breast ultrasound has become a standard breast - imaging procedure in addition to mammography , for work - up of patients referred with a palpable mass or with a suspicious lesion detected on the mammogram .
gray - scale breast ultrasound offers the ability to visualize the breast tumor in three dimensions and permits direct measurement of tumor size without magnification . to standardize lesion characterization on ultrasound ,
the american college of radiology ( acr ) developed a lexicon of sonographic descriptors of breast masses with attendant assessment categories , i.e. the sonographic breast imaging reporting and data system ( bi - rads ) lexicon .
technologic advances over the last decade have fueled research in the field of minimal - invasive image - guided ablation techniques for treatment of patients with limited - stage breast cancer .
techniques that have been studied include radiofrequency ablation , cryoablation , focused ultrasound and laser ablation of breast tumors .
different imaging modalities are used to guide the instruments , to monitor the therapeutic procedure and to assess treatment response . of all imaging modalities ,
gray - scale breast ultrasound is most often used for breast tumor visualization and real time monitoring of the ablation process .
accurate assessment of breast tumor size is important for planning surgical and minimal - invasive image - guided ablation procedures .
extensive surgical treatment may result in poor cosmetic results , whereas small tumor - free margins may influence the local recurrence rate46 .
several previous studies have assessed the accuracy of gray - scale ultrasound for breast tumor size measurement .
overall , these studies concluded that gray - scale ultrasound of the breast is a reliable method for determining tumor size and favors mammography , but in general true tumor size is underestimated with this technique . in recent years , ultrasound contrast agents have been developed that increase blood echogenicity and improve ultrasound image quality by detection of slow and low - volume blood flow in small tumor vessels ( < 5  mm ) .
contrast - enhanced ultrasound ( ceus ) of the breast has recently been studied for characterization of indeterminate breast lesions .
since breast tumors are strongly vascularized and display neo - angiogenesis in the vital border , it is hypothesized that ceus of the breast may also be a more accurate modality than gray - scale ultrasound for delineation of breast tumor boundaries and tumor size assessment .
this prospective feasibility study was designed to assess the accuracy of ceus of the breast for pre - operative tumor size measurement in patients diagnosed with invasive ductal carcinoma of the breast .
seven consecutive female patients , 49 years of age ( range 4257 years ) , with 9 breast lesions were prospectively included in this study .
all patients were referred to our department for ultrasound examination and ultrasound ( us)-guided large - core needle biopsy of a suspicious breast lesion ( bi - rads iv and v ) detected on mammography between june 2005 and june 2006 .
the diagnosis of invasive ductal breast cancer was confirmed in all patients by us - guided large - core needle biopsy ( 14 gage ) .
eligible patients for pre - operative tumor size measurement with contrast - enhanced ultrasound ( ceus ) of the breast had no history of previous breast surgery .
patients were excluded if use of the ultrasound contrast agent ( sonovue , bracco spa , milan , italy ) was contra - indicated , due to a history of cardiac failure , right to left shunt , severe pulmonary hypertension , uncontrolled systemic hypertension , adult respiratory disorders and hypersensitivity .
written informed consent was obtained from all patients and the study was performed in accordance with a protocol approved by our institutional panel .
all eligible patients prospectively underwent both gray - scale ultrasound and ceus of the breast according to a standardized protocol .
high - frequency gray - scale ultrasound examination of the breast was performed first with a philips iu22 scanner ( philips medical systems , best , the netherlands ) equipped with a 11  mhz linear array transducer .
breast lesion morphology was scored according to the sonographic bi - rads lexicon criteria and classified accordingly .
tumors size ( expressed in millimeters ) was documented in three dimensions ( length , width , and height ) . for measurements ,
the tumor edge was defined as the end of the hypoechoic mass before the hyperechoic transition border ( so called 
1 ) . the maximum dimension on gray - scale ultrasound was finally compared with the maximum histopathologic tumor size .
nonlinear harmonic imaging using a philips iu22 scanner ( philips medical systems , best , the netherlands ) equipped with a 48  mhz linear array transducer was performed at baseline with a low mechanical index of 0.1 , chosen to avoid gas bubble destruction .
a suspension of sulfur hexafluoride ( sf6 ) microbubbles was obtained by adding 5  ml saline ( 0.9% sodium chloride ) to 25  mg of the powder , followed by hand agitation .
we used a single dose of 2.4  ml sonovue as contrast agent ( sf6 volume in a 2.4  ml dose in 0.02  ml ) , which was intravenously administrated via a 20 gauge canula placed in an arm vein followed by a flushing of 10  ml standard saline .
directly after sonovue administration the microcirculation was studied by recording with clip function for 60  s , without chancing the transducer .
qlab software ( philips medical system , best , the netherlands ) was used to quantify enhancement on the ceus images in time . by using the region of interest quantification method
when enhancement was at peak level ( around 10  s ) breast tumor size was recorded and measured again in three dimensions . for the measurements ,
the tumor edge was defined as the end of the hyperechoic mass at the time of maximal contrast enhancement of the lesion ( fig .
the maximum dimension of the tumor on ceus of the breast was finally compared with the maximum histopathologic tumor size .
both gray - scale and ceus breast ultrasound examination were performed by the same experienced breast radiologist in all cases .
histologic sections of the resected tumors after hematoxylin and eosin ( h&e ) staining were examined under a light microscope and used for measurement of histopathologic tumor size in millimeters in three dimensions .
margin status was recorded as involved or not involved . for those patients who underwent re - excision for tumor - involved margins , the extent of invasive ductal carcinoma in the re - excision specimen was recorded . to assess the difference between the three methods of tumor size measurement
the greatest lesion diameters ( mm ) obtained by gray - scale breast ultrasound and ceus of the breast were compared with the greatest lesion diameter ( mm ) on pathology .
tumor size measured in greatest dimension was compared between the groups by using student t - test analysis ( p<0.05 ) .
furthermore , the percentage greatest tumor diameter as assessed by gray - scale ultrasound and ceus was within 2  mm of pathologic tumor size , which is considered accurate .
the percentage of over- and underestimated tumor size for each modality was calculated using fisher 's exact test , with a p - value < 0.05 considered to be significant .
the mean patient age in this study was 49 years ( range 4257 years ) .
two patients presented with two breast lesions in the same quadrant ( multifocal disease ) , and the remaining five patients presented with a solitary breast lesion .
the sonographic characteristics of the lesions according to the sonographic bi - rads criteria are presented in table 1 .
definitive diagnosis on pathology was invasive ductal carcinoma in all cases , with an additional ductal carcinoma in situ ( dcis ) component in two cases .
gray - scale ultrasound of the breast showed a mean greatest tumor diameter of 15.5  mm ( range 10.120.6  mm ) , compared to 16.5  mm ( range 11.518.5  mm ) in the ceus group .
mean greatest histopathologic tumor diameter was 15.6  mm ( range 9.025.0  mm ) .
table 2 shows the greatest tumor diameter as measured with each modality compared to pathologic tumor size .
mean greatest tumor diameter as assessed with both ultrasound techniques did not significantly differ ( p  =  0.23 ) . however , gray - scale ultrasound underestimated tumor size in 6/9 ( 67% ) cases , whereas ceus of the breast underestimated tumor size only in 3/9 ( 33% ) cases .
tumor as measured with gray - scale ultrasound of the breast was within 2  mm of the pathologic tumor size in only 2/9 cases ( 22% ) , whereas ceus of the breast accurately assessed tumor size within 2  mm of pathologic tumor size in 6/9 ( 67% ) of the cases ( p  <  0.05 ) .
margin status was recorded as not involved in all nine cases ; none of the patients underwent re - excision .
to our knowledge this is the first study to assess the accuracy of ceus for pre - operative size assessment of invasive ductal carcinomas of the breast . in this prospective feasibility study ceus of the breast
ceus of the breast was significantly more accurate than gray - scale ultrasound of the breast for tumor size measurement .
the maximal tumor diameter as assessed by ceus of the breast was within 2  mm of pathologic tumor size in 67% of cases , compared with 22% in the gray - scale ultrasound group ( p  <  0.05 ) .
the ability to accurately and reliably measure breast tumor size prior to any surgical treatment or primary medical treatment is essential . as a consequence previous research focused on different methods enabling non - invasive tumor size measurements , including clinical examination ( palpation ) , mammography , gray - scale ultrasound , and magnetic resonance imaging ( mri ) of the breast . of these methods palpation proved to have the lowest accuracy , because it is influenced by skin thickening , breast edema , and obesity , and is prone to overestimation of tumor size .
mammography proved to be more accurate than palpation , however it is taken in two standard projections ( cranio - caudal and medio - lateral - oblique ) not necessarily expressing the largest dimension of the tumor . as a consequence ,
although all studies showed significant correlation between mammographic and gray - scale ultrasound measurements , the latter technique is considered the most accurate for breast tumor size measurement .
previous studies that compared maximum breast tumor size as measured with gray - scale ultrasound of the breast to tumor size on pathology , reported correlation coefficients in the range of 4084% .
however , all concluded that gray - scale ultrasound of the breast still underestimates tumor size in more than half of the patients .
mri of the breast has been reported to be the most accurate imaging modality for non - invasive tumor size assessment . in a prospective study including 111 women with 177 breast lesions , mri was reported to have an accuracy of 85% for evaluation of disease extent . since , breast mri is expensive , time - consuming and still not available in every institute , we wanted to tackle the problem of tumor size underestimation rate on gray - scale ultrasound , by using contrast - enhanced ultrasound of the breast for tumor size measurement .
ceus of the breast is performed with the second generation contrast agent sonovue , which is made of microbubbles stabilized by phospholipids and containing the inert gas , sf6 .
the microbubbles have a high reflectivity and are not extravasated from the vessel lumen , and as a consequence act like true blood pool agents .
the effective vessel diameter from which an echo can be detected is in the range of a capillary .
it has been postulated that this technique reliably visualizes the neovascularization within and around the tumor , and can potentially be used for tumor boundary identification and lesion characterization .
several studies have proven the potential of ceus of the breast in differentiating malignant from benign breast lesions , with varying sensitivities ( 6795% ) and specificities ( 5882% ) depending on the patient population being studied , the type of equipment , and the criteria used for interpretation of the ceus images . to date , no studies have been performed evaluating the accuracy of ceus of the breast for size measurement of malignant breast tumors .
our study results showed that both gray - scale ultrasound and ceus of the breast underestimated tumor size .
gray - scale ultrasound of the breast underestimated tumor size in 6/9 ( 67% ) cases , which is in agreement with previous literature .
however , ceus of the breast underestimated tumor size only in 3/9 ( 33% ) of cases .
although the numbers in this study are small , a trend towards lower tumor size underestimation rate with ceus of the breast was found .
more important , the accuracy of ceus of the breast for determining tumor size within 2  mm of pathologic tumor size was 6/9 ( 67% ) , compared with 2/9 ( 22% ) for gray - scale ultrasound .
this implies that ceus of the breast is a more accurate technique than gray - scale ultrasound of the breast for breast tumor lesion size measurement .
a possible limitation of the study is the small number of patients included ; as a consequence a well - founded statistical analysis and firm conclusions can not be made .
furthermore , subgroup analysis reporting accuracy of tumor size assessment for different tumor subtypes could not be made .
second , it is known that ultrasound examination is operator dependent ; both the quality of ultrasound and the accuracy of tumor size estimation may depend on the clinician 's experience . since ,
in our study all the ultrasound measurements were performed by the same breast imaging radiologist , no inter- and intra - observer bias of ceus for lesion size measurement could be calculated .
third , whether to include the echogenic interface ( halo ) around the hypoechoic lesion for measurement purposes on gray - scale breast ultrasound examination is still a matter of debate in the current literature . in our study
the halo was not included for tumor size measurement , which is in agreement with most other previous studies . finally , currently no standard with regard to lesion size measurement on ceus of the breast exists . because it is a novel breast imaging modality ,
it is only rationally assumed that lesion size should be measured at the time of maximal contrast enhancement of the lesion , and that edges are defined as the end of the hyperechoic mass at that time . as a consequence ,
this feasibility study proves that ceus of the breast is a feasible and safe technique for breast tumor size measurement . in this small group of patients with invasive ductal carcinoma of the breast we showed that ceus of the breast was more accurate than gray - scale ultrasound of the breast for tumor size assessment
the maximal tumor diameter as assessed by ceus of the breast was within 2  mm of pathologic tumor size in 67% of cases , compared with 22% in the gray - scale ultrasound group .
gray - scale ultrasound image of an irregular , not parallel oriented , spiculated breast lesion , classified as bi - rads v in the upper outer quadrant of the left breast . for measurements ( see lines ) , the tumor edge was defined as the end of the hypoechoic mass before the hyperechoic transition border ( so - called  echogenic interface ) between tumor and healthy surrounding tissue .
image of the same lesions with ceus of the breast , lesion has become more hyperechoic due to centripetal contrast enhancement . for measurements ( see lines )
the tumor edge was defined as the end of the hyperechoic mass at time of maximal contrast enhancement of the lesion .
baseline characteristics of 10 breast tumors according to sonographic bi - rads lexicon criteria   combined pattern implied both posterior acoustic shadowing and enhancement .
 abstractour aim was to assess the feasibility and accuracy of contrast - enhanced ultrasound ( ceus ) of the breast with sonovue microbubbles for pre - operative size measurement of invasive breast carcinomas . 
 seven patients diagnosed with nine invasive breast carcinomas prospectively underwent gray - scale ultrasound and ceus of the breast according to a standardized protocol . 
 ceus of the breast was performed by a philips iu22 scanner equipped with a 48  mhz linear array transducer . 
 we used a single dose of 2.4  ml sonovue as contrast agent . 
 breast lesion morphology was scored according to the sonographic bi - rads lexicon criteria and classified accordingly . 
 the greatest tumor dimensions on gray - scale ultrasound and ceus of the breast were finally compared with the greatest histopathologic tumor sizes . 
 gray - scale ultrasound underestimated the histopathologic tumor size in 6/9 cases ( 67% ) , whereas ceus of the breast underestimated tumor size in only 3/9 ( 33% ) cases . 
 ceus of the breast was significantly more accurate for tumor size assessment . 
 greatest tumor dimension as measured with gray - scale ultrasound of the breast was within 2  mm of the pathologic tumor size in only 2/9 cases ( 22% ) , whereas ceus of the breast accurately assessed tumor size within 2  mm of pathologic tumor size in 6/9 ( 67% ) of the cases ( p<0.05 ) . 
 ceus of the breast proved to be a feasible and safe procedure . 
 it is more accurate than gray - scale ultrasound of the breast for pre - operative size assessment of invasive ductal breast carcinomas . 