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Review Article bersichtsarbeit

Breast Care 2010;5:109114 Published online: April 9, 2010

DOI: 10.1159/000297775

Prof. Dr. med. Helmut MadjarFachbereichsleiter GynkologieStiftung Deutsche Klinik fr Diagnostik GmbHAukammallee 33, 65191 Wiesbaden, GermanyTel. +49 611 577-612, Fax -580madjar.gyn@dkd-wiesbaden.de

2010 S. Karger GmbH, Freiburg

Accessible online at:www.karger.com/brc

Fax +49 761 4 52 07 14Information@Karger.dewww.karger.com

BreastCare

Role of Breast Ultrasound for the Detection and

Differentiation of Breast Lesions

Helmut Madjar

Fachbereich Gynkologie, Stiftung Deutsche Klinik fr Diagnostik, Wiesbaden, Germany

Schlsselwrter

Mammakarzinom Screening Risikofaktor Brustparenchym, dichtes Ultraschall

ZusammenfassungDie Diagnostik des Mammakarzinoms hat durch die Ent-wicklung der modernen, hochauflsenden Mammasono-grafie bedeutende Fortschritte erzielt. Ursprnglich nurzur Differenzierung zwischen zystischen und solidenRaumforderungen eingesetzt, dient der Ultraschall mitt-lerweile zur Verbesserung der Differenzialdiagnostik zwi-schen gutartigen und bsartigen Tumoren, zum propera-tiven lokalen Staging und zur interventionellen Diagnos-

tik. Bei jungen Frauen und dichtem Brustparenchym weistdie Mammografie eine erhebliche diagnostische Lckeauf. Auerdem haben Frauen mit dichtem Parenchym eindeutlich erhhtes Krebserkrankungsrisiko. Ultraschall eig-net sich sehr gut, um dichtes Brustgewebe zu untersu-chen. Mehrere Studien zeigen, dass die hochauflsendeSonografie bei diesen Frauen zustzlich 34 Karzinomepro 1000 Frauen mit unaufflligem klinischen und mam-mografischen Befund entdecken kann. Die Stadienvertei-lung ist dabei hnlich gnstig wie bei der mammografi-schen Frherkennung. In der kurativen Diagnostik wirdder Ultraschall hufig eingesetzt, um die diagnostischenProbleme der Mammografie zu kompensieren. Im Rah-men des bundesweiten Mammografiescreenings wird dieBrustdichte aber bislang nicht bercksichtigt. Der Ultra-schall kommt nur zum Einsatz, wenn mammografisch einverdchtiger Befund vorliegt. Interessanterweise wurde insterreich vor 2 Jahren ein Screeningprojekt begonnen,in dem bei mammografisch dichter Brust Ultraschall ein-gesetzt wird. Die vorlufigen Auswertungen zeigen eineSteigerung der Karzinomerkennung in derselben Gren-ordnung wie in den frheren Studien. Daher ist eine Ver-besserung der Brustkrebsdiagnostik durch die systemati-

sche Anwendung der Ultraschalldiagnostik zu erwarten.

Key Words

Breast cancer Screening Risk factor Dense breast Ultrasound

SummaryDiagnosis of breast cancer has been widely improvedsince the development of high-resolution ultrasoundequipment. In the past, ultrasound was only considereduseful for the diagnosis of cysts. Meanwhile, it improvesthe differential diagnosis of benign and malignant le-sions, local preoperative staging and guided interven-tional diagnosis. In dense breasts, mammography haslimited sensitivity. Furthermore, women with dense pa-

renchyma have a highly increased risk of breast cancerdevelopment. Ultrasound is useful to examine densebreast tissue. Recent studies have shown that the detec-tion of small cancers with high-resolution ultrasound isincreased by 34 cancers per 1,000 women without clini-cal or mammographic abnormalities. Furthermore, stagedistribution is similar between mammographically andsonographically detected carcinomas. Ultrasound is rou-tinely used for curative diagnosis, to overcome the limi-tations of mammography. However, within the mammo-graphic screening in Germany, breast density is not con-sidered as important. Ultrasound is only used if a suspi-cious lesion is detected by mammography. Interestingly,2 years ago, a screening project started in Austria inwhich ultrasound is always added in cases of densebreasts. Preliminary data show that the detection of ad-ditional carcinomas is increased in the same order asshown in previous studies. Therefore, an improved can-cer detection and differentiation can be expected withhigh-resolution ultrasound.

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110 Breast Care 2010;5:109114 Madjar

breast density is not even recognized as a predictor for poormammographic detection and high breast cancer risk. There-fore, mammographic density is often not reported on screen-ing mammograms.

Methods

The goal of this paper is to discuss the current role and potential futureaspects of ultrasound in a curative setting for tumor differentiation and inscreening. Therefore, a systematic search of the literature over the last10 years was performed. Key words were: breast neoplasms, diagnosis,screening, mammography and ultrasound or sonography or ultrasono-graphy. The papers were selected according to equipment quality, inves-tigator experience, relevant number of cases and quality of the studyprotocol.

Results

Curative Diagnosis

The role of breast ultrasound for improved differential diag-nosis was investigated over a period of more than 20 years,but case numbers of most studies were small, equipment qual-ity was variable and the diagnostic criteria for lesion descrip-tions were not standardized. The first large study including750 patients and using modern high-resolution ultrasoundequipment and standardized diagnostic criteria was publishedby Stavros et al. [4]. In 625 benign and 125 malignant lesions,ultrasound differentiated malignant from benign lesions witha sensitivity of 98.4% and a negative predictive value of

99.5%. These results were verified in later studies [13, 14]. Asa result of these promising findings, the ACR formed an inter-national expert working group in order to evaluate the role ofbreast ultrasound and to develop standardized diagnostic cri-teria. In 2003, the ultrasound breast imaging report and datasystem (BI-RADS) catalogue was published [15]. Based onthis classification system of breast lesions, many studies haveproven its usefulness [16]. A slight modification in the diag-nostic criteria was published in 2006 by a DEGUM (DeutscheGesellschaft fr Ultraschall in der Medizin e.V.) workinggroup together with the German-speaking ultrasound socie-

ties GUM (sterreichische Gesellschaft fr Ultraschall inder Medizin) and SGUMB (Schweizerische Gesellschaft frUltraschall in der Medizin und Biologie) [17].

The published data show improved differential diagnosis ofbreast lesions by ultrasound in addition to mammography(table 1). The sensitivity for cancer diagnosis increases by 1020% with ultrasound in comparison to mammography alone.However, the specificity is more variable [4, 14, 1820]. Insome of the studies, data analysis was stratified by age andshowed an inverse correlation between age and accuracy ofultrasound vs. mammography. However, comparisons are dif-ficult as these data are based on retrospective analysis and

study protocols were not uniform. But all studies demonstrate

Introduction

The value of ultrasound for breast cancer diagnosis has been acontroversial topic for many years. Depending on equipmentstandards, clinical objectives and skills of medical profession-als with different specializations, the interpretation of its roleis variable. First experimental ultrasound examinations of thebreast started 60 years ago, and it took about 30 years untiltechnological development and acceptance by clinicians madeit useful for clinical routine diagnosis. In the early studies, theuse of ultrasound was limited to the differentiation of pal-pable cysts from solid lesions [1]. The development of modernequipment in the past 15 years has allowed for accurate detec-tion and differential diagnosis of small lesions [2, 3]. In theongoing debate about the use of ultrasound, Stavros et al.published the first large study with modern high-resolutionbreast ultrasound, using standardized diagnostic criteria forlesion differentiation [4]. At the same time, other groups

started to evaluate the advantages of ultrasound in patientswith dense breasts for the detection of non-palpable andmammographically occult lesions [57].

Breast Cancer Detection

The value of early breast cancer detection by mammographyhas been demonstrated by a number of randomized screeningstudies in different countries from 1960 to the 1990s. All thesestudies were performed with mammography alone or in com-bination with palpation. In the last 10 years, ultrasound hasbeen employed as an adjunct to mammography whenever sus-picious lesions were detected, in order to better characterize

lesions and to decide whether an ultrasound-guided interven-tional procedure can be performed to confirm the diagnosis.This was established in the first edition of the German S3guidelines for early detection of breast cancer in 2003 [8].

Apart from screening, ultrasound is widely used in dailypractice in order to improve lesion detection and characteri-zation. Several large studies have proven the possible role ofultrasound for cancer detection and differentiation [47, 9,10]. However, despite the fact that mammography can onlydetect approximately 75% of the prevalent cancers, ultra-sound has never been implemented into regular screening tri-

als in order to improve cancer detection. Several studies haveshown that detection of breast cancer with mammography islimited in young women and in menopausal women withdense breast tissue [11, 12]. Furthermore, the risk of breastcancer development is highly increased in these patients. Astudy of more than 200,000 women showed that the breastcancer risk is 5 times increased in case of dense breasts com-pared to women with involutional changes [12]. Our own ob-servations show that dense breast tissue (American College ofRadiology (ACR) 34) is found in about 30% of the meno-pausal patients. In a clinical setting with curative diagnosis,these patients would routinely receive an additional ultra-

sound examination. However, in most screening programs,

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Breast Care 2010;5:109114Role of Breast Ultrasound 111

would have directed to wrong surgical decisions, occurred in33% of the mammograms and only in 3% of the ultrasoundexaminations [25].

Similar results were found at the same time with contrast-enhanced magnetic resonance imaging (MRI) with a high sen-sitivity for the detection of occult carcinomas [26]. However,disadvantages are the relatively low specificity, low cost effec-

tiveness, the need for injection of contrast agents, difficultlocalization of MRI-detected lesions, and preoperative inter-ventional assessment. Similar results were also obtained byother studies using ultrasound or ultrasound in combinationwith MRI, with a detection of additional malignant foci in2734% of breasts not seen after mammography [20, 2730].Dynamic MRI is superior to mammography and slightly supe-rior to ultrasound. However, in our own experience, second-look ultrasound after positive MRI detects many of themasses that were not detected by the primary examination.However, this requires further investigation.

The accurate measurement of tumor extension allows also

the use of ultrasound for accurate follow-up measurements inpatients receiving neoadjuvant chemotherapy [31]. Ultra-sound is also recognized for its ability to provide accurateguidance for interventional procedures [32].

Screening

According to the first edition of the German S3 guidelines forearly breast cancer detection, ultrasound had no role for can-cer detection but was only recommended in mammographicBI-RADS IV and V lesions for confirmation and ultrasound-guided interventions [8]. Meanwhile, the literature shows that

ultrasound also has a potential for the detection of lesions, es-pecially in women with dense breasts (ACR 24). Thereforein the new edition of the S3 guidelines published in 2008, be-sides mammographic lesions of BI-RADS 45, ultrasound isalso recommended in BI-RADS 0 and 3 cases and in densebreasts (ACR 34) to improve cancer detection and differen-tiation [32]. The rationale for using ultrasound as an adjunctto mammographic screening to compensate for the reducedsensitivity in dense breasts was described by Berg et al. [33].

An early study with ultrasound for the detection of earlybreast cancers was already performed 15 years ago [5]. In aprospective study of women without breast symptoms or pre-

vious mammography, whole-breast ultrasound was performed

improved accuracy in differentiating benign from malignantbreast lesions.

Due to the physics of sound propagation, ultrasound is par-ticularly useful in dense breasts compared with mammo-graphy. In contrast, mammography in dense breasts shows al-most no tissue details because of the lack of contrast betweenfibroglandular tissue and soft tissue masses. Ultrasound shows

even small lesions with low echogenicity in highly echogenicdense breast tissue. However, ultrasound is more operator de-pendent than mammography. Therefore, standardization ofexamination technique and interpretation and quality controlof technical standards is essential [21, 22].

Table 1 shows the results of studies analyzing the efficacyof ultrasound for breast lesion characterization in sympto-matic patients.

Preoperative Diagnosis, Local Staging

If breast cancer is suspected or proven by interventional diag-nosis, an accurate preoperative planning is essential. Tumor

size, localization within the breast, skin and nipple distance ormuscle involvement as well as multifocality and multicentric-ity are important to plan for tumor-adapted surgery or pre-operative chemotherapy and follow-up. From the early stud-ies of Holland et al. [23] in the 1980s, it is known that multipletumor foci and diffuse growth occur in 3040% of breast can-cers and are underestimated by mammography. This wasfound by extensive pathological work-up of mastectomy spec-imens. A few years later, Fornage et al. [24] showed that ultra-sound provides an accurate measurement of breast cancersize, with a correlation coefficient between histopathology

and ultrasound of 0.84, and 0.72 for mammography. However,this study did not include diagnosis of multifocal lesions.In order to improve preoperative local staging and to de-

fine the value of ultrasound, we performed a prospective blindstudy comparing palpation, mammography and ultrasound in100 patients with breast cancer [25]. Breast cancer was palpa-ble in 83% of cases, mammography visualized 96% and ultra-sound 98%. Measurement of tumor size showed the highestcorrelation between histopathology and ultrasound (0.91), formammography 0.79, and for palpation 0.77. Multifocal andmulticentric lesions were found in 39 of the cancer patients,whereof ultrasound detected 34 compared to 13 by mammog-

raphy. Underestimation of total tumor extension, which

Table 1. Studiesanalyzing the efficacyof breast ultrasound

n Cancers Breast ultrasound Mammography

Sensitivity, % Specificity, % Sensitivity, % Specificity, %

Stavros et al. 1995 [4] 747 125 98.4 67.8 76.8

Moss et al. 1999 [18] 559 256 88.9 77.9 78.9 82.7

Rahbar et al. 1999 [14] 161 38 95.0 42.0 89.0 42.0

Zonderland et al. 1999 [19] 4,728 338 91.0 98.0 83.0 97.0

Berg et al. 2004 [20] 258 177 83.0 34.0 67.8 75.0

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112 Breast Care 2010;5:109114 Madjar

number of unnecessary open biopsies, as ultrasound guidancefor percutaneous core needle biopsy is the method of choiceto make a definitive diagnosis [32].Indications for breast ultrasound are as follows: differentiation of mammographic lesions BI-RADS 0, 35; palpable lesions: differentiation between cystic/solid and

benign/malignant; preoperative planning for breast conservation or mastec-tomy: tumor size, localization, multifocality and multi-centricity;

follow-up measurements of tumor response under neo-adjuvant chemotherapy;

guidance for interventional diagnosis; additional breast survey scanning in mammographically

dense breasts (ACR 34); young women < 40 years and in pregnancy and lactation; additional screening in high-risk patients.

Discussion

Ultrasound has a high diagnostic yield in differentiating breastcancer from benign lesions, in preoperative assessment andeven in the detection of early cancers that are mammographi-cally and clinically occult. The advantage of breast ultrasoundcompared to mammography increases with higher breastdensity and in young women where the sensitivity of mam-mography is low. This is an important issue, as dense breasttissue is very common. More than half of the women youngerthan 50 years have heterogeneously dense (5075%) or verydense (> 75%) glandular breast tissue [36]. One-third ofwomen older than 50 years have also dense breasts [36] andthe sensitivity of mammography in women with dense breastsis as low as 3048% [10, 37]. The interval cancer rate is highlyincreased in this group [12, 37] and, furthermore, dense breasttissue is itself a marker of increased risk of breast cancer inthe order of 46-fold [12, 38, 39].

Unlike mammography, ultrasound has not been imple-mented in randomized screening studies, and a mortality re-duction with the additional detection of cancers has not beenproven. But small cancer size and nodal status are the most

important surrogate markers for the quality of screening, andthe distribution of cancer size and lymph node status in theultrasound studies is comparable to mammographic screen-ing-detected invasive cancers [40]. In two counties of Austria,Salzburg and Tirol, mammographic pilot screening studiescommenced 2 years ago. The difference compared to the Ger-man screening program is that an additional ultrasound ex-amination is offered to patients with increased breast density,and preliminary data demonstrate similar increased detectionrates of early cancer stages as in the studies discussed in thispaper (Prof. Buchberger, personal communication ).

In this context, it is remarkable that reporting breast den-

sity becomes already a legal issue. In the USA state of Con-

by a resident supervised in breast ultrasound over a period of3 months. During the following 3 study months, 1016 womenreceived a whole-breast ultrasound examination. Palpationand mammography were performed after documentation ofthe ultrasound findings. Four non-palpable carcinomas weredetected by ultrasound and only 3 were visible on the follow-

ing mammogram [5]. In addition, ultrasound detected 32 be-nign lesions, but only 3 were suspicious while 14 had suspi-cious mammograms.

Gordon and Goldenberg [6] examined a large populationof 12,706 women with normal mammograms and normal clini-cal findings. Previously detected cancers were not included inthis study. Using whole-breast ultrasound, they detected 1575solid tumors that were not palpable or visible by mammogra-phy. In 279 patients (2.2%), an interventional diagnosis wasperformed and 44 cancers were confirmed.

In a similar population of 11,220 women, Kolb et al. againstudied ultrasound for cancer detection. They found 3 occult

cancers per 1000 breast ultrasound examinations [7]. Theyselected only women with ACR breast density 24 (n = 3626)in order to reduce the number of ultrasound examinations.Comparison of tumor size with mammographically detectedcarcinomas showed a similar distribution of early tumorstages. In a following study with a similar protocol including13,547 patients, they confirmed these results [10]. Dividing thepatients in groups with breast density 2, 3 and 4, they found ahigher sensitivity of ultrasound and a lower sensitivity ofmammography in dense breasts. Besides cancers, Kolb et al.detected other lesions in 6% and an interventional diagnosiswas required in 2.6%.

Buchberger et al. found additional cancers in 4.1 per 1000ultrasound examinations among 8103 patients which were notdetected clinically or by mammography [34]. Additional le-sions were found in 5% of all examinations, and in 3.3% aninterventional diagnosis was required.

A multicentric American College of Radiology ImagingNetwork (ACRIN) screening study was recently published byBerg et al. [35], comparing ultrasound and mammography in2637 high-risk patients. 40 participants were diagnosed withcancer. 12 were suspicious on mammography, 8 on bothmammography and ultrasound, and 12 on ultrasound alone.

8 women had interval cancers within 12 months. In 8.8% of the2637 women, additional lesions were detected by ultrasoundand interventional diagnosis was performed in 5.7%. The rateof additional cancers detected with ultrasound was 4.2/1000.

All these studies prove that a significant number of cancersis detected if whole-breast ultrasound is used in addition tomammography, in the order of 34/1000 women. However,this increases the number of false positives from 0.3% in asingle-investigator study up to 5.7% in a multicenter study.But compared with a recall rate of 56% or higher in mam-mographic screening, this increase is relatively low and mayeven be lower in follow-up examinations. These additional

findings detected by ultrasound will also not increase the

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