) (86.2%Y) 86.7% (79.2%Y91.8%) (0.71Y0.91) MP MRI with DCE-MRI and 3D 1 H-MRSI (2 parameters) (93.6%Y) 61.5% (45.9%Y75.1%) 83.1% (74%Y89.5%) (86.2%Y) 86.7% (79.2%Y91.8%) (0.71Y0.91) MP MRI with DCE-MRI, DWI, and 3D 1 H-MRSI (3 parameters) (95.1%Y) 87.2%* (73.3%Y94.4%) 93.7%* (86.0%Y97.3%) (89.8%Y) 95.6%* (90.1%Y98.1%) 0.936* (0.87Y0.99) *Significantly different from DCE-MRI (P G 0.001). Significantly different from MP MRI with 2 MR imaging parameters (P G 0.001). 3D 1 H-MRSI indicates 3-dimensional proton spectroscopic imaging; AUC, area under the curve; DCE MRI, dynamic contrast-enhanced magnetic resonance imaging; DWI, diffusion-weighted imaging; MP, multiparametric; MRI, magnetic resonance imaging; NPV, negative predictive value; PPV, positive predictive value * 2014 Lippincott Williams & Wilkins

7 Investigative Radiology & Volume 49, Number 6, June 2014 Diagnostic Accuracy of Multiparametric Breast MRI FIGURE 4. The ROC curves illustrate the higher diagnostic value (that is, higher sensitivity, specificity, and larger AUC) that is reached for MP MRI with 3 parameters compared with DCE MRI of the breast and MP MRI with 2 parameters. studies that have proven the additional value of MP MRI with more than 2 parameters in other neoplastic diseases such as brain and prostate cancer. 31Y37 It is evident that MP MRI leads to an increased scan time; however, the increase in diagnostic accuracy resulting in a reduction of unnecessary breast biopsies is beneficial for the patient and might even be cost-effective, although no formal cost-effectiveness analysis was performed. Even with the use of MP MRI, there were some false-positive lesions. These comprised of 3 high-risk lesions at biopsy, which remained lesions with atypia at surgery. 38,39 Studies have demonstrated that high-risk lesions such as atypical ductal hyperplasia are genetically advanced nonyobligatory precursors of invasive breast cancer. 40 The fact that these lesions remained false positive with MP MRI with all 3 parameters possibly reflects malignant potential. Another false positive was a very metabolically active juvenile fibroadenoma with a high cellularity. 41,42 The other remaining false-positive lesion was a clinically asymptomatic chronic abscess, which demonstrated suspicious morphologic and kinetic features and decreased ADC levels, 43,44 but was negative on 3D 1 H-MRSI. In the past, several studies have evaluated the role of MP MRI with 2 parameters, that is, DCE MRI and either DWI or 1 H-MRSI, in breast cancer diagnosis. Kul et al 11 investigated the combination of DCE MRI and DWI in the assessment of breast tumors. The authors reported an increase in specificity of 86.5% but a decrease in sensitivity of 95.2%. Yabuuchi et al 21,45 and Ei Khouli et al, 9 who used a logistic regression model, reported similar results for MP MRI with DCE MRI and DWI. In all these studies, the improvement of specificity led to a trade-off in sensitivity. In contrast, the combination approach in this study led to an increase in sensitivity to but no increase in specificity. Several groups have evaluated the diagnostic accuracy of 1 H- MRSI with encouraging results. A recent meta-analysis reported pooled estimates of sensitivity and specificity of 73 and 88% and demonstrated that 1 H-MRSI has a high specificity for diagnosis of breast cancer. 20 Potentially, this specificity may further increase diagnostic accuracy in breast imaging. However, a practical algorithm for the combination of DCE MRI and 1 H-MRSI has not yet been proposed. According to Gruber et al, 12 3D 1 H-MRSI has a higher sensitivity of 97%. We applied the same 3D 1 H-MRSI technique, and our results are concordant with these findings. It has to be kept in mind that MR spectroscopy even if performed as a 3D technique is limited to a certain region of one breast. As a consequence, it can only be considered as an additional tool for the characterization of lesions in a prior known location. This limits its application for the characterization of incidental small and nonymasslike enhancements. In the current study, interpretation of DWI and 3D 1 H-MRSI data was always performed after identification of lesions on DCE MR images. There have been approaches described for lesion identification in DWI on high b-value images, 22,46 but no data exist for the application of 3D 1 H-MRSI in breast imaging without lesion identification on DCE MR images. Because lesion identification on DCE MR images is the most commonly used approach, we chose to use this in the current study; therefore, DWI and 3D 1 H-MRSI were not assessed individually or in combination. The data suggest that MP MRI with 2 parameters is not as beneficial as MP MRI with 3 parameters with respect to diagnostic accuracy. However, there are other approaches for the combination of quantitative multiparametric data than the empirical approach chosen in this study. Methods such as classification trees, logistic regression, or artificial neural networks have been described. These methods are able to combine raw quantitative data and assign a probability of malignancy. Although desirable, these approaches are limited FIGURE 5. Positive predictive values of DCE MRI and MP MRI with either 3 or 2 parameters. * 2014 Lippincott Williams & Wilkins 427

8 Pinker et al Investigative Radiology & Volume 49, Number 6, June 2014 TABLE 3. Detailed Histopathological Results of False-Negative and False-Positive Lesions 1 False Postives Mass/NMLE Size (mm) n False Negatives Mass/NMLE Size (mm) n DCE-MRI (1 parameter) FA Mass metastasis FA Mass 28 FA NMLE 39 FAH Mass 10 DH, CCC Mass 8 DH, CCC NMLE 10 DH, CCC NMLE 20 Miscellaneous Mass 20 Miscellaneous Mass 90 Miscellaneous NMLE 19 High risk Mass 7 High risk Mass 8 High risk Mass 10 High risk NMLE 58 MP MRI with DCE-MRI and DWI (2 parameters) MP MRI with DCE-MRI and 3D 1 H-MRSI (2 parameters) MP MRI with DCE-MRI, DWI, and 3D 1 H-MRSI (3 parameters) FA Mass FA Mass 28 FA NMLE 39 FAH Mass 10 DH, CCC Mass 8 DH, CCC Mass 8 DH, CCC NMLE 10 DH, CCC NMLE 20 Miscellaneous Mass 20 Miscellaneous Mass 90 Miscellaneous NMLE 19 High risk Mass 7 High risk Mass 8 High risk Mass 10 High risk NMLE 58 FA Mass FA Mass 28 FA Mass 36 FA NMLE 39 FAH Mass 10 DH, CCC Mass 8 DH, CCC NMLE 10 DH, CCC NMLE 20 Miscellaneous Mass 20 Miscellaneous Mass 90 Miscellaneous NMLE 19 High risk Mass 7 High risk Mass 8 High risk Mass 10 High risk NMLE 58 FA NMLE Miscellaneous Mass 90 High risk Mass 7 High risk Mass 8 High risk NMLE 50 3D 1 H-MRSI indicates 3-dimensional proton MR spectroscopic imaging, CCC, columnar cell changes; DCE-MRI, dynamic contrast-enhanced magnetic resonance imaging; DH, ductal hyperplasia; DWI, diffusion-weighted imaging; FA, fibroadenoma; FAH, fibroadenomatous hyperplasia; FCC, fibrocystic changes; IDC, invasive ductal carcinoma; NMLE, nonymasslike enhancing lesions * 2014 Lippincott Williams & Wilkins

9 Investigative Radiology & Volume 49, Number 6, June 2014 Diagnostic Accuracy of Multiparametric Breast MRI because no internationally accepted reference values for quantitative MP MRI results do exist. Providing such values in a multiparametric approach would require case numbers beyond the scope of this study. To date, because of these limitations, only little data on multivariate data combinations and no data using MP MRI has been published in breast MRI. 47,48 The approach used in the current study was defined before commencement of the study, was readily applicable in clinical practice, and achieved high diagnostic accuracies. There was a relatively small number of pure ductal carcinoma in situ and invasive lobular cancers as compared with the number of invasive ductal cancers. Consequently, there was also a relatively small number of NMLEs, which often represent ductal carcinoma in situ and invasive lobular carcinoma. This limits the specific insights into the performance of MP MRI in these subgroups. However, in a prospective study with consecutive patients, the collective distribution of malignant lesion subtypes is as expected and underlines the representativeness of our patient sample. In addition, the readers in this study were experienced breast radiologists with extensive training in the interpretation of breast MR images; therefore, the results might not be applicable to every radiologist. However, it can be expected that dedicated training and the addition of computer-aided detection systems that implement all MR imaging parameters will be helpful for radiologists in everyday practice. All MR examinations were performed at 3 T instead of 1.5 T, which is the most commonly used field strength in breast MRI. 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