Innovations in Ultrasound & Breast Cancer Imaging Azra Alizad, MD Department of Radiology Mayo Clinic College of Medicine 2018 AAPM Annual meeting 2012 MFMER slide-1 Disclosure Mayo Clinic and some investigators have potential financial interests related to the technologies referenced in this presentation. 2012 MFMER slide-2 Research Areas: Ultrasound Vibro-acoustography (VA) Elastography techniques High Resolution Microvasculature imaging and quantification Deep Learning (Automatic segmentation and classification of breast masses) 2012 MFMER slide-3 1
Breast Imaging X-ray mammography: Low sensitivity Limitations: Pregnant women Lactating women Young women with dense breasts High-risk women Conventional Breast Ultrasound- Low specificity MRI - High sensitivity Limitations: Low specificity High cost Less available Need: Low cost, non-invasive, high specificity imaging tool for breast cancer detection 2012 MFMER slide-4 Advantages of Ultrasound Imaging Advantages: Non-ionizing Real-time Large imaging depth Cost-effective Portable and widely available Ultrasound is the most widely used imaging modality in clinical practice 2012 MFMER slide-5 Ultrasound Technology Trends Seeking new information Acoustic imaging Ultrasound elastography techniques Contrast-enhanced imaging Ultrafast Doppler microvasculature imaging 2012 MFMER slide-6 2
Vibro-acoustography (VA) in Breast Cancer Detection 2012 MFMER slide-7 7 Imaging and estimation of tissue stiffness VA and ultrasound elastography techniques: palpation like information 2012 MFMER slide-8 VA: New Breast Imaging Methodology Tissue stiffness is closely related to pathology of tissue. Goal: To develop a new high-resolution imaging method that is sensitive to tissue stiffness. Approach: Use Vibro-acoustography (VA) for breast imaging A. Alizad AIUM, M a r c h 2012 MFMER slide-9 / 2 3
Principles of Vibro-acoustography Concept: Vibro-acoustography uses Radiation force of US to produce images at low frequencies Main steps in vibro-acoustography: 1. Vibrate object by radiation force of ultrasound 2. Record the sound from object response 3. Image object by scanning 2012 MFMER slide-10 Transducer Hydrophone RECEIVER Beam 1 @ f 1 Beam 2 @ f 2 Intersection region Object Oscillatory radiation force, @ f Image Vibro-acoustography Sound of tissue 2012 MFMER slide-12 4
In Vivo Breast Applications of VA Objective: Evaluate the Performance of VA in differentiation of breast masses Description of Study Cohort: 60 patients with suspicious breast lesions Age>18 years System Used: Integrated mammography ultrasound system ( Vivid 7 GE) 2012 MFMER slide-13 2012 MFMER slide-14 Combined Vibro-acoustography- Mammography System Scanning mechanism Ultrasound transducer External water tank ( transducer housing) VA Scanner MF 10/09 2012 MFMER slide-15 5
Main Features of VA VA image features Provides new information not available from sonography Sensitive to stiffness. Speckle-free Sensitive to calcification High contrast images Implications More Diagnostic Information 2012 MFMER slide-16 X-ray Vibro-acoustography 2012 MFMER slide-17 Examples of Breast VA Breast Fibroadenoma 71 years old woman Right breast Mammography:2 cm, sharply marginated mass with coarse lobulation Left breast Mammography: calcified mass Alizad et. al., Breast Cancer Research, 2012. 2012 MFMER slide-18 6
Examples of Breast VA Infiltrating lobular carcinoma, GII 67 years old woman Mammography : Spiculated mass US: Hypoechoic mass with irregular border Alizad et. al., Breast Cancer Research, 2012. 2012 MFMER slide-19 Examples of Breast VA Invasive ductal carcinoma G. II 64 years old woman Mammography : Minimal architectural distortion, increased soft-tissue density US: 5 7 mm hypoechoic lesion with posterior shadowing VA: mass with higher contrast fine spiculations Alizad et. al., Breast Cancer Research, 2012. 2012 MFMER slide-20 Breast Fibroadenoma Examples of Breast VA 42 year old woman with palpable abnormality Mammography: dense but unremarkable VA: Round mass with defined border and some lobulations Diagnostic accuracy : Sensitivity (95% CI), % 80 Specificity (95% CI), % 94 Alizad et. al., Breast Cancer Research, 2012. 2012 MFMER slide-21 7
Breast VA: Concluding Remarks Diagnostic accuracy Sensitivity (95% CI), % 80 Specificity (95% CI), % 94 VA can be used breast cancer diagnostic tool as a complementary to conventional US VA is sensitive to tissue stiffness, detect MCs, a sensitive tool for early diagnosis and in patients with dense breast where mammography fails Future work is to improve handheld VA for a clinical utility 2012 MFMER slide-22 High Resolution Microvasculature Imaging and Quantification 2012 MFMER slide-23 Angiogenesis Understanding the Microvasculature differences in Malignant and Benign Masses 2012 MFMER slide-24 8
Angiogenesis: Growth of New Blood Vessels Normal First vessels in the developing embryo Vital process in growth/ development Wound healing Abnormal Tumor vessels lack protective mechanisms Lack functional perivascular cells Sometimes lack endothelial cells in vessel wall Transition of tumors from a benign to a malignant state. 2012 MFMER slide-25 Toward and within tumor Tumor Angiogenesis Starts in tumor as small as 2-4 mm VEGF 2012 MFMER slide-26 Role of Microvasculature in Breast Cancer Breast tumor growth and metastasis are dependent to tumor angiogenesis Extent of angiogenesis can be used as prognostic factor Statistically significant correlation of microvessel density with tumor grade 2012 MFMER slide-27 9
Role of Microvasculature Morphology in Malignant/Benign masses MVD alone not always a good marker for benign and malignant Need: To quantify other morphological parameters Vessel tortuosity obenign: Straight and regular vessels omalignant: tortuous and irregular vessels Vessel diameter Number of vessel segments Imaging and quantification microvascular architecture could be used for breast tumor differentiation 2012 MFMER slide-28 Method: Non-invasive Imaging of Microvessels Conventional US Doppler can only display large vessels Value of US Doppler in differentiation of breast masses is limited Need: Develop new non-invasive tools to provide quantitative information about microvessels of the breast lesion 2012 MFMER slide-29 Breast Microvasculature Imaging and Quantification Hypothesis: Microvasculature of breast masses changes with pathology Goal: Differentiation of breast masses based on microvasculature morphology analysis Method: Ultrafast ultrasound imaging of micro-vessels Quantification of microvasculature architecture Use the quantified of morphological parameters of microvasculature for differentiation 2012 MFMER slide-30 10
Case 3 Case 2 Case 1 axial (mm) axial (mm) axial (mm) Representative malignant cases Contrast enhanced MRI B-mode US Color Flow Microvasculature Imaging 0 0.5 5 10 15 20 25 0.4 0.3 0.2 30 35 0 40 0 10 20 30 5 lateral (mm) 10 0.1 0 0.5 0.4 0.3 15 0.2 20 0.1 25 0 5 10 15 20 25 30 35 lateral (mm) 5 10 0.5 0.4 0 15 20 0.3 0.2 25 0.1 30 0 0 5 10 15 20 25 30 35 lateral (mm) 2012 MFMER slide-31 Method Patents pending Singular Value Decomposition 2012 MFMER slide-32 Method Patent Pending Number of vessel segments 2012 MFMER slide-33 11
Vessel Tortuosity Metrics Sum of Angles Metric = SOAM SOAM = Sum (all angles) / Vessel length 2012 MFMER slide-34 Vessel Tortuosity Metrics Distance metric (DM) Length A Distance B DM = Vessel Length/Distance 2012 MFMER slide-35 Fibroadenoma. Focal atypical ductal hyperplasia. Fibrocystic changes Morphological Parameters # of vessel segments 30 # of branch points 15 Mean(Diameter) 435 Invasive/Infiltrating Ductal Carcinoma (IDC) Grade III Morphological Parameters # of vessel segments 91 # of branch points 47 Mean(Diameter) 637 2012 MFMER slide-36 12
Fibroadenoma Morphological Parameters # of vessel segments 20 # of branch points 11 Mean(Diameter) 394 Invasive/Infiltrating Ductal Carcinoma (IDC) G-III D F Morphological Parameters # of vessel segments 5mm 154 # of branch points 102 Mean(Diameter) 474 2012 MFMER slide-37 Fibroadenomatoid nodule Morphological Parameters # of vessel segments 10 # of branch points 6 Mean(Diameter) 463 Metastatic renal cell carcinoma Morphological Parameters # of vessel segments 52 # of branch points 40 Mean(Diameter) 393 2012 MFMER slide-38 Fibroadenoma Morphological Parameters # of vessel segments 16 # of branch points 7 Mean(Diameter) 416 Pathology: Invasive ductal carcinoma, grade II. Lesion Dilation / Parameter # of vessel segments 58 # of branch points 38 Mean(Diameter) 451 2012 MFMER slide-39 13
Identifying metastatic AXL Reactive lymph node negative for malignancy Invasive poorly differentiated carcinoma consistent with metastatic breast primary A B 2012 MFMER slide-40 A Assessment of neoadjuvant therapy Before therapy B # of segments =38 2 mon s after therapy C # of segments =10 A Before therapy B # of segments =96 2 mon s after therapy C # of segments =25 2012 MFMER slide-41 Results of microvessel Diameter P=0.001 2012 MFMER slide-42 14
Number of Vessel segments P=0.006 Benign: 57 Malignant: 40 2012 MFMER slide-43 Differentiation of Breast Lesion Using Microvasculature Biomarker Biomarker: Vessel Tortuosity - Distance Metric p-value = 0.00015 Conclusion: Breast masses may be differentiated using microvasculature quantification 2012 MFMER slide-44 Future Direction: 3D Microvasculature Imaging Articulated arm Motor Scanning direction Ultrasound Probe Flow phantom: 4 Vessels 2D View 3D vessel views 2012 MFMER slide-45 15
Summary Introducing a high resolution ultrasound imaging of microvasculature Novelty: Significant clutter reduction: Visualized microvasculature structure with high resolution 300-200m No contrast enhanced agents Quantified morphology of microvasculature architecture First validation on pre-biopsy breast patients Will use 3D microvasculature imaging for better quantification Prediction of ALN metastasis in breast cancer patients Assessment of neoadjuvant therapy Can extended to other organs involving soft tissues 2012 MFMER slide-46 Acknowledgements The research projects supported by several grants from National Institute of Health and a Fund by The Komen for the Cure. Funding Sources: R01CA195527 R01CA148994 R01CA168575 R21CA121579 R01CA127235 BCTR0504550 (Komen for the Cure) 2012 MFMER slide-47 Acknowledgements Collaborators: Mostafa Fatemi, PhD Robert Fazzio, MD, PhD Dana Whaley, MD Lab Members: M. Bayat, PhD V. Kumar, PhD B. Kim, PhD R. Nayak, PhD A. Gregory, PhD student J. Webb, MS S. Adabi, PhD S. Ghavami, PhD P. Lee, PhD student S. Bae, PhD student N. Bulegato. Grad student M. Lattanzi, Grad student 2012 MFMER slide-48 16
Thank you! 2012 MFMER slide-49 2012 MFMER slide-50 2012 MFMER slide-51 17
2012 MFMER slide-52 Acoustic Radiation Force Elastography Techniques Vibro-acoustography (Sound of tissue) Acoustic Radiation Force Impulse (ARFI) Imaging Shear Wave Elastography: Supersonic Imaging Virtual Touch IQ SWE CUSE Shear Wave Dispersion Ultrasound Elastography 2012 MFMER slide-53 Shear wave Elastography 2012 MFMER slide-54 18
Shear wave Elastography Elastography is a technique to measure the stiffness of tissues. Tumor stiffening Collagen crosslinking ECM stiffening Increased focal adhesion Levental et. al. Cell. 2009 November 25; 139(5): 891 906 2012 MFMER slide-55 Elastography Elasticity imaging modalities Magnetic Resonance Elastography (MRE) Static Elastography Acoustic radiation Force Impulse (ARFI) Supersonic Imagine (SSI) VTIQ Comb-Push Ultrasound Shear Elastography (CUSE) Each technique has certain limitations. 2012 MFMER slide-56 Shear Wave Elasticity Imaging (SWEI) US push beam Shear wave Shear wave ARF Elasticity ~ (Shear wave speed)^2 2012 MFMER slide-57 19
z (mm) z (mm) z (mm) z (mm) Principles of CUSE 1,2 10 20 30 40 50 10 20 30 x (mm) 5 5 5 10 10 4 10 4 4 20 20 3 20 3 3 30 30 2 30 2 2 40 40 1 40 1 1 50 50 10 20 30 x (mm) 10 m/s 0 20 30 x (mm) 50 m/s 0 10 20 30 x (mm) m/s 0 1 Song, et. al., IEEE Trans. On Medical Imaging, 2012 2 Song, P., et al., IEEE Trans Med Imaging. 2013 Aug;32(8):1435-47. 2012 MFMER slide-58 Objectives Breast Shear wave Elastography (CUSE) To investigate the feasibility and performance of a new ultrasound-based shear elastography, comb-push ultrasound shear elastography, to measure elasticity in breast masses. Fund: Grant R01 CA148994(NIH) 2012 MFMER slide-59 Materials and Methods Description of Study Cohort: 227 patients with suspicious breast lesions Scheduled for biopsy Age range from 18 years and older Exclusion criteria: Women with breast implants Women who had mastectomies Ultrasound scanner Verasonics investigational ultrasound platform GE Logiq E 9 2012 MFMER slide-60 20
Results: Review of Selected Cases Invasive lobular carcinoma, G. II 66 years old, BIRAD 4, 10 x 7 x 8 mm hypoechoic mass with a hyperechoic rim and angular margins SWE: high elasticity value E mean =145kPa 2012 MFMER slide-61 Results: Review of Selected Cases Mucinous carcinoma, G. I 79 years old with palpable abnormality in left breast US:12 x 9 mm oval circumscribed mass as shown SWE: high elasticity value with E mean =132.7kPa. 2012 MFMER slide-62 Results: Review of Selected Cases Invasive mammary carcinoma with mixed ductal and lobular features 72 years old, BI-RADS 4 US:13 mm irregular region with posterior shadowing SWE: Elasticity value E mean =97.7kPa 2012 MFMER slide-63 21
Results: Review of Selected Cases Benign Fibroadenoma 45 years old, palpable abnormality US; hypoechoic mass SWE: Elasticity Value Emean=26.7kPa 2012 MFMER slide-64 SWE LE9 Breast Results Box plot: Pathology Number Mean (kpa) Std. Dev. (kpa) Benign (B) 119 30.18 27.81 Malignant (M) 108 90.66 35.55 p-value <0.0001* 2012 MFMER slide-65 SWE LE9 Breast Results ROC Analysis 227 patients Cutoff: 62kPa AUC: 91% Sensitivity: 84% Specificity: 90% PPV: 88% NPV: 86% 2012 MFMER slide-66 22
Conclusion Specificity: 90% and sensitivity: 84% Small malignant case tend to be softer (FN) (apparently or naturally) False positives: Benign breast features with High Elasticity value diabetic mastopathy, post operative scar, sclerosis and presence of calcification Potential clinical utility CUSE as Quantitative and diagnostic tool complementary to B-mode ultrasound for differentiating malignant and benign breast lesions Azra Alizad, MD 2012 MFMER slide-67 23