Suzan Vreemann

Surveillance of Women with the BRCA1 or BRCA2 Mutation by Using Biannual Automated Breast US, MR Imaging, and Mammography

Purpose To evaluate a multimodal surveillance regimen including yearly full-field digital (FFD) mammography, dynamic contrast agent-enhanced (DCE) magnetic resonance (MR) imaging, and biannual automated breast (AB) ultrasonography (US) in women with BRCA1 and BRCA2 mutations. Materials and Methods This prospective multicenter trial enrolled 296 carriers of the BRCA mutation (153 BRCA1 and 128 BRCA2 carriers, and 15 women with first-degree untested relatives) between September 2010 and November 2012, with follow-up until November 2015. Participants underwent 2 years of intensified surveillance including biannual AB US, and routine yearly DCE MR imaging and FFD mammography. The surveillance performance for each modality and possible combinations were determined. Results Breast cancer was screening-detected in 16 women (age range, 33-58 years). Three interval cancers were detected by self-examination, all in carriers of the BRCA1 mutation under age 43 years. One cancer was detected in a carrier of the BRCA1 mutation with a palpable abnormality in the contralateral breast. One incidental breast cancer was detected in a prophylactic mastectomy specimen. Respectively, sensitivity of DCE MR imaging, FFD mammography, and AB US was 68.1% (14 of 21; 95% confidence interval [CI]: 42.9%, 85.8%), 37.2% (eight of 21; 95% CI: 19.8%, 58.7%), and 32.1% (seven of 21; 95% CI: 16.1%, 53.8%); specificity was 95.0% (643 of 682; 95% CI: 92.7%, 96.5%), 98.1% (638 of 652; 95% CI: 96.7%, 98.9%), and 95.1% (1030 of 1088; 95% CI: 93.5%, 96.3%); cancer detection rate was 2.0% (14 of 702), 1.2% (eight of 671), and 1.0% (seven of 711) per 100 women-years; and positive predictive value was 25.2% (14 of 54), 33.7% (nine of 23), and 9.5% (seven of 68). DCE MR imaging and FFD mammography combined yielded the highest sensitivity of 76.3% (16 of 21; 95% CI: 53.8%, 89.9%) and specificity of 93.6% (643 of 691; 95% CI: 91.3%, 95.3%). AB US did not depict additional cancers. FFD mammography yielded no additional cancers in women younger than 43 years, the mean age at diagnosis. In carriers of the BRCA2 mutation, sensitivity of FFD mammography with DCE MR imaging surveillance was 90.9% (10 of 11; 95% CI: 72.7%, 100%) and 60.0% (six of 10; 95% CI: 30.0%, 90.0%) in carriers of the BRCA1 mutation because of the high interval cancer rate in carriers of the BRCA1 mutation. Conclusion AB US may not be of added value to yearly FFD mammography and DCE MR imaging surveillance of carriers of the BRCA mutation. Study results suggest that carriers of the BRCA mutation younger than 40 years may not benefit from FFD mammography surveillance in addition to DCE MR imaging.

Automated detection of breast cancer in false-negative screening MRI studies from women at increased risk

PURPOSE To evaluate the performance of an automated computer-aided detection (CAD) system to detect breast cancers that were overlooked or misinterpreted in a breast MRI screening program for women at increased risk. METHODS We identified 40 patients that were diagnosed with breast cancer in MRI and had a prior MRI examination reported as negative available. In these prior examinations, 24 lesions could retrospectively be identified by two breast radiologists in consensus: 11 were scored as visible and 13 as minimally visible. Additionally, 120 normal scans were collected from 120 women without history of breast cancer or breast surgery participating in the same MRI screening program. A fully automated CAD system was applied to this dataset to detect malignant lesions. RESULTS At 4 false-positives per normal case, the sensitivity for the detection of cancer lesions that were visible or minimally visible in retrospect in prior-negative examinations was 0.71 (95% CI=0.38-1.00) and 0.31 (0.07-0.59), respectively. CONCLUSIONS A substantial proportion of cancers that were misinterpreted or overlooked in an MRI screening program was detected by a CAD system in prior-negative examinations. It has to be clarified with further studies if such a CAD system has an influence on the number of misinterpreted and overlooked cancers in clinical practice when results are given to a radiologist.

New reconstruction algorithm for digital breast tomosynthesis: better image quality for humans and computers:

Background The image quality of digital breast tomosynthesis (DBT) volumes depends greatly on the reconstruction algorithm. Purpose To compare two DBT reconstruction algorithms used by the Siemens Mammomat Inspiration system, filtered back projection (FBP), and FBP with iterative optimizations (EMPIRE), using qualitative analysis by human readers and detection performance of machine learning algorithms. Material and Methods Visual grading analysis was performed by four readers specialized in breast imaging who scored 100 cases reconstructed with both algorithms (70 lesions). Scoring (5-point scale: 1 = poor to 5 = excellent quality) was performed on presence of noise and artifacts, visualization of skin-line and Cooper’s ligaments, contrast, and image quality, and, when present, lesion visibility. In parallel, a three-dimensional deep-learning convolutional neural network (3D-CNN) was trained (n = 259 patients, 51 positives with BI-RADS 3, 4, or 5 calcifications) and tested (n = 46 patients, nine positives), separately with FBP and EMPIRE volumes, to discriminate between samples with and without calcifications. The partial area under the receiver operating characteristic curve (pAUC) of each 3D-CNN was used for comparison. Results EMPIRE reconstructions showed better contrast (3.23 vs. 3.10, P = 0.010), image quality (3.22 vs. 3.03, P < 0.001), visibility of calcifications (3.53 vs. 3.37, P = 0.053, significant for one reader), and fewer artifacts (3.26 vs. 2.97, P < 0.001). The 3D-CNN-EMPIRE had better performance than 3D-CNN-FBP (pAUC-EMPIRE = 0.880 vs. pAUC-FBP = 0.857; P < 0.001). Conclusion The new algorithm provides DBT volumes with better contrast and image quality, fewer artifacts, and improved visibility of calcifications for human observers, as well as improved detection performance with deep-learning algorithms.

The correlation of background parenchymal enhancement in the contralateral breast with patient and tumor characteristics of MRI-screen detected breast cancers

Purpose Higher background parenchymal enhancement (BPE) could be used for stratification of MRI screening programs since it might be related to a higher breast cancer risk. Therefore, the purpose of this study is to correlate BPE to patient and tumor characteristics in women with unilateral MRI-screen detected breast cancer who participated in an intermediate and high risk screening program. As BPE in the affected breast may be difficult to discern from enhancing cancer, we assumed that BPE in the contralateral breast is a representative measure for BPE in women with unilateral breast cancer. Materials and methods This retrospective study was approved by our local institutional board and a waiver for consent was granted. MR-examinations of women with unilateral breast cancers screen-detected on breast MRI were evaluated by two readers. BPE in the contralateral breast was rated according to BI-RADS. Univariate analyses were performed to study associations. Observer variability was computed. Results Analysis included 77 breast cancers in 76 patients (age: 48±9.8 years), including 62 invasive and 15 pure ductal carcinoma in-situ cases. A negative association between BPE and tumor grade (p≤0.016) and a positive association with progesterone status (p≤0.021) was found. The correlation was stronger when only considering invasive disease. Inter-reader agreement was substantial. Conclusion Lower BPE in the contralateral breast in women with unilateral breast cancer might be associated to higher tumor grade and progesterone receptor negativity. Great care should be taken using BPE for stratification of patients to tailored screening programs.

Influence of Risk Category and Screening Round on the Performance of an MR Imaging and Mammography Screening Program in Carriers of the BRCA Mutation and Other Women at Increased Risk

Purpose To evaluate the real-life performance of a breast cancer screening program for women with different categories of increased breast cancer risk with multiple follow-up rounds in an academic hospital with a large screening population. Materials and Methods Screening examinations (magnetic resonance [MR] imaging and mammography) for women at increased breast cancer risk (January 1, 2003, to January 1, 2014) were evaluated. Risk category, age, recall for workup of screening-detected abnormalities, biopsy, and histopathologic diagnosis were recorded. Recall rate, biopsy rate, positive predictive value of recall, positive predictive value of biopsy, cancer detection rate, sensitivity, and specificity were calculated for first and follow-up rounds. Results There were 8818 MR and 6245 mammographic examinations performed in 2463 women. Documented were 170 cancers; of these, there were 129 screening-detected cancers, 16 interval cancers, and 25 cancers discovered at prophylactic mastectomy. Overall sensitivity was 75.9% including the cancers discovered at prophylactic mastectomy (95% confidence interval: 69.5%, 82.4%) and 90.0% excluding those cancers (95% confidence interval: 83.3%, 93.7%). Sensitivity was lowest for carriers of the BRCA1 mutation (66.1% and 81.3% when including and not including cancers in prophylactic mastectomy specimens, respectively). Specificity was higher at follow-up (96.5%; 95% confidence interval: 96.0%, 96.9%) than in first rounds (85.1%; 95% confidence interval: 83.4%, 86.5%) and was high for both MR imaging (97.1%; 95% confidence interval: 96.7%, 97.5%) and mammography (98.7%; 95% confidence interval: 98.3%, 99.0%). Positive predictive value of recall and positive predictive value of biopsy were lowest in women who had only a family history of breast cancer. Conclusion Screening performance was dependent on risk category. Sensitivity was lowest in carriers of the BRCA1 mutation. The specificity of high-risk breast screening improved at follow-up rounds.

3D volume reconstruction from serial breast specimen radiographs for mapping between histology and 3D whole specimen imaging

Purpose: In breast imaging, radiological in vivo images, such as x‐ray mammography and magnetic resonance imaging (MRI), are used for tumor detection, diagnosis, and size determination. After excision, the specimen is typically sliced into slabs and a small subset is sampled. Histopathological imaging of the stained samples is used as the gold standard for characterization of the tumor microenvironment. A 3D volume reconstruction of the whole specimen from the 2D slabs could facilitate bridging the gap between histology and in vivo radiological imaging. This task is challenging, however, due to the large deformation that the breast tissue undergoes after surgery and the significant undersampling of the specimen obtained in histology. In this work, we present a method to reconstruct a coherent 3D volume from 2D digital radiographs of the specimen slabs. Methods: To reconstruct a 3D breast specimen volume, we propose the use of multiple target neighboring slices, when deforming each 2D slab radiograph in the volume, rather than performing pairwise registrations. The algorithm combines neighborhood slice information with free‐form deformations, which enables a flexible, nonlinear deformation to be computed subject to the constraint that a coherent 3D volume is obtained. The neighborhood information provides adequate constraints, without the need for any additional regularization terms. Results: The volume reconstruction algorithm is validated on clinical mastectomy samples using a quantitative assessment of the volume reconstruction smoothness and a comparison with a whole specimen 3D image acquired for validation before slicing. Additionally, a target registration error of 5 mm (comparable to the specimen slab thickness of 4 mm) was obtained for five cases. The error was computed using manual annotations from four observers as gold standard, with interobserver variability of 3.4 mm. Finally, we illustrate how the reconstructed volumes can be used to map histology images to a 3D specimen image of the whole sample (either MRI or CT). Conclusions: Qualitative and quantitative assessment has illustrated the benefit of using our proposed methodology to reconstruct a coherent specimen volume from serial slab radiographs. To our knowledge, this is the first method that has been applied to clinical breast cases, with the goal of reconstructing a whole specimen sample. The algorithm can be used as part of the pipeline of mapping histology images to ex vivo and ultimately in vivo radiological images of the breast.

Improvements of an objective model of compressed breasts undergoing mammography: Generation and characterization of breast shapes

Purpose To develop a set of accurate 2D models of compressed breasts undergoing mammography or breast tomosynthesis, based on objective analysis, to accurately characterize mammograms with few linearly independent parameters, and to generate novel clinically realistic paired cranio‐caudal (CC) and medio‐lateral oblique (MLO) views of the breast. Methods We seek to improve on an existing model of compressed breasts by overcoming detector size bias, removing the nipple and non‐mammary tissue, pairing the CC and MLO views from a single breast, and incorporating the pectoralis major muscle contour into the model. The outer breast shapes in 931 paired CC and MLO mammograms were automatically detected with an in‐house developed segmentation algorithm. From these shapes three generic models (CC‐only, MLO‐only, and joint CC/MLO) with linearly independent components were constructed via principal component analysis (PCA). The ability of the models to represent mammograms not used for PCA was tested via leave‐one‐out cross‐validation, by measuring the average distance error (ADE). Results The individual models based on six components were found to depict breast shapes with accuracy (mean ADE‐CC = 0.81 mm, ADE‐MLO = 1.64 mm, ADE‐Pectoralis = 1.61 mm), outperforming the joint CC/MLO model (P ≤ 0.001). The joint model based on 12 principal components contains 99.5% of the total variance of the data, and can be used to generate new clinically realistic paired CC and MLO breast shapes. This is achieved by generating random sets of 12 principal components, following the Gaussian distributions of the histograms of each component, which were obtained from the component values determined from the images in the mammography database used. Conclusion Our joint CC/MLO model can successfully generate paired CC and MLO view shapes of the same simulated breast, while the individual models can be used to represent with high accuracy clinical acquired mammograms with a small set of parameters. This is the first step toward objective 3D compressed breast models, useful for dosimetry and scatter correction research, among other applications.

Whole Mastectomy Volume Reconstruction from 2D Radiographs and Its Mapping to Histology

Women that are diagnosed with breast cancer often undergo surgery to remove either the tumour and some of the surrounding tissue lumpectomy or the whole breast mastectomy. After surgery, the excised tissue is sliced at the pathology department, where specimen radiographs of the slices are typically acquired. Representative parts of the tissue are then sampled for further processing, staining and examination under the microscope. The results of histopathological imaging are used for tumour characterisation. As the 3D structure of the specimen is inevitably lost during specimen handling, reconstructing a volume from individual specimen slices could facilitate the correlation of histology to radiological imaging. This work proposes a novel method for a whole specimen volume reconstruction and is validated on six mastectomy cases. We also demonstrate how these volumes can be used as a means to map multiple histology slides to a whole mastectomy image MRI or CT.

Fully automated detection of breast cancer in screening MRI using convolutional neural networks

Abstract. Current computer-aided detection (CADe) systems for contrast-enhanced breast MRI rely on both spatial information obtained from the early-phase and temporal information obtained from the late-phase of the contrast enhancement. However, late-phase information might not be available in a screening setting, such as in abbreviated MRI protocols, where acquisition is limited to early-phase scans. We used deep learning to develop a CADe system that exploits the spatial information obtained from the early-phase scans. This system uses three-dimensional (3-D) morphological information in the candidate locations and the symmetry information arising from the enhancement differences of the two breasts. We compared the proposed system to a previously developed system, which uses the full dynamic breast MRI protocol. For training and testing, we used 385 MRI scans, containing 161 malignant lesions. Performance was measured by averaging the sensitivity values between 1/8—eight false positives. In our experiments, the proposed system obtained a significantly (p=0.008) higher average sensitivity (0.6429±0.0537) compared with that of the previous CADe system (0.5325±0.0547). In conclusion, we developed a CADe system that is able to exploit the spatial information obtained from the early-phase scans and can be used in screening programs where abbreviated MRI protocols are used.

How does wide-angle breast tomosynthesis depict calcifications in comparison to digital mammography? A retrospective observer study.

Digital breast tomosynthesis (DBT) provides superior breast cancer detection performance compared to digital mammography (DM), but it is unclear whether DBT alone is sufficient to accurately visualize lesions with calcifications, or supplemental DM is needed. In this work, we performed a retrospective observer study to assess and compare the depiction of calcifications on DM, DBT, and synthetic mammography (SM). Eighty views from 40 lesions with calcifications in 39 patients acquired with a wide-angle DBT system were included (two views per case - cranio-caudal and medio-lateral oblique). Four experienced researchers (3, 10, 11, 21 years) in breast imaging scored the images. For each case, the regions-of-interest containing calcifications in DM, DBT and SM were shown simultaneously. The readers ranked (ties allowed) the three modalities for the depiction of calcifications and assessed if more blurring was present in DM or DBT. DM was ranked as the best modality to depict calcification lesions in 84% of the cases, DBT in 22%, and SM in 7% (P<0.001). Similarly, for 86% of the views, DBT had more blurring of the calcifications than DM. In some cases, DBT showed higher contrast of calcifications providing better visualization, but worse characterization due to signal blurring. For cases with subtle calcifications, the higher noise of DBT images deteriorated their visualization. SM was preferred over DBT for large clusters, while it failed in some cases to display any calcifications. In conclusion, our results show the current limitations of DBT and its derived SM to depict calcifications in comparison to DM.