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Copyright © 2013 American Scientific PublishersAll rights reservedPrinted in the United States of America

R E S E A R CH AR T I C L E

Journal of Medical Imaging andHealth Informatics

Vol. 3, 1–14, 2013

Ultrasound Diagnosis of Breast CancerYufeng Zhou

School of Mechanical and Aerospace Engineering, Nanyang Technological University, Singapore

Ultrasound is a popular imaging modality for its safety and low cost. Its role in the diagnosis of breast canceris discussed, and its performance is then compared those of mammography (gold standard) and MRI. Besidesconventional B-mode and color or power Doppler ultrasound images, latest development of acoustic radiationforce impulse (ARFI) and supersonic shear imaging and their application in breast diagnosis are introduced.

Keywords: Breast Cancer, Sonography, Magnetic Resonance Imaging, Doppler Ultrasound, AcousticRadiation Force Impulse Imaging, Supersonic Shear Imaging.

1. SONOGRAPHY IN BREASTCANCER DIAGNOSIS

Ultrasound (US) is becoming a popular clinical diagnosis modal-ity in the past decades with the major advances in transducer,electrical circuit, digital signal processing, and system control,and has already been applied to large varieties of diseasesbecause of its uniqueness of low cost, flexibility, non-invasion,and non-ionization. US has the ability to image and evaluatepatient’s internal anatomy structure and physiology in real-timewith astounding clarity. Therefore, it makes significant contribu-tions to healthcare.

The breast examination by US started from 1951 with an opti-mistic opinion that US would replace mammography eventuallyin detecting breast cancer.1 However, with more comprehensivestudies, it illustrates that US is only valid for the discriminationbetween cysts and solid masses. The performance of US dependson the size, number, location, and properties of the lesions, theoperation skills, and the system specifications (i.e., resolution andfrequency).

The diagnosis of cysts is clinically and socially important forremarkable reduction on the number of breast biopsies and earlytherapy, particularly for those non-palpable ones. Aspiration orbiopsy is not required to simple cysts,2 which reduces the health-care cost, anxiety and discomfort of patients during with surgery.However, for palpable masses, aspiration is advocated due to itsless expense, availability at many centers, and often accompanieswith therapy, but not much desirable for many women due toits discomfort. US is the appropriate method of lesion diagnosiswith accuracy of 96–100% if it is not palpable and applicablefor aspiration.2–5 A simple cyst usually has smooth walls, sharpanterior and posterior borders, no internal echoes, and posteriorenhancement (Fig. 1). Using a gel or fluid offset and aligningthe target to the focal region with better resolution could definethe anterior wall, especially for superficial lesions. In compari-son, posterior enhancement is mostly inconsistent. The smallest

detectable cysts in the breast depends on the type, location, breastsize, and US system, and are usually 2–3 mm.4 Scanning thelesion carefully in two projections and discriminating wall irreg-ularities are useful in finding intracystic tumors.3�6 Occasion-ally, inappropriate equipment setting (i.e., time compensated gain(TCG), locations of focal point(s), or brightness), technical lim-itation (i.e., low driving frequency of transducer, inherent noisein beam forming, or poor resolution), or missing subtle changesby the operator may result in diagnostic error.

However, it is hard to judge whether a visible mass is benignor malignant in the sonography because of the similar features.Only circumscribed masses, such as a cyst, require differen-tial US diagnosis (Fig. 2). A mass with stellate or spiculatedborders as well as a circumscribed mass contains suspiciousmicro-calcifications does not require US for further evaluation.However, calcium deposition inside a cyst is easily mistaken asmicro-calcifications because of the similar granular appearance.7

Both benign and malignant breast masses may be partially orcompletely obscured by the normal tissue. When a palpable massis not visible in the mammography, US will be applied to deter-mine whether it is cystic or solid. Because all solid masses maynot be visible in the sonography even in dense breasts, the false-negative detection of breast cancer is about 25%.8 A palpablemass that is invisible in both mammography and sonographystrongly needs biopsy histology (Fig. 3).

Occasionally, diffuse mastitis does not have an appropriateresponse to antibiotics, which suggests abscess formation. There-fore, mammography may not be appropriate for pain and edemaof the breast and will not display a discrete abscess cavitywith inflammation-induced higher density. US is an alternativeapproach for diagnosing and guidance of surgical drainage ofabscesses, which have various sonographic characteristics, suchas irregular hypoechoic or anechoic cavities, occasional fluid-fluid or fluid-debris levels, posterior enhancement, distortion onsurrounding, and overlying skin thickening (Fig. 4).

J. Med. Imaging Health Inf. Vol. 3, No. 2, 2013 2156-7018/2013/3/001/014 doi:10.1166/jmihi.2013.1157 1

R E S E A R CH AR T I C L E J. Med. Imaging Health Inf. 3, 1–14, 2013

(a) (b)

(c)

Fig. 1. A palpable lesion in the left upper inner quadrant of breast shown in (a) oblique and (b) craniocaudal mammograms (arrows), and (c) a simple cystin the transverse sonogram (arrows) with smooth borders, no internal echoes, posterior enhancement, and lateral shadows from the smoothly curved walls.

US seems a more sensitive imaging modality for positive axil-lary lymph nodes in the breast cancer that is commonly involvedbut rarely evaluated than physical examination and axillary mam-mography with compression.9 The capability of metastatic nodesby US and physical examination are 72.7% and 45.4%, respec-tively, with equal specificities of these two techniques (97.3%)in a study of 60 patients.10 Furthermore, US has success in the

(a) (b)

Fig. 2. A 3-cm palpable fibroadenoma found by biopsy is shown in (a) oblique mammogram (arrows) and (b) the longitudinal sonogram as a well-outlined,slightly lobulated, and homogeneous solid mass (arrows).

guidance of fine-needle aspiration of cyst, biopsy of solid masses,preoperative needle, and wire localization.11–13

Fibroadenomas are smoothly round, oval, or lobulated lesionswith homogeneous internal echoes and posterior enhancementwhile carcinomas are irregular solid masses with internal echoesand attenuated brightness.14�15 Therefore, their US images havecertain overlaps, and accurate determination is possible with

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R E S E A R CH AR T I C L EJ. Med. Imaging Health Inf. 3, 1–14, 2013

(a) (b)

(c)

Fig. 3. False-negative (a) oblique and (b) craniocaudal mammograms with moderate density but no discrete mass and (c) the longitudinal sonogram of a4-cm palpable mass in the lower inner quadrant of the right breast, which was revealed as ductal carcinoma in biopsy.

conventional sonography.3�16–19 Ratios of the length to the antero-posterior diameter of the cancer and fibroadenomas are signifi-cantly different, and the oblong configuration in fibroadenomasis more apparent in superficial position.20

US has been implemented in screening breast cancer, par-ticularly those with dense tissue, in Japan, Europe, and Aus-tralia. However, its inability of detecting all types of breastcancers and a substantial number of non-palpable cancers whoare visible and invisible at mammography, respectively, pre-vents US being a valuable screening modality because of itsunacceptably high false-negative rate, (0.3–47% with mean of20.7%), which may be even higher for small and clinically occultcancers.21 Most importantly, US detection of a significant numberof non-palpable carcinomas with good-quality negative mammo-grams is not always satisfactory. In addition, US has a remark-able false-positive rate in asymptomatic patients because of the

Fig. 4. Longitudinal sonogram of (a) a mastitis and large area of induration that has an irregular abscess cavity with echoes and posterior enhancement, and(b) a severe mastitis with multiple small (3-9 mm) scattered abscesses (solid arrows), thick skin (open arrows), high echogenicity, structure distortion, and asharp interface between normal and abnormal tissue (curved arrow).

shadowing produced by many normal structures22 and similarsonographic features between fat lobules and solid tumors.23 USdiagnosis is unable to exclude malignancy and identify an under-lying reason for the asymmetric fibroglandular tissue, but mam-mography and physical examination.8

In summary, sonography at high quality and high frequencyused in a judicious manner is a valuable tool in the clinics. Sonog-raphy is applied to the evaluation of circumscribed lesions foundin the mammography, palpable masses invisible in the mam-mography, and a cyst is in the differential diagnosis. The needfor biopsy on a simple cyst could be eliminated after the USdiagnosis. Otherwise, a biopsy or mammographic follow-up isrequired no matter of the sonography results, in which US pro-vides not much clinically useful information and, subsequently, isnot suggested.4

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2. COMPARISON OF MAMMOGRAPH,SONOGRAPHY AND MRI

The diagnostic sonography in the breast has been investigatedfor at least 30 years.1 Sonography did not detect any provencancers that were missed by mammography. Mammography wasfound superior in detecting 97% of the 64 pathologically con-firmed cancers, while sonography can only seek 58% of them.Mammography detected more than 90% in all cancer categories,including those amenable to cure, but the value for sonographyis only 48% (40% of the non-palpable malignancies and 8% ofthe cancers smaller than 1 cm that did not yet spread to axillarylymph nodes). Tumor size and axillary lymph node status arethe most important prognostic indicators for breast cancer, andthe mammography done far outperformed sonography in detect-ing the smallest cancers and those that did not yet spread toaxillary nodes. A major factor limiting the ability of sonogra-phy for non-palpable breast cancers seems to be its inability toimage the micro-calcifications (individual particles 0.2–0.5 mm).Mammography-positive sonography-negative cancers usually aresmall, non-palpable, and have not yet spread to axillary lymphnodes, whereas very rare sonography-positive mammography-negative cancers are always detectable by physical examinationand more likely to have metastasized. Therefore, upgrading tostate-of-the-art mammography is preferred to improving the can-cer detection ability rather than purchasing an US system.24

The role of sonography in breast diagnosis is an ongoinginvestigation.25 US is a widely accepted method for discriminat-ing cysts from solid masses and guiding interventional proce-dures. Sensitivities and accuracy of the US in the discriminationbetween benign and malignant breast nodules are not highenough to reply on, and its value in comparison or addition tomammography is still in debate.26 Thus, US is not recommendedas a screening tool due to the failure in establishing its efficacy.27

US was performed to detect(1) circumscribed lesions (possible cysts),(2) palpable lesions visible in mammography,(3) palpable lesions not visible in mammography, and(4) non-palpable lesions visible in mammography in a 2-yearprospective study of 4,811 cases.

As a result, 1,103 cases (23%) were reclassified their suspicionlevels of malignancy.25

US can achieve a certain improvement in breast cancer diagno-sis as an adjunct to mammography. Although it not very dramaticfor the total cohort of patients, such an improvement was consid-erable for the subgroup of patients, especially among the youngpatients with low sensitivity of mammography. Mammographicclassification based on a relatively high threshold for biopsy pro-vides US opportunity of increasing sensitivity. If further advancesare achieved in US diagnosis, especially for diffusely growingcancers, a further acceptance of US in the breast cancer diagnosisis expected.25

Young breasts, despite low occurrence, are more sensitive toradiation so that the limited exposure is desired. US imagingis usually performed in the initial study. No further evalua-tion is necessary for a cyst. If the mass is solid or invisible insonography, at least one mammogram will be obtained to seekmicro-calcifications. Although mammography allows detection ofalmost all palpable masses, adequate positioning may not be pos-sible for very deep lesions adjacent to the chest wall or in a

slim woman with a mass at the extreme periphery of the breast.Altogether, US is not a substitute for mammography, nor does anegative sonogram rule out carcinoma.4

3. DIAGNOSIS OF MICROCALCIFICATIONThe identification of micro-calcification (i.e., smaller than0.5 mm) on mammography has been widely studied and is indis-pensable in the early detection of breast cancer.12 35–45% ofdiscovery of non-palpable breast cancers depends on the pres-ence of clusters of micro-calcification on mammography.2 Micro-calcifications are brighter reflectors than the surrounding breastparenchyma without an acoustic shadow in sonography.6 In astudy of 89 tumors found in 84 patients, micro-calcificationswere visible in 44 breast cancers using high resolution ultrasound(HRUS, 49%), 40 cancers using X-ray mammography (XRM)(45%) and 46 breast cancers on histology (53%).28 HRUS hasthe sensitivity of 95%, specificity of 87.8%, and accuracy of91% in the detection of micro-calcification. The correspondingvalues for histology are 80%, 71.4% and 75.3%, respectively.Therefore, US is a sensitive and reliable diagnosis modalityfor micro-calcification in breast cancer presented within a masslesion.28 HRUS detected micro-calcification in 6 cancers thatwere negative on XRM, among them 4 were positive on his-tology. These false positives may be due to the requirement ofsufficient deposition of calcium phosphate for the identificationof micro-calcifications for XRM but not necessary for US. Inaddition, XRM is a survey of the entire breast, whilst US istomographic and its multi-section analysis may increase detec-tion accuracy.28

Calcifications that occur within masses are more visible on US,which is partially because most malignant solid nodules providea great echogenicity. In contrast, sonography for benign calcifi-cations with many hyperechoic and heterogeneous fibers are lessreliable. Hence, malignant are more visible in the sonographythan benign calcifications. Although the sensitivity of sonogra-phy for calcifications is lower than that of mammography, sono-graphically visible calcifications within a solid mass have highpossibility of malignant.29

The different types of ductal carcinoma in situ (both comedoand non-comedo) correlate with mammographic patterns ofmicro-calcifications and the latter inconsistent foci of micro-calcifications. Malignant micro-calcifications within ductal car-cinoma in situ and microscopically invasive ductal carcinoma,which do not have associated sonographically demonstrablemasses, are difficult to identify on US.28

4. DIAGNOSIS OF LYMPH NODEMETASTASES

The presence of axillary lymph node metastases in breast canceris an important symptom in assessing prognosis and determiningthe treatment plan. Axillary staging is conventionally performedby axillary lymph node dissection. The use of sonography indetecting metastases is feasible and would reduce the number offalse-negatives at sentinel node biopsy.30

In the studies including palpable and non-palpable nodes,if the size (>5 mm) or node visibility in sonography wasused as the criterion for positivity, sensitivity varying between66.1% (95% confidence interval: 52.6–77.9%) and 72.7% (49.8–89.3%), with no heterogeneity between them, including both

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(a) (b)

(c)

Fig. 5. Extensive clustered pleomorphic micro-calcification within a large area of (a) increased soft tissue density, highly suspicious of malignancy in mam-mogram, (b) multiple bright echogenic spots (small white arrows) within a large markedly hypoechoic mass lesion in sonography, corresponding to themammographic findings of micro-calcification, and (c) infiltrative ductal carcinoma with micro-calcifications (arrows) in H&E histology with magnification of 125×.

gold standard of axillary lymph node dissection and sentinelnode biopsy. However, the variation of specificity is from 44.1%(34.3–54.3%) to 97.9% (88.7–99.9%), and heterogeneity is foundbetween the results.30 If the lymph node morphology was usedfor positivity, variations of sensitivity and specificity are frombetween 54.7% (41.7–67.2%) and 80.4% (73.9–86.2%) to 92.3%(74.9–99.1%) and 97.1% (90–99.6%), respectively. Whist in thestudies, including only non-palpable nodes, if the node size insonography (>5 mm) or its visibility was used as a criterion forpositivity, sensitivity varies from 48.8% (39.6–58%) to 87.1%(76.1–94.3%) and specificity from 55.6% (44.7–66.3%) to 97.3%(86.1–99.9%). If the node morphology was used as the crite-rion for positivity, variations of sensitivity and specificity werefrom 26.4% (15.3–40.3%) and 88.4% (82.1–93.1%) to 75.9%(56.4–89.7%) and 98.1% (90.1–99.9%), respectively. In the USguided biopsy, the sensitivity varies between 43.5% (33–54.7%)and 94.9% (88.5–98.3%) and specificity between 96.9% (91.3–99.4%) and 100% (96.2–100%), although sensitivity is reducedbecause it is necessary to visualize the node or to fulfill the sono-graphic criteria for malignancy.

Therefore, sonography is moderately sensitive and specific inthe diagnosis of axillary metastases in breast cancer. However,it cannot be used as a sole method for decision, whether to per-form axillary lymph node dissection. When suspicious metastaticaxillary nodes are found, a US guided biopsy can be performed,which increases the specificity (100% vs. 96.5% use of sonogra-phy alone) at the cost of certain aggression and extra resources.Subsequently, about half of the axillae with metastases would bedetected with a high specificity (96.5%) and a good sensitivity(48.4%), and then those positive patients would undergo axillary

lymph node dissection. The remaining negative would be can-didates for sentinel node biopsy, which improves the negativepredictive value of the sentinel node biopsy because of the lowerprevalence of metastases and thereby increases the certainty ofsonography-based diagnosis.30

5. SURVEILLANCE OF WOMEN AT HIGHFAMILIAL RISK FOR BREAST CANCER

Breast cancer susceptibility gene (BRCA) mutation carriers, whoexhibit adverse histopathologic features of biologic aggressive-ness, has a lifetime risk for up to 65–80% to develop breastcancers rather than sporadic ones.31 A comparative cohort studywas carried out to investigate the effectiveness of mammogra-phy, US, and MRI in 529 women with increased familial risk.32

Annual conventional mammography was performed with at leasttwo views (medio-lateral oblique and cranio-caudals) per breast,and additional or spot compression views where appropriate.Diagnoses were coded according to the Breast Imaging Report-ing and Data system (BI-RADS) diagnostic categories. Breastultrasound was performed with 7.5- to 13-MHz probes. Stan-dard contrast-enhanced MRI of both entire breasts was performedon a 1.5 T system after injection of 0.1 mmol/kg gadopentetatedimeglumine.

43 breast cancers were identified in the total cohort (34 inva-sive, 9 ductal carcinoma in situ). Overall sensitivity of diagnosticimaging was 93% (40 of 43); overall node-positive rate was 16%,and one interval cancer occurred (1 of 43, or 2%). In the anal-ysis by modality, sensitivity was low for mammography (33%)and US (40%) or the combination of both (49%). MRI offered

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Fig. 6. (A) Mammogram and (B) sonogram of suggestive of cancer (arrowhead) on a 53-year-old patient with a family history of breast cancer and personalhistory of benign breast biopsy on the left breast revealed no clinical findings. (C) MRI showed only scar tissue on the left (arrowhead), but revealed asuspicious lesion in the right breast (long arrow), which was an invasive ductal cancer, pT1b, G3, N0, M0 by biopsy. Absence of cancer in the left breast wasconfirmed by 4-year follow-up.

a much higher sensitivity (91%). The sensitivity of mammog-raphy in the higher-risk groups was 25%, compared to 100%for MRI. Specificity of MRI (97.2%) was equivalent to that ofmammography (96.8%).33 Mammography, either alone or com-bined with sonography, seems insufficient for diagnosis of earlybreast cancer in patients who are at increased familial risk withor without BRCA mutation. If MRI is used for surveillance, asignificantly higher sensitivity, specificity, and positive predictivevalue (PPV) could be achieved for diagnosis of intraductal andinvasive familial or hereditary cancer at a more favorable stage.33

Indeed, not even half of all cancers were prospectively diagnosedwith a combination of mammography and sonography, whereasbreast MRI alone diagnosed 91% (39 of 43). However, MRI isstill an investigational technique for surveillance and screening ofasymptomatic women with normal conventional diagnosis. Apartfrom cost, the most important reason of breast MRI is low PPV,low specificity, and allegedly low sensitivity for ductal carcinomain situ (DCIS). However, MRI has the highest sensitivity for inva-sive as well as intraductal cancers, which was not achieved at theexpense of similar specificity as that of mammography.33 Com-bined with mammography, sonography can compensate some butnot all the shortcomings of mammography with a substantialnumber of false-positive diagnoses. In comparison to surveillanceby MRI, mammography was of limited and US of no additionalvalue. US screening may, however, be useful in the long intervalbetween the annual surveillances.33

Altogether, surveillance with MRI allows an earlier diagno-sis of familial breast cancer and has better performance thanmammography or the combination of mammography with high-frequency sonography.

6. DOPPLER ULTRASOUNDThe well-known phenomenon of tumor angiogenesis is asso-ciated with an increase in malignancy.34�35 These abnormali-ties included tumor stains, irregular large caliber vessels, andeither prolonged or rapid emptying of vessels presumably dueto blood pooling, leaky vessels, and/or arterio-venous shunts.Among the established breast diagnosing techniques, mammog-raphy and sonography have undisputed contributions. However,no adequate information on the growth pattern and the prognosisof breast humps are available. Doppler US has been investigatedto differentiate benign lesion from malignant solid breast massesfrom their different Doppler characteristics, (i.e., symmetric sig-nals in normal tissue, no signals in cysts, and higher maximumsystolic and end-diastolic pressures in malignant tumors)36–38

with high sensitivity and specificity despite considerable overlapin the benign and malignant types.39�40 Highly sensitive colorDoppler on even minute tumor vessels could map the tumorblood flow both quantitatively and qualitatively.

Color Doppler in 2 of 39 malignant breast disease patientswith the tumor size of 0.6–8.0 cm (median 2.0 cm) did notshow any vascularity. In comparison, no blood vessels were

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found in 10 of 73 benign masses (0.3–4.7 cm with the medianof 1.4 cm). In patients with puerperal mastitis, abscess, phyl-loides tumor, and haemangioma, vascularization was extremelyhigh. Benign and malignant breast lesions have significantly dif-ferent Doppler US features. There is a remarkable overlap ofcarcinoma and benign tumor in peak flow velocity.41 The dis-crepancies between reported studies may be related to the USsystem and the scanning techniques.42 The accuracy for smallerblood vessels, especially for poorly vascularized masses, couldbe improved using a high-frequency and high-resolution sys-tem. Furthermore, color Doppler may also be able to reduce thenumber of biopsy and histological evaluations for patients withsuspicious mammograms.41

In another prospective study, the color Doppler flow images of55 proven breast cancers were performed, and 82% of them wereclassified on a three-level scale of vascularity (minimal: 14%,moderate: 29%, marked: 53%), suggesting its clinical potentialuse. 4% of the flow images had no detectable flow. 69% of thenormal breasts had moderate or marked vascularity (minimal:28%, moderate: 41%, marked: 28%), and 3% were avascular.Because of poor distinction between normal tissues and cancer,more sensitive Doppler methods are required for the low vesselflow that is rather specific for malignancy.

Power Doppler sonography has advantages over color Dopplertype with high sensitivity in the detection of vascular flow. PowerDoppler findings were considered positive when at least onevessel was associated with the solid breast mass (Fig. 7). Inone study comprising 176 breast cancers in 176 patients (27–91years, mean± std: 56± 15 years), 65% and 10% of the caseswere invasive ductal carcinoma and invasive lobular carcinoma,

(a) (b)

(c) (d)

Fig. 7. Patterns of tumor vascularity in breast cancer revealed by power Doppler sonography. (a) penetrating, irregularly branching prominent vessels,(b) peripheral and penetrating vessels, (c) few central vessels, and (d) no vessels.

respectively.43 Among them, 73% showed vascularity and 27%showed no vascularity on power Doppler sonography. The sizesof the lesions in which power Doppler sonography revealed ves-sels and no vessels were 7–80 (21± 15) mm and 3–55 (14±14) mm, respectively (p < 0�01); however, these two categoriesoverlapped. Tumor vascularity revealed by power Doppler sonog-raphy correlated strongly with detection of lymph node involve-ment and lymphatic vascular invasion with sensitivities of 93%and 90%, but low specificities of 32% and 35%, respectively.More importantly, patients with breast cancer in whom ves-sels were not revealed by power Doppler sonography were alsounlikely to have lymph node involvement and lymphatic vascu-lar invasion with negative predictive values of 90% and 87%,respectively.

In conclusion, Doppler US could detect moderately small ves-sels around and within tumors, even if they were too small to bedisplayed on conventional B-mode images. Although only can-cer patients were involved, the presence of similar vessels in thenormal breast indicates Doppler imaging as a technique with apresumably higher specificity but much lower sensitivity.

7. ACOUSTIC RADIATION FORCEIMPULSE IMAGING

The limitations of palpation and biopsy as well as CT, MRI,and US imaging require a noninvasive, cost-effective, safe, andaccurate modality for detecting changes in tissue pathology. Sev-eral groups have developed elasticity-based imaging modality inorder to exploit the relationship between pathology and tissue’smechanical properties.

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Acoustic radiation force is due to the momentum transfer fromthe propagation of acoustic waves to the dissipative medium.44

The absorption is in the direction of wave propagation, whereasthe reflection depends on the angular scattering properties of thetarget.45 Under plane-wave assumptions, the generated radiationforce in the tissue is.44�46

F = 2�Ic

(1)

where F is a force per unit volume, � is tissue attenuation, I isthe acoustic intensity, and c is the sound speed of tissue.

Acoustic radiation force impulse (ARFI) imaging, a novel tran-sient elastography method, generates radiation force inside thetissue, detects the consequent localized displacements by corre-lating the ultrasonic echoes, and then estimate the mechanicalproperties of target.47 All tissues are inherently viscoelastic andresponse differently to mechanical excitation, on the order of tenmicrometers, which can be monitored both spatially and tempo-rally and is inversely proportional to local tissue stiffness. Thetissue volume exposed to radiation force is determined by thefocal characteristics of the transmitting transducer, and the tem-poral profile of the force is dependent on transmitted pulse shape,usually with the duration less than 1 ms. In this method, a singlediagnostic transducer is used both to apply localized radiationforces inside the tissue and to track the resulting tissue displace-ments, which guarantees good alignment and ease of real-timeimplementation. ARFI imaging has many potential advantages,such as identifying and characterizing a wide variety of soft tis-sue lesions, atherosclerosis, plaque, and thrombosis in clinics.

There is good correlation between the ARFI image and thematched B-mode image in the breast at the depth of 5–25 mm(Fig. 8(a)). In the ARFI image, the boundary of an infectedlymph node as a palpable lesion appears stiffer than its interiorand the tissue above it (i.e., smaller displacements). The ovalstructure in the B-mode image immediately above and to the leftof the lesion (upper arrow) is outlined as a softer region of tissuethan its surroundings in the ARFI image. The transient responseto ARFI excitation depends on tissue structure and mechanicalproperties. In Figure 8(b) the region of tissue spanning 13–18 mmmoves further, and exhibits a later peak displacement than theothers, which is slightly darker in the matched B-mode image.

Fig. 8. (a) ARFI image of tissue displacement at 0.8 ms (right), and matched B-mode image (left) in an in vivo female breast. The transducer is located atthe top of the images, and the colorbar scale is microns. (b) Displacement through time at different depths in the center of the ARFI image (0 mm laterally).

Peak displacements of ARFI images range from 5 to 13 �min vivo, and the lesion in the B-mode image exhibits a stiffouter boundary and a softer interior in the matched ARFI image(Fig. 9). Core biopsy of this lesion demonstrated an infectedlymph node with a more liquid abscessed component. Whilethese findings are circumstantial, they do suggest potential cor-relation between the clinical pathology and the ARFI image.The discrepancy of the brightness in the B-mode image anddetected stiffness indicates no direct relationship between themas expected.

There is no speckle in the ARFI images. Thus, the tradition-ally defined speckle SNR of a conventional US imaging systemis in general lower than that of the ARFI imaging system. Com-parison of the contrast of the ARFI and B-mode images yieldsvariable results. The applied radiation force and resulting tissuedisplacements are predominantly in the direction of wave propa-gation. With the current imaging geometry, only these axial dis-placements are tracked, and the anticipated error is ±0.14 �m.48

While useful information might be derived from the lateral dis-placement, tracking of such small lateral displacements (<1 �m)is extremely challenging. The increase in displacement estima-tion error with depth rather than the decreased SNR does notdegrade image quality.49 The resolution of an ARFI imaging sys-tem depends on transducer specifications and configuration, thenumber and location of pushing beam, spatial relationship ofpushing locations and tracking beams, and the pulse length andkernel size in the tracking algorithm as well as the tissue prop-erty itself, and is at least comparable to that in the conventionalB-mode imaging.

The acoustic energy required to generate detectable displace-ments in vivo is large (<1,000 W/cm2 in situ), but its duration isshort (0.7 ms in each pushing location). So the radiation force-induced displacement in soft tissue is detectable while main-taining a temperature increase below 1 �C.50�51 Altogether, theoperating parameters of ARFI imaging are safe, and will notresult in an increased risk to the patient.

In summary, ARFI imaging is feasible in vivo for the diag-nosis of breast. Differences in displacement maps are correlatedwith tissue structure as observed in the matched B-mode images.The transient response of tissue varied with tissue type and its

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Fig. 9. ARFI images at times of (a) 0.4 ms, (b) 1.2 ms, (c) 2.1 ms, and (d) 3.0 ms in the in vivo female breast (the same dataset as shown in Fig. 8).

visco-elastic behavior. Although these findings are preliminary,they present several opportunities for ARFI imaging with a con-siderable clinical promise.

8. SUPERSONIC SHEAR IMAGINGSupersonic shear imaging (SSI) is another transient elastogra-phy approach and combines the remote palpation of the ARFItechnique and the ultrafast echographic imaging approach, whichprovides a quantitative elasticity map with less dependence onoperator in comparison to static elastography.52�53 The initial

Fig. 10. Generation of a conical shear wave front propagating in the imag-ing plane of the echographic probe.

clinical investigation illustrates its potential as an adjunct forsonography.

SSI generates a remote radiation force by focused ultrasonicbeams as ARFI. Consequently, a transient shear wave will beformed by the remote tissue vibration. Several pushing beamsat increasing depths are transmitted to generate a quasi-planeshear wave front that propagates throughout the region-of-interest(Fig. 10). After that, successive raw radiofrequency (RF) datais acquired at an ultrafast frame rate (2,000 frames/s). Contraryto conventional sonography formed using line-by-line scanning,ultrafast echoic images are achieved by transmitting a singlequasi-plane ultrasonic wave which has slight diffraction along thetransducer elevation direction and then performing the imagingprocess (i.e., beam forming, array signal processing) only in thereceiving mode. Because of the memory limit, only 128 succes-sive ultrafast echoic images can be stored at a total duration of30 ms.54�55

3 successive SSI sequences were performed to locate the lesion(Fig. 11). The first SSI sequence was performed using pushing

Fig. 11. Protocol of quantitative elastography for a lesion located in thecenter using the SSI method. Three SSI sequences are performed. The firstSSI sequence corresponds to a pushing line along the central line of theultrasound image. The second and third SSI sequences correspond to twosuccessive pushing lines located on the right and left edges of the image.These three pushing modes enable the final recovery of a quantitative elas-ticity map over the entire ultrasound region.

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Fig. 12. Comparison between the B-mode ultrasound and the elasticity image obtained in the SSI with colorbar presenting the shear wave speed (0–9 m/s,E = 0–240 kPa) with the delineation between soft fatty tissues (∼7 kPa) and breast parenchyma (∼30 kPa) in normal breast tissue.

beams centered along the central line, which allowed elasticityimaging on both left and right parts. Then, the second and thirdSSI sequences were performed with a left and a right pushingline, respectively, and allow elasticity imaging in the middle ofthe imaging plane.

In the initial clinical trial, a total of 15 lesions were assessedquantitatively for its elasticity at an image window of 38×44 mm2. The elasticity map displays the local shear wave speedcs on a color scale ranging from 0–9 m/s with the correspondingYoung’s Modulus, E = 3�c2s , ranging from 0–240 kPa. Elastic-ity maps exhibit good concord with the spatial heterogeneitiesand structures in normal breast tissue and provide quantitativehighlighting for benign and malignant lesions. In general, benignsolid and malignant lesions in that study had a mean Young’smodulus of 45–80 kPa and 100 kPa (in some cases >180 kPa),

Fig. 13. Comparison between B-mode ultrasound and quantitative elasticity map in the SSI mode for infiltrating ductal carcinoma grade III. Hypoechoic lesionwith indistinct margins, slightly posterior shadowing classified as BI-RADS category 5.

respectively. It is known, however, that some cancers such as themucinous subtype can be rather soft, and some mature fibroade-nomas can be extremely stiff.

8.1. Normal Breast TissueThe quantitative elasticity in normal breast tissue clearly delin-eated the different structures of breast. Young’s modulus rangedbetween 3 kPa for fatty tissues to 45 kPa in the parenchyma.Figure 12 compares the US gray scale and Young’s modulusimage, which presents a fibrous mass (benign lesion correspond-ing to a fibrocystic disease). The Young’s modulus is easilyrecovered in the normal breast tissue areas. There is nice delin-eation between fatty tissue (∼7 kPa) and breast parenchyma(∼40–50 kPa) on both the US grayscale and elasticity images.These characteristic values were found in all healthy patients.55

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Fig. 14. Comparison between B-mode ultrasound and quantitative elasticity map in the SSI for small (5-mm diameter) hypoechoic lesion classified as BI-RADScategory 5, which is difficult to detect on B-mode ultrasound. The elasticity map clearly delineates a small and stiff region (∼165 kPa), which was confirmedby biopsy exam as an infiltrating ductal carcinoma grade III.

8.2. Malignant LesionsA typical example of a BI-RADS category 5 lesion and its cor-responding elasticity map is shown in Figure 13. The B-modeUS depicted a 10-mm hypoechoic mass with indistinct marginsand posterior shadowing, which strongly indicates a high suspi-cion of malignancy and is confirmed in the pathologic diagnosisas an infiltrating ductal adenocarcinoma (grade III with a highmitotic activity). SSI clearly exhibits higher stiffness of the lesionwith mean elasticity value of 150–175 kPa and better delineationof the lesion margins than B-mode US images. The lesion sizemeasured on the elasticity map was confirmed by the pathologicanalysis (8× 10 mm). In addition, the Young’s modulus imagein the SSI enables a satisfactory discrimination between fatty tis-sues (∼5 kPa), breast parenchyma (∼40 kPa), and lesion location(∼170 kPa) in the resolution of roughly 1.5 mm.

The potential ability of the SSI for the guided percuta-neous procedures (core biopsies or fine needle aspirations) with

Fig. 15. Comparison between B-mode ultrasound and quantitative elasticity map in the SSI for hypoechoic, homogeneous, lobular-shaped lesion classified asBI-RADS category 4, which was diagnosed as fibrocystic disease by biopsy and has comparable elasticity with the surrounding healthy tissues (E :12–27 kPa).

clinically satisfactory location precision was illustrated inFigure 14 for a small, slightly hypoechoic nodular lesion withindistinct contours measuring 5 mm, which was classified asBIRADS category 4. This lesion is rather difficult to discrim-inate on B-mode US because of its low echogenicity contrastin comparison to the normal parenchyma after local anesthesia,thus necessitating multiple sampling. In comparison, the elastic-ity map clearly delineates a small and stiff region (∼165 kPa)and properly depicted margins with an average 5 mm diameter.This lesion size was confirmed after biopsy by the pathologist.

8.3. Benign Solid LesionsSSI was also able to detect benign solid lesions such as fibroade-nomas or fibrocystic disease changes. In all cases, these lesionswere detected on the elasticity mapping as rather soft struc-tures with mean Young’s modulus <80 kPa for, whereas malig-nant lesions exhibited mean elasticity >100 kPa. A hypoechoic,

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(a)

(b)

Fig. 16. Comparison between B-mode image and quantitative elasticity map in the SSI of (a) hypoechoic lesions with lobulated margins, discretely reinforcingultrasound beam, classified as BI-RADS category 4, which was diagnosed as a cyst containing inflammatory cells and debris in fine-needle aspiration, and(b) another patient with a benign cyst nodule.

homogenous, lobular-shaped lesion classified as BI-RADS cat-egory 4 can be observed in Figure 15. SSI describes struc-tures with different elasticity in good concord with the structuresdepicted in the B-mode image, but comparable elasticity with thesurrounding healthy tissues (E:8–15 kPa). Biopsy was performedunder US guidance and led to a histologic diagnosis in favor offibrocystic disease.

8.4. Benign CystsSSI was also useful in the diagnosis of cystic lesions.Figure 16(a) corresponds to hypoechoic lesions with lobulatedmargins and a discretely reinforced US beam, which was clas-sified as BI-RADS category 4. Fine-needle aspiration was per-formed under US guidance, and a yellow-colored liquid wasevacuated, which led to a histologic examination as a cyst con-taining inflammatory cells and debris. The SSI elasticity mapprovided local Young’s modulus in healthy surrounding tissuesexcept in the lesion, which is consistent with the fact that shearwaves do not propagate in liquids. All data corresponding to non-propagating shear waves are intrinsically filtered by the imag-ing post processing algorithm. Two reasons for this filtering canbe evoked. First, the strong acoustic streaming induced in the

liquid can lead to a de-correlation of the successive US data.Second, the strong modification of the shear displacement versusthe propagation direction yields to a de-correlation of shear dis-placement time profiles at neighboring locations, resulting in afalse time-of-flight estimation. This de-correlation can be in bothcases filtered, leading to an absence of Young’s modulus esti-mation in the liquid. Figure 16(b) corresponds to another moreclearly hypo-echoic cystic lesion which is identified as a liquidarea surrounded by soft tissues in the SSI.

In summary, quantitative mapping of breast tissue elasticity isfeasible in vivo using the SSI approach. Discrimination betweenbreast fat and parenchyma and identification of malignant lesion,benign solid lesion, cystic lesions are feasible, reliable, andclearly visible. This novel imaging modality is significantly lessoperator dependent than static elastography as the mechanicalexcitation that interrogates breast tissues is induced by the sys-tem itself. It could have a potential in clinics for breast lesiondiagnosis.

9. CONCLUSIONHigh-frequency high-quality sonography system has significanttechnical improvements with high resolution, great contrast, large

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dynamic range, less speckle noise, high frame rate, and multi-ple ultrasound imaging modality (i.e., color Doppler and real-time three-dimensional scanning) in the past decades. Althoughdigital signal/image processing techniques aided the automatedtumor/cancer detection and enhanced the outcome, the supe-riority of state-of-the-art mammography over sonography hasbeen shown in a variety of clinical studies. However, in thedetection and diagnosis of benign lesions, for example, a dis-tinction between cystic and solid masses, mammography is notnecessarily the preeminent examination, and sonography is theuseful procedure of choice. Meanwhile, development of novelultrasound-based elastography, especially the transient type thatgenerates remote pushing force to the target, enables the detec-tion of the mechanical properties of tissue, which has highersensitivity, specificity and contrast than the conventional B-modeultrasound images. Although the preliminary results are verypromising, its role in breast cancer diagnosis will be carried outin multiple and randomized clinic centers and then be comparedwith mammography for performance evaluation.

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Received: 10 December 2012. Revised/Accepted: 12 January 2013.

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