National Medical Policy

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1 National Medical Policy Subject: Policy Number: Breast Elastography NMP320 Effective Date*: February 2007 Updated: October 2015 This National Medical Policy is subject to the terms in the IMPORTANT NOTICE at the end of this document For Medicaid Plans: Please refer to the appropriate State's Medicaid manual(s), publication(s), citations(s) and documented guidance for coverage criteria and benefit guidelines prior to applying Health Net Medical Policies The Centers for Medicare & Medicaid Services (CMS) For Medicare Advantage members please refer to the following for coverage guidelines first: Use Source Reference/Website Link National Coverage Determination (NCD) National Coverage Manual Citation Local Coverage Determination (LCD)* Article (Local)* Other X None Use Health Net Policy Instructions Medicare NCDs and National Coverage Manuals apply to ALL Medicare members in ALL regions. Medicare LCDs and Articles apply to members in specific regions. To access your specific region, select the link provided under Reference/Website and follow the search instructions. Enter the topic and your specific state to find the coverage determinations for your region. *Note: Health Net must follow local coverage determinations (LCDs) of Medicare Administration Contractors (MACs) located outside their service area when those MACs have exclusive coverage of an item or service. (CMS Manual Chapter 4 Section 90.2) Breast Elastography Oct 15 1

2 If more than one source is checked, you need to access all sources as, on occasion, an LCD or article contains additional coverage information than contained in the NCD or National Coverage Manual. If there is no NCD, National Coverage Manual or region specific LCD/Article, follow the Health Net Hierarchy of Medical Resources for guidance. Current Policy Statement Health Net, Inc. considers breast elastography performed either by ultrasound or magnetic resonance, investigational. Although there are ongoing studies and clinical trials, there continues to be inadequate evidence in the peer-reviewed medical literature to support its efficacy. When used in conjunction with conventional ultrasound, breast elastography appears to be promising in assisting to differentiate potentially benign from malignant lesions, however, large prospective clinical trials addressing appropriate patient selection, diagnostic parameters, and practical application of this technique are necessary prior to widespread clinical use. Definitions US Ultrasonography USE Ultrasound elastography; Ultrasound strain elastography USB B-mode ultrasound SWE Shear-wave elastography FLR Fat-to-lesion strain ratio GLR Gland-to-lesion strain ratio ROC Receiver operating characteristic RTE Real-time elastography Codes Related To This Policy NOTE: The codes listed in this policy are for reference purposes only. Listing of a code in this policy does not imply that the service described by this code is a covered or noncovered health service. Coverage is determined by the benefit documents and medical necessity criteria. This list of codes may not be all inclusive. On October 1, 2015, the ICD-9 code sets used to report medical diagnoses and inpatient procedures will be replaced by ICD-10 code sets. Health Net National Medical Policies will now include the preliminary ICD-10 codes in preparation for this transition. Please note that these may not be the final versions of the codes and that will not be accepted for billing or payment purposes until the October 1, 2015 implementation date. ICD-9 Codes (May not be an all inclusive list) Malignant neoplasm of breast Secondary and unspecified malignant neoplasm of lymph nodes of axilla and upper limb Secondary malignant neoplasm of breast 217 Benign neoplasm of breast Carcinoma in situ of breast Neoplasm of uncertain behavior of breast Disorders of breast Unspecified and other nonspecific abnormal findings on radiological and other examination of breast Mechanical complications due to breast prosthesis Breast Elastography Oct 15 2

3 ICD-10 Codes C C Malignant neoplasm of breast C77.3 Secondary and unspecified malignant neoplasm of axilla and upper limb lymph nodes C79.81 Secondary malignant neoplasm of breast D05.10-D05.92 Carcinoma in situ of breast D24.1-D24.9 Benign neoplasm of breast N60.01-N65.1 Disorders of breast R92.0-R92.8 Abnormal and inconclusive findings on diagnostic imaging of breast T85.49XA Other mechanical complication of breast prosthesis and implant, initial encounter CPT Codes Unlisted ultrasound procedure (eg, diagnostic, interventional) 2014 CPT Code 0346T Ultrasound, elastography HCPCS Codes N/A Scientific Rationale Update October 2015 The National Comprehensive Cancer Network (NCCN) does not address elastography in their guidelines on Breast Cancer (3.2015) or Breast Cancer Screening and Diagnosis (1.2015). In addition, the USPSTF does not address elastography in their recommendations on breast cancer screening (2009). Lee et al (2015) sought to evaluate the accuracy of shear-wave elastography (SWE) in the detection of residual breast cancer after neoadjuvant chemotherapy (NAC). Seventy-one women with stage II-III breast cancers who underwent B-mode ultrasound (US), SWE, and magnetic resonance imaging (MRI) after NAC were included. The presence of residual cancer was determined on B-mode US and MRI, and the maximum elasticity of residual lesions was assessed on SWE. The sensitivity, specificity, accuracy, and area under the receiver operating characteristic curve (AUC) of B-mode US, SWE, and MRI were compared. Sixty-one of 71 women (86 %) had residual cancer and showed higher maximum elasticity values (mean ± 74.1 kpa) than those without residual cancer (26.4 ± 21.0 kpa; p < 0.001). B-mode US showed 72.1 % (44/61) sensitivity, 50.0 % (5/10) specificity, and 69.0 % (49/71) accuracy. The sensitivity, specificity, and accuracy of SWE were 83.6 % (51/61), 80.0 % (8/10), and 83.1 % (59/71) when a maximum elasticity value of >30 kpa was considered to indicate the presence of residual cancer. The combined AUC of B-mode US and SWE (0.877) was significantly higher than that of B-mode US (0.702) (p = 0.014) and comparable to that of MRI (0.939) (p = 0.147). The authors concluded SWE allowed relatively accurate assessment for the presence of residual lesion after NAC and improved the diagnostic performance of B-mode US. Džoić et al (2015) evaluated SWE features of triple negative breast cancers (TNBC) and determine useful discriminators from other types of invasive breast cancers. SWE features of 26 TNBC were reviewed and compared to 32 non-tnbc. Qualitative SWE features of lesion color appearance, shape and homogeneity were analyzed. Breast Elastography Oct 15 3

4 Quantitative features were measured: mean (El mean), maximum (El max) and minimum (El min) elasticity value of the stiffest portion of the mass, mean elasticity of the surrounding tissue (El mean surr) and lesion to fat elasticity ratio (E ratio). TNBC are more often regularly shaped (57.7 % vs. 6.2 %), while non-tnbc are more commonly red (93.7 % vs 42.3 %) and heterogeneous (68.7 % vs 42.3 %). The stiffness of TNBC is significantly lower compared to non-tnbc. The two groups could be distinguished on the basis of El max (p=0.001), El mean (p=0.001), El min (p=0.001) and E ratio (p=0.0017). Lesion to fat elasticity ratio in TNBC group was statistically significantly lower than in the non-tnbc control group (p=0.009). The authors concluded TNBC often demonstrate benign morphological features, are softer on SWE and have a lower lesion to fat stiffness ratio compared to the other, more common types of invasive breast cancers. Berg et al (2015) compared quantitative maximum breast mass stiffness on SWE with histopathologic outcome. From September 2008 through September 2010, at 16 centers in the United States and Europe, 1647 women with a sonographically visible breast mass consented to undergo quantitative SWE in this prospective protocol; 1562 masses in 1562 women had an acceptable reference standard. The quantitative maximum stiffness (termed "Emax") on three acquisitions was recorded for each mass with the range set from 0 (very soft) to 180 kpa (very stiff). The median Emax and interquartile ranges (IQRs) were determined as a function of histopathologic diagnosis and were compared using the Mann-Whitney U test. We considered the impact of mass size on maximum stiffness by performing the same comparisons for masses 9 mm or smaller and those larger than 9 mm in diameter. The median patient age was 50 years (mean, 51.8 years; SD, 14.5 years; range, years), and the median lesion diameter was 12 mm (mean, 14 mm; SD, 7.9 mm; range, 1-53 mm). The median Emax of the 1562 masses (32.1% malignant) was 71 kpa (mean, 90 kpa; SD, 65 kpa; IQR, kpa). Of 502 malignancies, 23 (4.6%) ductal carcinoma in situ (DCIS) masses had a median Emax of 126 kpa (IQR, kpa) and were less stiff than 468 invasive carcinomas (median Emax, 180 kpa [IQR, kpa]; p = 0.002). Benign lesions were much softer than malignancies (median Emax, 43 kpa [IQR, kpa] vs 180 kpa [IQR, kpa]; p < ). Usual benign lesions were soft, including 62 cases of fibrocystic change (median Emax, 32 kpa; IQR, kpa), 51 cases of fibrosis (median Emax, 36 kpa; IQR, kpa), and 301 fibroadenomas (median Emax, 45 kpa; IQR, kpa). Eight lipomas (median Emax, 14 kpa; IQR, 8-15 kpa), 154 cysts (median Emax, 29 kpa; IQR, kpa), and seven lymph nodes (median Emax, 17 kpa; IQR, 9-40 kpa) were softer than usual benign lesions (p < for lipomas and cysts; p = for lymph nodes). Risk lesions were slightly stiffer than usual benign lesions (p = 0.002) but tended to be softer than DCIS (p = 0.14). Fat necrosis and abscesses were relatively stiff. Conclusions were similar for both small and large masses. The authors concluded despite overlap in Emax values, maximum stiffness measured by SWE is a highly effective predictor of the histopathologic severity of sonographically depicted breast masses. Park et al (2015) evaluated the diagnostic performance of SWE in palpable breast mass and to compare with color overlay pattern in SWE with conventional US and quantitative SWE for assessing palpable breast mass. SWE and conventional breast US were performed in 133 women with 156 palpable breast lesions (81 benign, 75 malignant) between August 2013 to June Either pathology or periodic imaging surveillance more than 2 years was a reference standard. Existence of previous image was blinded to performing radiologists. US BI-RADS final assessment, qualitative and quantitative SWE measurements were evaluated. Diagnostic Breast Elastography Oct 15 4

5 performances of grayscale US, SWE and US combined to SWE were calculated and compared. Correlation between pattern classification and quantitative SWE was evaluated. Both color overlay pattern and quantitative SWE improved the specificity of conventional US, from 81.48% to 96.30% (p=0.0005), without improvement in sensitivity. Color overlay pattern was significantly related to all quantitative SWE parameters and malignancy rate (p< ). The optimal cutoff of color overlay pattern was between 2 and 3. Emax with optimal cutoff at 45.1kPa showed the highest Az value, sensitivity, specificity and accuracy among other quantitative SWE parameters (p<0.0001). Echogenic halo on grayscale US showed significant correlation with color overlay pattern and pathology (p<0.0001). The authors concluded in evaluation of palpable breast mass, conventional US combine to SWE improves specificity and reduces the number of biopsies that ultimately yield a benign result. Color overlay pattern classification is more quick and easy and may represent quantitative SWE measurements with similar diagnostic performances. Lee et al (2015) sought to evaluate the additional role of SWE in differential diagnosis of complex cystic and solid breast lesions. From January 2013 to November 2013, 140 complex cystic and solid breast lesions from 139 consecutive patients were performed ultrasound and SWE prior to biopsy. BI-RADS ultrasound final assessment and SWE parameters were recorded for each lesion. Histopathologic diagnosis was used as the reference standard. Among the 140 lesions, 30 lesions (21.4%) were malignant. The mean maximum elasticity (Emax) of malignant lesions (184.3 kpa) was significantly higher than that of benign lesions (45.5 kpa) (P<0.001). Homogeneity of elasticity and color pattern were significantly different from malignancy and benign lesions (P<0.05). Emax with cutoff value at kpa showed Az value of (95% CI, ) with sensitivity of 86.7% and specificity of 97.3%. Using this cutoff value, false-positive rate was 2.7% and falsenegative rate was 13.3%. By applying an Emax value of kpa or less as a criterion for downgrading BI-RADS category 4a lesions to category 3 lesions, 103/123 (83.7%) lesions could be downgraded to category 3 lesions. The authors concluded additional use of SWE could reduce unnecessary benign biopsies in complex cystic and solid breast lesions. Athanasiou et al (2015) evaluates the feasibility and diagnostic performance of three-dimensional (3D) SWE volume measurements in patients with breast lesions compared to breast dynamic contrast-enhanced magnetic resonance imaging (DCE- MRI) lesion volumes and 3D-US B-mode volumes. Secondly, the authors assessed the treatment monitoring performance of 3D-SWE in patients under neoadjuvant chemotherapy for breast cancer by comparing it to 3D-US lesion volume. 33 patients with 33 lesions were included. The feasibility of 3D-SWE was evaluated in 23 patients. In the 10 remaining patients receiving neoadjuvant chemotherapy, 3D-SWE was evaluated before and during treatment. Tumor volume and qualitative and quantitative elasticity analysis measurements were performed and compared to the tumor volume as estimated by 3D-US and DCE-MRI. Statistical analysis was performed using the Pearson correlation coefficient. 3D-SWE was feasible in patients with breast lesions. Tumor volume calculated with 3D-US and 3D-SWE showed very good and moderate concordances with DCE-MRI volume, respectively (Pearson correlation coefficients equal to ρ=r=0.88, p< and ρ=r=0.5, p=0.32, respectively). Modification of tumor elasticity and heterogeneity was correlated with response to treatment. In good responders, elasticity and elasticity heterogeneity diminished. The authors concluded tumor 3D-US volume measurements showed very good concordance with DCE-MRI volume. 3D-SWE can provide valuable information: reduction of tissue stiffness during treatment could be a potential indicator of Breast Elastography Oct 15 5

6 response. These preliminary results should be confirmed on a larger number of patients. Park et al (2014) sought to determine the diagnostic value of strain elastography (SE) alone and in combination with gray-scale ultrasound in the diagnosis of benign versus metastatic disease for abnormal axillary lymph nodes in breast cancer patients. Patients with breast cancer and axillary lymph nodes suspicious for metastatic disease on conventional ultrasound who underwent SE of the suspicious node before ultrasound-guided fine-needle aspiration biopsy (FNAB) were included in this study. On conventional ultrasound, the long- and short-axis diameters, longaxis-to-short-axis ratio, cortical echogenicity, thickness, and evenness were documented. The nodal vascularity was assessed on power Doppler imaging. Elastograms were evaluated for the percentage of black (hard) areas in the lymph node, and the SE-ultrasound size ratio was calculated. Two readers assessed the images independently and then in consensus in cases of disagreement. ROC AUCs were calculated for conventional ultrasound, SE, and both methods combined. Interreader reliability was assessed using kappa statistics. A total of 101 patients with 104 nodes were examined; 35 nodes were benign, and 69 had metastases. SE alone showed a significantly lower AUC (62%) than did conventional ultrasound (92%) (p<0.001). There was no difference between the AUC of conventional ultrasound and the AUC of the combination of conventional ultrasound and SE (93%) (p=0.16). Interreader reliability was moderate for all variables (κ 0.60) except the SE-ultrasound size ratio (κ=0.35). The authors concluded added SE does not improve the diagnostic ability of conventional ultrasound when evaluating abnormal axillary lymph nodes. Rjosk-Dendorfer et al (2014) evaluated the use of color Doppler sonography and free hand sonoelastography in the assessment of breast fibroadenomas according to their size and shape. From December 2012 to March 2013 women with 16 solid breast masses, classified as BI-RADS category 3 or 4 were examined with B-mode ultrasound, sonoelastography and color Doppler sonography. Lesions were subdivided according to their shape in round, ovoid or macrolobulated and according to their size (<2.0 cm or 2.0 cm). Two readers assessed sonoelastographic findings at 12.5 MHz using the tsukuba elasticity score and results of Doppler sonography using a score of 0, 1 or 2, depending on the degree of perfusion. Among the 16 examined lesions 3 showed a round shape, 9 were ovoid and in 4 cases a macrolobulated appearance could be seen. No significant differences concerning Tsukuba-score depending on various shapes of fibroadenomas in B-mode sonography could be shown (p = 0.91) and also comparison of Tsukuba-scores and size of masses revealed no significant differences (p = 1.0). Sizes of fibroadenomas 2 cm were significantly associated with an increased vascularization of the lesions (p = 0.04) and a macrolobulated appearance in B-mode sonography (p = 0.04). The authors concluded the combination of color Doppler sonography and sonoelastography in addition to B-mode sonography leads to an increased accuracy in distinguishing benign from malignant breast masses and to an improvement in characterization of fibroadenomas independent of their shape or size. Scientific Rationale Update October 2014 The National Comprehensive Cancer Network (NCCN) does not address elastography in their guidelines on Breast Cancer or Breast Cancer Screening and Diagnosis (v1.2014) Breast Elastography Oct 15 6

7 Chen et al (2014) examined the performance of shear-wave elastography (SWE) for the differentiation of benign and malignant breast lesions using a meta-analysis. PubMed, Embase and the Cochrane library were searched for studies published up to January The references of retrieved relevant articles were reviewed to identify potential publications. Random-effect meta-analysis was conducted to assess the overall sensitivity and specificity of SWE in the differentiation of breast lesions. A total of 11 articles, including 2424 patients, were included in the meta-analysis. The summarized sensitivity and specificity of the shear wave elastography performance based on maximum elasticity were 0.93 (95 % CI ) and 0.81 (95 % CI ), respectively. For the mean elasticity, the summarized sensitivity and specificity were 0.94 (95 % CI ) and 0.71 (95 % CI ), respectively. The summarized sensitivity and specificity were 0.77 (95 % CI ) and 0.88 (95 % CI ) for the SD of elasticity. The reviewers concluded SWE has a high sensitivity and specificity in the differentiation of benign and malignant breast lesions. More large and prospective studies are warranted to further examine the performance of SWE. Zhou et al (2014) compared the diagnostic performance of the fat-to-lesion strain ratio (FLR) and gland-to-lesion strain ratio (GLR) in the diagnosis of breast lesions in a prospective study. One hundred and ninety-three breast lesions in 193 women (mean age, 46.03±13.60 years, range years) were examined with conventional and elastographic US. Both the FLR and GLR of the lesions were calculated. The elasticity scores of the lesions were also evaluated using the fivepoint elasticity scoring system. For diagnostic performance, the sensitivity, specificity and receiver operating characteristic (ROC) analysis were obtained. Seventy lesions were malignant and 123 were benign. Both the FLR and GLR of the lesions were significantly higher in malignant cases than in benign ones (P<0.001 for both). The Az values for the FLR (0.847) and the elasticity score (0.829) were significantly higher than that for the GLR (0.752) (P=0.009, P=0.029, respectively). However, there was no significant difference in the Az value between the FLR and the elasticity score (P=0.443). The authors concluded the FLR yielded better diagnostic performance than GLR in breast lesions; the fatty tissue was better than glandular tissue as the reference normal tissue for calculating strain ratio in breast elastography Fleury Ede et al (2014) assessed factors influencing the sonoelastographic presentation of breast carcinoma in a prospective collaborative study conducted on 540 breast lesions in women referred for percutaneous breast biopsy. Eighty-four carcinomas showing lesions on ultrasonography (US) were included. These lesions were classified into four sonoelastographic scores, where scores of 1, 2, and 3 were considered false-negative, and a score of 4 was considered true-positive. Scores were compared against histopathologic results, which were divided into two groups, ie, soft lesions (group 1) and hard lesions (group 2). False-negative and true-positive results were also assessed for variation according to patient age and mean lesion diameter. Of the 84 lesions studied, nine yielded false-negative results on sonoelastography and 75 yielded true-positive results. In terms of histopathologic classification, eight were assigned to group 1 and 76 to group 2. The chi-squared test showed a correlation between sonoelastographic scores and histopathologic lesion type. No statistically significant differences were observed according to patient age or largest lesion diameter. The authors concluded the results revealed an association between sonoelastographic presentation of breast lesions and histology. False-negative results on sonoelastography were influenced by histologic type of lesion and not by lesion size or patient age. Breast Elastography Oct 15 7

8 Au et al (2014) assessed the diagnostic performance of quantitative SWE in the evaluation of solid breast masses and sought to determine the most discriminatory parameter. B-mode US and SWE were performed before core biopsy of 123 masses in 112 women. The diagnostic performance of US and quantitative SWE parameters (mean elasticity, maximum elasticity, and elasticity ratio) were compared. The added effect of SWE on the performance of US was determined. The mean elasticity, maximum elasticity, and elasticity ratio were 24.8 kpa, 30.3 kpa, and 1.90, respectively, for 79 benign masses and kpa, kpa, and 11.52, respectively, for 44 malignant masses (p < 0.001). The optimal cutoff value for each parameter was determined to be 42.5 kpa, 46.7 kpa, and 3.56, respectively. The AUC of each shear wave elastography parameter was higher than that of US (p < 0.001); the AUC value for the elasticity ratio (0.943) was the highest. By adding SWE parameters to the evaluation of BI-RADS category 4a masses, about 90% of masses could be downgraded to BI-RADS category 3. The numbers of downgraded masses were 40 of 44 (91%) for mean elasticity, 39 of 44 (89%) for maximum elasticity, and 42 of 44 (95%) for elasticity ratio. The numbers of correctly downgraded masses were 39 of 40 (98%) for mean elasticity, 38 of 39 (97%) for maximum elasticity, and 41 of 42 (98%) for elasticity ratio. There was improvement in the diagnostic performance of US of mass assessment with SWE parameters added to BI-RADS category 4a masses compared with US alone. Combined US and elasticity ratio had the highest improvement, from 35.44% to 87.34% for specificity, from 45.74% to 80.77% for positive predictive value, and from 57.72% to 90.24% for accuracy (p < ). The AUC of combined US and elasticity ratio (0.914) was the highest compared with the other combined parameters. The authors concluded there was a statistically significant difference in the values of the quantitative SWE parameters of benign and malignant solid breast masses. By adding SWE parameters to BI-RADS category 4a masses, 90% of them could be correctly downgraded to BI- RADS category 3, thereby avoiding biopsy. Elasticity ratio (cutoff, 3.56) appeared to be the most discriminatory parameter. Lee et al (2014) evaluated the additional value of SWE to B-mode US and sought to determine an appropriate guideline for the combined assessment of screening USdetected breast masses. From March 2010 to February 2012, B-mode US and SWE were performed in 159 US-detected breast masses before biopsy. For each lesion, Breast Imaging Reporting and Data System (BI-RADS) category on B-mode US images and the maximum stiffness color and elasticity values on SWE images were assessed. A guideline for adding SWE data to B-mode US was developed with the retrospective cohort to improve diagnostic performance in sensitivity and specificity and was validated in a distinct prospective cohort of 207 women prior to biopsy. Twenty-one of 159 masses in the development cohort and 12 of 207 breast masses in the validation cohort were malignant. In the development cohort, when BI-RADS category 4a masses showing a dark blue color or a maximum elasticity value of 30 kpa or less on SWE images were downgraded to category 3, specificity increased from 9.4% (13 of 138) to 59.4% (82 of 138) and 57.2% (79 of 138) (P <.001), respectively, without loss in sensitivity (100% [21 of 21]). In the validation cohort, specificity increased from 17.4% (34 of 195) to 62.1% (121 of 195) and 53.3% (104 of 195) (P <.001) respectively, without loss in sensitivity (91.7% [11 of 12]). The authors concluded the addition of SWE to B-mode US improved diagnostic performance with increased specificity for screening US-detected breast masses. BI- RADS category 4a masses detected at US screening that showed a dark blue color or a maximum elasticity value of 30 kpa or less on SWE images can be safely followed up instead of performing biopsy. Breast Elastography Oct 15 8

9 Cho et al (2014) evaluated the negative predictive value (NPV) of US elastography for non-palpable Breast Imaging Reporting and Data System (BI-RADS) category 3 lesions on ultrasonography and to determine whether US elastography is helpful in reducing the number of BI-RADS category 3 lesions on ultrasonography. Two hundred seventy-six consecutive, non-palpable BI-RADS category 3 lesions in 256 women who underwent US elastography and US-guided core biopsy, and who had at least 12 months of follow-up data, comprised our study group. The BI-RADS final assessment category and elasticity score were prospectively and independently classified. The rate of malignancy and NPV according to the elasticity score were analysed. We also investigated whether there was a subset of BI-RADS category 3 lesions that were of benign histology but negative on elastography. Of the 276 nonpalpable BI-RADS category 3 lesions, three lesions (1.0%) were finally confirmed as ductal carcinomas in situ. No cancers were found in the remaining 273 lesions with benign biopsy histology at a mean follow-up of 39.4 months (range, 12 to 72 months). The NPV of a negative elasticity score (elasticity score of 1) was 99.3% (165 of 166). If BI-RADS category 3 lesions showing a negative elasticity score were downgraded to BI-RADS category 2, 60.4% (165 of 273) of them with benign histology could have been safely followed without biopsy with an increased malignancy rate from 1% (3 of 276) to 1.8% (2 of 110), which is not significantly higher (P=0.626). The authors concluded US elastography has the potential to reduce the number of BI-RADS category 3 lesions on ultrasonography. Plecha et al (2014) sought to determine if adding SWEto second-look US after breast dynamic contrast material-enhanced (DCE) magnetic resonance (MR) imaging helps find or target lesions seen on DCE MR images for US-guided biopsy in a prospective study. 73 women with 96 Breast Imaging Reporting and Data System (BI-RADS) category 4 or 5 lesions after DCE MR imaging prospectively consented to undergo SWE during second-look US. If a lesion was not confidently seen with B-mode US, SWE during real-time scanning was performed to determine if SWE helped find or target lesions for US biopsy. A qualitative SWE six-point color scale was used to record the maximum elasticity in and around lesions. All lesions underwent US or DCE MR imaging-guided core biopsy. Results Median participant age was 52 years (range, years). In 72 patients who underwent DCE MR imaging, 96 BI-RADS category 4 or 5 lesions were detected in 81 breasts. There were 29 (30%) malignancies (one malignancy was of nonbreast origin), 14 (15%) high-risk lesions, and 53 (55%) benign lesions. US revealed 22 cancers, and seven cancers were detected only with MR imaging. Real-time SWE helped find one lesion and target four lesions that were incompletely assessed with gray-scale US. These five lesions that were localized or targeted for biopsy were invasive cancers, representing 23% of the 22 malignancies detected with US. Investigators concluded real-time SWE added to second-look US after DCE MR imaging increased the detection rate of cancers and helped target cancers for US-guided biopsy. Zhou et al (2014) evaluated the stiffness of the surrounding tissue of breast lesions using the strain ratio assessment method by US elastography in a prospective study. A total of 127 breast lesions in 118 women (mean age 48.23±14.32, range 20-90) were examined with conventional and elastographic US. The strain ratio assessment method was utilized to semi-quantitatively evaluate the stiffness of the breast lesions and the surrounding tissue. Fifty-five lesions were malignant and 72 were benign. The strain ratio of the surrounding tissue was significantly higher in malignant cases (1.49±0.67) than in benign ones (1.17±0.44) (P=0.001), and yielded an Az value of in the diagnosis of breast lesions. There was a significant high positive Breast Elastography Oct 15 9

10 correlation between the strain ratio of the lesion and the strain ratio of the surrounding tissue in the malignant group (r=0.740, P<0.001), and a significant moderate positive correlation in the benign group (r=0.595, P<0.001). The investigators concluded the stiffness of the surrounding tissue of malignant breast lesions was higher than that of benign lesions. The strain ratio of the surrounding tissue and the lesions was significantly correlated, and has potential for breast lesion diagnosis. Çebi Olgun et al (2014) aimed to determine the correlations between the elasticity values of solid breast masses and histopathological findings to define cutoff elasticity values differentiating malignant from benign lesions. A total of 115 solid breast lesions of 109 consecutive patients were evaluated prospectively using SWE. Two orthogonal elastographic images of each lesion were obtained. Minimum, mean, and maximum elasticity values were calculated in regions of interest placed over the stiffest areas on the two images; The authors also calculated mass/fat elasticity ratios. Correlation of elastographic measurements with histopathological results were studied. Eighty-three benign and thirty-two malignant lesions were histopathologically diagnosed. The minimum, mean, and maximum elasticity values, and the mass/fat elasticity ratios of malignant lesions, were significantly higher than those of benign lesions. The cutoff value was 45.7 kpa for mean elasticity (sensitivity, 96%; specificity, 95%), 54.3 kpa for maximum elasticity (sensitivity, 95%; specificity, 94%), 37.1 kpa for minimum elasticity (sensitivity, 96%; specificity, 95%), and 4.6 for the mass/fat elasticity ratio (sensitivity, 97%; specificity, 95%). The authors concluded SWE yields additional valuable quantitative data to ultrasonographic examination on solid breast lesions. SWE may serve as a complementary tool for diagnosis of breast lesions. Long-term clinical studies are required to accurately select lesions requiring biopsy. Vinnicombe et al (2014) sought to characterise breast cancers which are not stiff on quantitative SWE, to elucidate potential sources of error in clinical application of SWE to evaluation of breast masses. Three hundred and two consecutive patients examined by SWE who underwent immediate surgery for breast cancer were included. Characteristics of 280 lesions with suspicious SWE values (mean stiffness >50 kpa) were compared with 22 lesions with benign SWE values (<50 kpa). Statistical significance of the differences was assessed using non-parametric goodness-of-fit tests. Pure ductal carcinoma in situ (DCIS) masses were more often soft on SWE than masses representing invasive breast cancer. Invasive cancers that were soft were more frequently: histological grade 1, tubular subtype, 10 mm invasive size and detected at screening mammography. No significant differences were found with respect to the presence of invasive lobular cancer, vascular invasion, hormone and HER-2 receptor status. Lymph node positivity was less common in soft cancers. Investigators concluded malignant breast masses classified as benign by quantitative SWE tend to have better prognostic features than those correctly classified as malignant. Scientific Rationale Update December 2012 The National Comprehensive Cancer Network (NCCN) does not address elastography in their guidelines on Breast Cancer or Breast Cancer Screening and Diagnosis. According to NCCN guideline on Breast Cancer Screening and Diagnosis: Mammography and ultrasonography are complementary imaging methods for diagnosing breast cancer. However, breast ultrasonography does not detect most microcalcifications. Breast Elastography Oct 15 10

11 Initial diagnostic imaging with breast ultrasonography is recommended as the preferred option for women aged <30 years presenting with a palpable mass or asymmetric thickening/nodularity. Breast ultrasonography is recommended for women > 30 years of age with a palpable mass and a diagnostic mammogram assessed as BI-RADS 1-3, and as an adjunct to diagnostic mammography for women in this age group with a finding of asymmetric thickening/nodularity. In addition, breast ultrasonography should be considered as an adjunct to mammography for those of all ages with skin changes consistent with serious breast disease or with spontaneous nipple discharge in the absence of a palpable mass, and as a possible option for women with a BI-RADS category 0 screening mammographic assessment. Consideration of a follow-up ultrasound testing is also recommended when initial ultrasound findings of a solid mass (<2 cm with low clinical suspicion) are classified as a probably benign finding, or when biopsy results are found to benign and image concordant. Ultrasound-guided biopsy is included in the guidelines for women with a complex cyst or persistant mass following cyst aspiration. According to the NCCN, after the ultrasonographic evaluation is completed, the results are classified according to one of the BI-RADS categories: Category 0: Needs additional imaging evaluation. This represents an incomplete assessment. A finding for which additional evaluation is needed. If ultrasound is the initial study, mammography might be indicated, or if mammography and ultrasound findings are nonspecific, MRI might be appropriate. Category 1: Negative. This is a negative ultrasound. No abnormalities detected Category 2: Benign finding(s). This is also a negative ultrasound, but their may an actual finding that is benign. Included in this category are simple cyst s and breast implants. Category 3: Probably benign finding(s). Short-interval follow-up suggested. This is a ultrasound that is usually benign. Close monitoring of the finding is recommended to ensure its stability. The risk of malignancy is estimated to be less than 2%. Fibroadenomas and nonpalpable complicated cysts and clustered microcysts might be placed in this category for short-term follow-up. Category 4: Suspicious abnormality Biopsy should be considered. These lesions fall into the category of having a wide range of probablity of being malignant but are not obviously malignant ultrasonographically. The risk of malignacy is widely variable and is greater than that for category 3 but less than that for category 5. A complex cyst would be included in this group. Category 5: Highly suggestive of malignancy-appropriate action should be taken. These lesions have a high probability (< 95%) of being a cancer. Category 6: Known biopsy-proven malignancy- Appropriate action should be taken. This category is for breast lesions identified on the imaging study with biopsy proof of malignancy but prior to definitive therapies. Breast Elastography Oct 15 11

12 Cho et al (2012) investigated the effect of the combined use of ultrasonographic (US) elastography and color Doppler US on the accuracy of radiologists in distinguishing benign from malignant nonpalpable breast masses and in making the decision for biopsy recommendations at B-mode US in a prospective study. A cohort of 367 biopsy-proved cases in 319 women with B-mode US, US elastographic, and Doppler US images was included. Five blinded readers independently scored the likelihood of malignancy for four data sets (ie, B-mode US alone, B-mode US and elastography, B-mode US and Doppler US, and B-mode US, US elastography, and Doppler US). The area under the receiver operating characteristic curve (A(z)) values, sensitivities, and specificities of each data set were compared. The A(z) of B- mode US, US elastography, and Doppler US was greater than that of B-mode US alone for all readers. When both elastography and Doppler scores were negative, leading to strict downgrading, the specificity increased for all readers from an average of 25.3% (75.4 of 298; range, 6.4%-40.9%) to 34.0% (101.2 of 298; range, 26.5%-48.7%) without a significant change in sensitivity. Investigators concluded the combined use of US elastography and color Doppler US increases both the accuracy in distinguishing benign from malignant masses and the specificity in decision-making for biopsy recommendation at B-mode US. Sadigh et al (2012) conducted an individual patient data meta-analysis comparing the diagnostic performance of ultrasound elastography (USE) versus B-mode ultrasound (USB) across size ranges of breast masses. An extensive literature search of PubMed and other medical/general purpose databases from inception through August 2011 was conducted. Corresponding authors of published studies that reported a direct comparison of the diagnostic performance of USE using the elasticity score versus USB for characterisation of focal breast masses were contacted for their original patient-level data set. Summary diagnostic performance measures were compared for each test within and across three mass size groups (<10 mm, mm, and >19 mm). The patient-level data sets were received from five studies, providing information on 1,412 breast masses. For breast masses <10 mm (n=543; 121 malignant), the sensitivity/specificity of USE and USB were 76 %/93 % and 95 %/68 %, respectively. For masses mm of size (n=528; 247 malignant), sensitivity/specificity of USE and USB were 82 %/90 % and 95 %/67 %, respectively. For masses >19 mm of size (n=325; 162 malignant), sensitivity and specificity of USE and USB were 74 %/94 % and 97 %/55 %, respectively. Reviewers concluded regardless of the mass size, USE has higher specificity and lower sensitivity compared to USB in characterising breast masses. The performance of each of these two tests does not vary significantly by mass size. Soliman et al (2012) sought to examine the effect of the presence of DCIS on the accuracy of the ultrasonographic measuring malignant breast tumor size using B- mode and real time elastography. Materials and Methods. Investigators recruited histologically confirmed breast cancer patients in a prospective observational study. 50 breast cancer patients with a median age of 57.5 years were recruited. DCIS was confirmed to accompany 42% (n = 21) of the cases. Tumor size estimation using B- mode sonography as well as using real time elastography was statistically significant correlated to the actual tumor size. Presence of DCIS in 42% of the recruited patients affected the tumor size estimation using both methods thus losing the correlation between both estimations. Investigators concluded this study shows that the presence of DCIS significantly affects the accuracy of measuring the sizes of malignant breast tumors when using either B-mode ultrasonography or real time elastography. Breast Elastography Oct 15 12

13 Evans et al (2012) assessed the performance of shear wave elastography combined with BI-RADS classification of greyscale ultrasound images for benign/malignant differentiation in one hundred and seventy-five consecutive patients with solid breast masses on routine ultrasonography undergoing percutaneous biopsy. The mean elasticity values from four shear wave images were obtained. For mean elasticity vs greyscale BI-RADS, the performance results against histology were sensitivity: 95% vs 95%, specificity: 77% vs 69%, Positive Predictive Value (PPV): 88% vs 84%, Negative Predictive Value (NPV): 90% vs 91%, and accuracy: 89% vs 86%. The results for the combination (positive result from either modality counted as malignant) were sensitivity 100%, specificity 61%, PPV 82%, NPV 100%, and accuracy 86%. The combination of BI-RADS greyscale and shear wave elastography yielded superior sensitivity to BI-RADS alone or shear wave alone. The NPV was superior in combination compared with either alone. Investigators concluded together, BI-RADS assessment of greyscale ultrasound images and shear wave ultrasound elastography are extremely sensitive for detection of malignancy. Zhi et al (2012) evaluated the additive value of USE to BI-RADS for the differentiation of benign and malignant breast small lesions. Breast masses ( 2cm) with histological diagnosis examined by ultrasonography and USE in one department were reviewed. Conventional B-mode ultrasound findings were classified according to the BI-RADS classification. USE findings were classified according to the 5-point scale. Histological diagnosis was used as the reference standard. 401 (246 benign (61.3%), 155 malignant (38.7%)) from 370 consecutive patients were included in the study. Sensitivity and specificity were 90.3%, 68.3% for BI-RADS; 72.3%, 91.9% for USE. The sensitivity of BI-RADS was better than that of USE, while the specificity of USE was better than that of BI-RADS. A revised BI-RADS combined with USE results was proposed in this study. Sensitivity and specificity were 83.9% and 87.8% for revised BI-RADS. The diagnostic performance of revised BI-RADS was better than BI-RADS. Investigators conlcuded USE could give BI-RADS some help in the differentiation of benign and malignant breast small lesions. The addition of elastography to BI-RADS could improve the diagnostic performance in <2cm lesions. Mansour and Omar (2012) investigated the possible additional value of using USE in the specification of questionable breast lesions. Questionable breast lesions on gray scale ultrasound examination had been further evaluated by USE in 97 cases with median age of 42 years. The studied lesions were pathologically proven (58 benign and 39 malignant) using true cut tissue/surgical excision biopsy that was considered the gold standard of reference. Conventional ultrasound categorization before biopsy included: category 3 (probably benign) in 42.3% (n=41), category 4a (low suspicion of malignancy) in 13.4% (n=13), category 4b (intermediate suspicion of malignancy) in 16.5% (n=16) and category 4c (moderate suspicion of malignancy) in 27.8% (n=27). Investigators evaluated USE regarding elastography strain scoring and quantitative strain ratio. Sensitivity, specificity and accuracy were 89.7%, 86.2% and 87.6% for conventional ultrasound, 92.3%, 74.1% and 81.4% for elastogram 5- point scoring method and 87.1%, 89.6% and 88.6% for the calculated strain ratios respectively in the assessment of the examined breast lesions. USE, using both qualitative and quantitative methods can improve the performance of conventional B-mode ultrasound and enhance its specificity and accuracy in the diagnosis of questionable (BI-RADS categories 3 and 4) breast lesions. Choi et al (2012) compared the diagnostic performance of elastography, conventional ultrasonography (US) and combined conventional US and elastography for differentiation of papillary breast lesions. A total of 95 papillary lesions (69 Breast Elastography Oct 15 13

14 benign, 20 atypical and 6 malignant) in 87 patients were examined with conventional US and elastography. Investigators evaluated conventional US images according to the Breast Imaging Reporting and Data System and internal composition (solid vs. cystic) and elastographic images according to elasticity scores. Investigators compared diagnostic performances of elastography, conventional US and the combined method. Areas under the receiver-operating curve were for elastography, for conventional US and for the combined method. When the elasticity score cutoff was between 2 and 3, the sensitivity, specificity, positive predictive value and negative predictive value were 100, 55.1, 13 and 100 %, respectively. The combined method showed similar sensitivity (100 vs. 100 %) to and higher specificity (57.3 vs. 5.6 %) than conventional US alone. No significant difference was found in the elasticity scores of cystic papillary lesions according to pathology. Investigators concluded elastography improved the specificity of conventional US in differentiating between benign or atypical and malignant papillary breast lesions when it was combined with conventional US. Sadigh et al (2012) systematically reviewed recent literature on diagnostic performance of strain ratio and length ratio, two different strain measurements in USE, for differentiating benign and malignant breast masses. Published studies that evaluated the diagnostic performance of USE alone reporting either strain ratio or length ratio for characterization of focal breast lesions and using cytology (fine needle aspiration) or histology (core biopsy) as a reference standard were included. Summary diagnostic performance measures were assessed using bivariate generalized linear mixed modeling. Nine studies reported strain ratio for 2,087 breast masses (667 cancers, 1,420 benign lesions). Summary sensitivity and specificity were 88 % and 83 %, respectively. The positive and negative likelihood ratios (LR) were 5.57 and 0.14, respectively. The inconsistency index for heterogeneity was 6 % for sensitivity and 8 % for specificity. Analysis of three studies reporting length ratio for 450 breast masses demonstrated sensitivity and specificity of 98 % and 72 %, respectively. Strain ratio and length ratio have good diagnostic performance for distinguishing benign from malignant breast masses. Investigators concluded, although, this performance may not be incrementally superior to that of breast imaging reporting and data system (BIRADS) in B-mode ultrasound, the application of USE using strain ratio or length ratio in combination with USB may have the potential to benefit the patients, and this requires further comparative effectiveness and cost-effectiveness analyses. Barr et al (2012) sought to determine the sensitivity and specificity of real-time compression elasticity imaging in characterizing breast lesions as benign or malignant. A cohort of 578 women scheduled for sonographically guided biopsy of breast lesions were recruited from 6 sites. All participants received an elastogram, which displayed both the B-mode and elasticity images in real time. The longest dimensions of the lesion on the B-mode and elasticity imaging were measured. An elasticity imaging/b-mode ratio of at least 1.0 was considered positive for malignant lesions. The reference standard was based on biopsy. A total of 635 lesions were imaged and biopsied. There were 222 (35%) malignant or borderline lesions and 413 (65%) benign lesions. The benign lesions were either cystic (145 [35%]) or solid (268 [65%]). Of the 222 malignant lesions, 219 had an elasticity imaging/b-mode ratio of at least 1.0. Of the 413 benign lesions, 361 had an elasticity imaging/bmode ratio less than 1.0. These results corresponded to overall sensitivity of 98.6% and overall specificity of 87.4%. Individual site sensitivities ranged from 96.7% to 100% whereas specificities ranged from 66.7% to 95.4%. Investigators concluded Breast Elastography Oct 15 14

15 elasticity imaging has high sensitivity in characterizing malignant lesions of the breast. Variability in specificity between sites and sonographers is possibly due to individual technique differences in performing elastography and measuring lesions. Further work in standardizing the technique is required. Scientific Rationale Update December 2011 Cho et al (2011) investigated the effect of the combined use of ultrasonographic (US) elastography and color Doppler US on the accuracy of radiologists in distinguishing benign from malignant nonpalpable breast masses and in making the decision for biopsy recommendations at B-mode US in a prospective study. A cohort of 367 biopsy-proved cases in 319 women with B-mode US, US elastographic, and Doppler US images was included. Five blinded readers independently scored the likelihood of malignancy for four data sets (ie, B-mode US alone, B-mode US and elastography, B-mode US and Doppler US, and B-mode US, US elastography, and Doppler US). The area under the receiver operating characteristic curve (A(z)) values, sensitivities, and specificities of each data set were compared.the A(z) of B- mode US, US elastography, and Doppler US (average, 0.844; range, ) was greater than that of B-mode US alone (average, 0.771; range, ) for all readers (P =.001 for readers 1, 2, and 3; P <.001 for reader 4; P =.002 for reader 5). When both elastography and Doppler scores were negative, leading to strict downgrading, the specificity increased for all readers from an average of 25.3% (75.4 of 298; range, 6.4%-40.9%) to 34.0% (101.2 of 298; range, 26.5%- 48.7%) (P <.001 for readers 1, 2, 4, and 5; P =.016 for reader 3) without a significant change in sensitivity. Investigators concluded combined use of US elastography and color Doppler US increases both the accuracy in distinguishing benign from malignant masses and the specificity in decision-making for biopsy recommendation at B-mode US. Taylor et al (2011) compared the performance of ultrasound elastography with conventional ultrasound in the assessment of axillary lymph nodes in suspected breast cancer and whether ultrasound elastography as an adjunct to conventional ultrasound can increase the sensitivity of conventional ultrasound used alone. Fifty symptomatic women with a sonographic suspicion for breast cancer underwent ultrasound elastography of the ipsilateral axilla concurrent with conventional ultrasound being performed as part of triple assessment. Elastograms were visually scored, strain measurements calculated and node area and perimeter measurements taken. Theoretical biopsy cut points were selected. The sensitivity, specificity, positive predictive value (PPV), and negative predictive values (NPV) were calculated and receiver operating characteristic (ROC) analysis was performed and compared for elastograms and conventional ultrasound images with surgical histology as the reference standard. The mean age of the women was 57 years. Twenty-nine out of 50 of the nodes were histologically negative on surgical histology and 21 were positive. The sensitivity, specificity, PPV, and NPV for conventional ultrasound were 76, 78, 70, and 81%, respectively; 90, 86, 83, and 93%, respectively, for visual ultrasound elastography; and for strain scoring, 100, 48, 58 and 100%, respectively. There was no significant difference between any of the node measurements. Investigators concluded initial experience with ultrasound elastography of axillary lymph nodes, showed that it is more sensitive than conventional ultrasound in detecting abnormal nodes in the axilla in cases of suspected breast cancer. The specificity remained acceptable and ultrasound elastography used as an adjunct to conventional ultrasound has the potential to improve the performance of conventional ultrasound alone. Breast Elastography Oct 15 15

16 Bartolotta et al (2011) sought to to evaluate the role of ultrasound (US) elastography in characterising focal breast lesions classified as indeterminate on B- mode US. Eighty-four focal breast lesions, 64 benign and 20 malignant (mean diameter, 15.1 mm), detected but not characterised on B-mode US in 72 women, Breast Imaging Reporting and Data System (BI-RADS) US category 3 (n=56) or category 4 (n=28), were studied with US elastography and classified in consensus by two radiologists according to a five-point colour scale. Sensitivity, specificity and positive and negative predictive values (PPV and NPV) of US elastography compared with conventional US were calculated in relation to microhistology (n=67) and cytology (n=17), which were used as the reference standard. A total of 65/84 (77.4%) lesions were correctly classified as benign or malignant using US elastography, whereas the remaining 19/84 (22.6%) were incorrectly assessed. There were no statistically significant differences between US elastography and B- mode US with regard to sensitivity (70% vs. 68.4%), specificity (79.6% vs. 78.5%), PPV (51.8% vs. 48.1%) and NPV 89% vs. 89.5% (p>0.5). By contrast, a statistically significant difference was noted in the evaluation of BI-RADS 3 lesions, in which US elastography had 50% sensitivity, 86% specificity, 30% PPV and 93.5% NPV compared with BI-RADS 4 lesions (78.6%, 57.1%, 64.7% and 72.7%) (p<0.5). Investigators concluded the high NPV of US elastography may help reduce the use of biopsy in BI-RADS 3 lesions, but its low PPV in BI-RADS 4 lesions does not allow avoidance of biopsy on the basis of the US elastographic score alone in this group of lesions. Yoon et al (2011) evaluated the interobserver variability of elastography on real-time ultrasound and how it influences the agreement of final assessment on ultrasound. From April to May 2009, 65 breast lesions of 53 patients (mean age, 42.6 years; range, years) who underwent ultrasound-guided core biopsy were included in this study. Ultrasound and elastography images of the lesion subjected to biopsy were obtained and prospectively analyzed by three radiologists with individual realtime image scanning prior to biopsy. Each radiologist recorded final ultrasound BI- RADS assessments using ultrasound and combined ultrasound and elastography and the fat-to-lesion ratio and elasticity score. The histopathologic results obtained from ultrasound-guided core biopsy or excision were used as the reference standard. Diagnostic performances and interobserver agreement were analyzed. Of the 65 lesions, 43 (66.2%) were benign, and 22 (33.8%) were malignant. Specificity ( %), positive predictive value ( %), and accuracy ( %) were significantly improved in combined ultrasound and elastography (p < 0.001). Area under the curve (AUC) values for all three performers did not show significant differences in ultrasound (AUC, 0.959) and combined ultrasound and elastography (AUC, 0.957) (p = 0.92). Interobserver agreement was not improved with combined ultrasound and elastography (κ = 0.25) in comparison to ultrasound only (κ = 0.37). Interobserver agreement of real-time elastography was fair in both fat-to-lesion ratio (intraclass correlation coefficient score, 0.25) and elasticity score (κ = 0.28). Moderate agreement (κ = 0.46) was seen with static elastography. Investigators concluded elastography improves the specificity, positive predictive value, and accuracy of ultrasound. However, significant interobserver variability exists, with real-time elastographic performance showing fair agreement. Chang et al (2011) investigated factors influencing the quality of ultrasonographic (US) elastography in the evaluation of suspicious breast masses in a prospective study. Between January 2009 and February 2009, real-time US elastography of 312 breast masses (245 benign, 67 malignant) was performed in 268 consecutive Breast Elastography Oct 15 16

17 patients (mean age, 45.7 years ± 10.2 [standard deviation]) prior to US-guided core biopsy. Five breast radiologists who had performed the examinations assessed the quality of elasticity images as inadequate, low, or high without histologic information. Age, body mass index (BMI), mammographic density, lesion size, lesion depth, and breast thickness at US were analyzed for their association with image quality by using the χ(2) test, Student t test, and multivariate analysis. Sensitivities and specificities for the differentiation of benign from malignant masses on the basis of elastography were calculated and compared between groups of quality scores by using the logistic regression method. The quality of elasticity images was assessed as inadequate in 21 (6.7%) cases, low in 134 (42.9%), and high in 157 (50.3%). According to univariate analysis, smaller lesion size (P =.001), shallower lesion depth (P =.005), less breast thickness where the lesion was located (P <.0001), and benign pathologic finding (P =.004) were significantly associated with higher image quality. There was no correlation of image quality with age (P =.213), BMI (P =.191), mammographic density (P =.091), or distance from the nipple (P =.100). Multivariable analysis showed that breast thickness at the location of target lesions was the most important factor influencing elasticity image quality (P =.001). There were significant differences in sensitivity between higher-quality and lower-quality images (87.0% vs 56.8%, respectively; P =.015) in the differentiation of benign from malignant masses. Investigators concluded breast thickness at the location of the lesion was the most important factor influencing image quality at US elastography. Sensitivity for classification of benign and malignant masses improved with higher quality scores. Scientific Rationale Update March 2011 Breast biopsy remains the gold standard for diagnosis of suspicious lesions, however, a large proportion of biopsy specimens reveal a benign result. Elasography has been investigated as a noninvasive method of evaluating breast lesions to differentiate between benign and malignant breast tumors. Leong et al (2010) compared the diagnostic performance of breast elastography versus conventional ultrasound in the assessment of breast lesions in a prospective study involving 99 consecutive women. One hundred and ten breast lesions were evaluated separately by conventional ultrasound, elastography and combined conventional ultrasound with elastography. Ultrasound assessment was based on the BIRADS classification, whereas elastographic assessment was based on strain pattern and the elastographic size ratios. Histological diagnosis was used as the reference standard. The sensitivity, specificity, and accuracy of each technique were compared. The mean age of the patients was 46.7 years. Twenty-six lesions were malignant and 84 were benign. Sensitivity, specificity, and accuracy were 88.5, 42.9 and 53.6%, respectively, for conventional ultrasound, 100, 73.8, and 80%, respectively, for elastography, and 88.5, 78.6, and 80.9%, respectively, for combined imaging. The specificity and accuracy of elastography and combined imaging were significantly better than that of conventional ultrasound (p<0.0001), whereas there was no statistically significant difference in the sensitivity between all three groups. Two-thirds (66.7%) of sonographic false-positive lesions had benign elastogram findings, which might have been spared from biopsy. The investigators concluded this initial experience with ultrasound breast elastography showed that it was more specific and more accurate than conventional ultrasound. Combining elastography with ultrasound improved specificity and accuracy of ultrasound and can potentially reduce unnecessary breast biopsies. Breast Elastography Oct 15 17

18 Kumm et al (2010) assessed the application and diagnostic performance of elastography for the characterization of breast lesions in patients referred for biopsy. Individuals referred for ultrasound-guided biopsy of sonographically apparent breast lesions were included in this study. The Hitachi Hi-Vision 900 ultrasound was used to generate index test results for elastography scoring (ES) and for strain ratio (SR) measurement. Sensitivity, specificity, and positive and negative predictive values were determined using pathologic results from 14-gauge core needle biopsy as the reference standard. A total of 310 lesions in 288 patients were included in this series. Of these 310 lesions, 223 (72%) were benign and 87 (28%) were malignant. Sensitivity was 0.76 for ES and 0.79 for SR. Specificity was 0.81 for ES and 0.76 for SR. Positive predictive value was 0.60 for ES and 0.57 for SR. Negative predictive value was 0.90 for ES and 0.90 for SR. SR values for malignant lesions were significantly higher (median ratios 10.5 and 2.7, respectively, P <.001). The investigator concluded while the initial clinical performance of elastography imaging shows potential to reduce biopsy of low-risk lesions, however, a large-scale trial addressing appropriate patient selection, diagnostic parameters, and practical application of this technique is necessary prior to widespread clinical use. Barr et al (2010) sought to determine the sensitivity and specificity of a real-time elasticity imaging (EI) ultrasound (US) system in the characterization of breast lesions as benign or malignant. A total of 208 patients with 251 lesions were scheduled to undergo a US-guided breast biopsy for a mass identified on B-mode US, and each received a real-time elasticity image of the lesion before the biopsy. The lesion size measurements were obtained, and the EI/B-mode size ratio was obtained. The pathology report was obtained and correlated with the EI/B-mode ratio. An EI/Bmode ratio equal to or greater than 1 was considered malignant lesion, whereas EI/B-mode ratios of less than 1 were considered benign. Sensitivity, specificity, positive predictive values, and negative predictive values were calculated. Of the 251 lesions biopsied, 197 were pathologically benign, and 54 were malignant. Of the 54 malignant lesions, all had an EI/B-mode ratio > 1. Of the 197 benign lesions, 187 had an EI/B-mode ratio of < 1. Ten benign lesions had an EI/B-mode ratio of >1. The benign lesions that had an EI/B-mode ratio of > 1 were lesions with dense fibrosis, and in addition, a characteristic artifact was identified, which was visualized in all simple and complex cysts. The results correspond with a sensitivity of 100%, specificity of 95%, a positive predictive value of 84%, and a negative predictive value of 100%. The investigators concluded initial results of a real-time EI system for characterization of breast lesions suggest this technique can provide significant new diagnostic information. As a result, this information may significantly improve the ability to select patients for breast biopsy, resulting in a reduction in the number of benign breast biopsies. In a multicentere study, Wojcinski et al (2010) evaluated whether sonoelastography improves the differentiation of benign and malignant breast lesions. In a multicenter approach sonoelastography of focal breast lesions was carried out in 779 patients with subsequent histological confirmation. Data from 3 study centers focusing on the sensitivity (SE), specificity (SP) and the positive (PPV) and negative predictive value (NPV) of sonoelastography was obtained. In addition an analysis of the diagnostic performance, expressed by the pretest and posttest probability of disease (POD), in BI-RADS -US 3 or 4 lesions were performed as these categories can imply both malignant and benign lesions and a more precise prediction would be a preferable aim. Sonoelastography demonstrated an improved SP (89.5 %) and an excellent PPV (86.8 %) compared to B-mode ultrasound (76.1 % and 77.2 %). Especially in dense breasts ACR III-IV, the SP was even higher (92.8 %). In BI-RADS-US 3 Breast Elastography Oct 15 18

19 lesions, a suspicious elastogram significantly modified the POD from 8.3 % to a posttest POD of 45.5 %. In BI-RADS-US 4 lesions, we found a pretest POD of 56.6 %. The posttest POD changed significantly to 24.2 % with a normal elastogram and to 81.5 % with a suspicious elastogram. The investigators concluded the data demonstrates that the complementary use of sonoelastography improves the performance in breast diagnostics. Raza et al (2010) prospectively assessed the performance of real-time tissue elastography (RTE) in the evaluation of breast masses and correlate RTE and American College of Radiology Breast Imaging Reporting and Data System (BI- RADS) assessments with pathologic findings. Patients with sonographically visible breast lesions for which a biopsy was recommended were considered potential study participants. 186 consecutive women with 200 lesions were enrolled. Twelve lesions in 11 patients were excluded, resulting in a study population of 188 lesions in 175 women. After routine B-mode sonographic examination, RTE was performed using a manual free-hand compression technique. Study lesions were assigned elasticity scores (ES) based on the system proposed by Itoh et al (Radiology 2006; 239: ), where 1 is normal and 5 represents abnormal strain. The lesion size on RTE and B-mode imaging was compared. Results were correlated with BI-RADS assessment and pathologic findings. Pathologic examination revealed 61 of 188 malignancies (32.4%) and 127 of 188 benign lesions (67.6%). Of the malignant lesions, 84% had ES of 5 and 4, whereas 76% of benign lesions had ES of 1 and 2. The sensitivity of RTE was 92.7%, and specificity was 85.8%, with 4 false-negative and 16 false-positive results. Of the biopsy-proven benign BI-RADS 4A lesions, 63 of 76 (82.9%) had ES of 1 and 2, consistent with normal tissue. The investigators concluded real-time tissue elastography may provide additional characterization of breast lesions, improving specificity, particularly for low-suspicion lesions. Used in conjunction with conventional ultrasound, breast elastography appears to be promising in assisting to differentiate potentially benign from malignant lesions, however, a large prospective clinical trial addressing appropriate patient selection, diagnostic parameters, and practical application of this technique is necessary prior to widespread clinical use. Scientific Rationale Update February 2010 Ultrasound elastography has been investigated in a variety of clinical applications, including, but not limited to, breast imaging, assessment of liver fibrosis, endoscopic, vascular and prostate imaging as well as thyroid, skin and brain tumors. It has been proposed that elastography may be useful in evaluating breast lesions visualized on ultrasound. Elastography has shown potential in differentiating benign from malignant breast tumors, but interobserver variability between experienced and inexperienced readers limits its wide usage. Schaefer et al (2009) evaluated the diagnostic performance of ultrasound elastography in 193 breast masses. The lesions (129 benign, 64 malignant) were analyzed with the EUB 8500 Logos-ultrasonic-unit (Hitachi Medical, Japan) and a linear-array-transducer of MHz. Standard of reference was cytology (FNAfine needle aspiration) or histology (core biopsy). The elastic-score was classified according to a 6-point color-scale (Ueno classification; 1-3=benign, 4-5=malignant). Conventional B-mode ultrasound (US) findings were classified according to the BI- RADS classification. Statistical analysis included sensitivity, specificity, ROC-analysis and kappa-values for intra-/interobserver reliability. The investigators reported that Breast Elastography Oct 15 19

20 the mean score for elasticity was 4.1+/-0.9 for malignant lesions, and 2.1+/-1.0 for benign lesions (p<0.001). With a best cut-off point between elasticity scores 3 and 4, sensitivity was 96.9%, and specificity 76%. Setting a best cut-off point for conventional US between BI-RADS 4 and 5, sensitivity was 57.8%, and specificity 96.1%. Elastography provided higher sensitivity and lower specificity than conventional US, but two lesions with elasticity score 1 were false negative, whereas no lesion scored BI-RADS 1-3 were false negative. ROC-curve was for elastography, and for conventional US (p<0.001). Weighted kappa-values for intra-/interobserver reliability were 0.784/0.634 for BI-RADS classification, and 0.720/0.561 for elasticity scores. The investigator concluded that elastography does not have the potential to replace conventional B-mode US for the detection of breast cancer, but may complement conventional US to improve the diagnostic performance. Sohn et al (2009) evaluated the diagnostic performance of conventional sonography combined with sonographic elastography for differentiation between benign and malignant breast lesions and to assess the diagnostic performance with two types of interpretation criteria for sonographic elastography. 281 lesions from 267 patients that were diagnosed as benign or malignant by sonographically guided biopsy were included in the study. The histopathologic results from sonographically guided biopsy were used as a reference standard. The final assessments were made prospectively on the basis of conventional sonography alone and then by sonographic elastography combined with conventional sonography. The diagnostic performance using area under the receiver operating characteristic (ROC) curve analysis (A(z)) was compared on the basis of conventional sonography alone and on elastography combined with conventional sonography. The area ratio of lesions detected by elastography and the elasticity score reported by Itoh et al (Radiology 2006; 239: ) were also calculated. The investigator reported that the areas under the ROC curve for conventional sonography and the combination of conventional sonography and sonographic elastography were and 0.876, respectively. The area ratio of the lesion had better diagnostic performance (A(z), 0.757) than the elasticity score (A(z), 0.54; P <.05). The investigator concluded that the diagnostic performance of radiologists with respect to the characterization of breast masses as benign or malignant was not significantly improved with sonographic elastography. The area ratio of the lesion had a better diagnostic value in elastography than the elasticity score. In a retropsective study, Cho et al. (2009) evaluated the use of US elastography in the differentiation of mammographically detected suspicious microcalcifications, using histology as the reference standard in 77 patients with 77 mammographically detected areas of microcalcifications (42 benign and 35 malignant lesions) prior to needle biopsy. Two experienced radiologists reviewed cine clips of elasticity and B- mode images and assigned an elasticity score of 1 to 3 in consensus, based on the degree of strain in the hypoechoic lesion without information of mammography and histology. For the elasticity score, the mean +/- standard deviation was 1.5 +/- 0.7 for benign and 2.7 +/- 0.7 for malignant lesions (P < 0.001). When a cutoff point between elasticity scores of 1 and 2 was used, US elastography showed 97% (34/35) sensitivity, 62% (26/42) specificity, 68% (34/50) PPV, and 96% (26/27) NPV with an Az value of ( , 95% confidence interval) in the differentiation of benign and malignant microcalcifications. The investigators concluded that US elastography has the potential to differentiate benign and malignant lesions associated with microcalcifications detected at screening mammography. Breast Elastography Oct 15 20