Early detection of breast cancer: benefits and risks of supplemental breast ultrasound in asymptomatic women with mammographically dense breast tissue. A systematic review

  • Monika Nothacker1,

    Affiliated with

    • Volker Duda2,

      Affiliated with

      • Markus Hahn3,

        Affiliated with

        • Mathias Warm4,

          Affiliated with

          • Friedrich Degenhardt5,

            Affiliated with

            • Helmut Madjar6,

              Affiliated with

              • Susanne Weinbrenner7 and

                Affiliated with

                • Ute-Susann Albert8Email author

                  Affiliated with

                  BMC Cancer20099:335

                  DOI: 10.1186/1471-2407-9-335

                  Received: 6 March 2009

                  Accepted: 20 September 2009

                  Published: 20 September 2009



                  Mammographic screening alone will miss a certain fraction of malignancies, as evidenced by retrospective reviews of mammograms following a subsequent screening. Mammographic breast density is a marker for increased breast cancer risk and is associated with a higher risk of interval breast cancer, i.e. cancer detected between screening tests. The purpose of this review is to estimate risks and benefits of supplemental breast ultrasound in women with negative mammographic screening with dense breast tissue.


                  A systematic search and review of studies involving mammography and breast ultrasound for screening of breast cancer was conducted. The search was performed for the period 1/2000-8/2008 within the data source of PubMed, DARE, and Cochrane databases. Inclusion and exclusion criteria were determined prospectively, and the Oxford evidence classification system for diagnostic studies was used for evidence level. The parameters biopsy rate, positive predictive value (PPV) for biopsy, cancer yield for breast ultrasound alone, and carcinoma detection rate by breast density were extracted or constructed.


                  The systematic search identified no randomized controlled trials or systematic reviews, six cohort studies of intermediate level of evidence (3b) were found. Only two of the studies included adequate follow-up of subjects with negative or benign findings. Supplemental breast ultrasound after negative mammographic screening permitted diagnosis of primarily invasive carcinomas in 0.32% of women in breast density type categories 2-4 of the American College of Radiology (ACR); mean tumor size for those identified was 9.9 mm, 90% with negative lymph node status. Most detected cancers occurred in mammographically dense breast ACR types 3 and 4. Biopsy rates were in the range 2.3%-4.7%, with PPV of 8.4-13.7% for those biopsied due to positive ultrasound, or about one third of the PPV of biopsies due to mammography. Limitations: The study populations included wide age ranges, and the application to women age 50-69 years as proposed for mammographic screening could result in less striking benefit. Further validation studies should employ a uniform assessment system such as BI-RADS and report not only PPV, but also negative predictive value, sensitivity and specificity.


                  Supplemental breast ultrasound in the population of women with mammographically dense breast tissue (ACR 3 and 4) permits detection of small, otherwise occult, breast cancers. Potential adverse impacts for women in this intermediate risk group are associated with an increased biopsy rate.


                  Up until the early 1990's, breast ultrasound examinations were primarily used to distinguish between cysts and solid breast masses and for image-guided, minimally invasive interventions [13], but the diagnostic potential of breast ultrasound has improved since then. Evolving sonographic technology with high-frequency transducers in the 7.5-10 MHz range and evolving knowledge has established breast ultrasound in the past few years as an imaging procedure to supplement mammography [46].

                  In order to ensure standardized evaluation criteria, the American College of Radiology (ACR) developed a Breast Imaging Reporting And Data System (BI-RADS) classification for breast ultrasound examinations in 2003 [7], which is analogous to the BI-RADS classification for mammography [8]. The classification for breast ultrasound (US BI-RADS) consists of seven categories: 1) negative, 2) benign, 3) probably benign, 4) suspicious abnormality, 5) highly suggestive of malignancy, and 6) known malignancy. Category 0 is assigned for results requiring additional imaging due to limited assessment. Several international comprehensive quality standards for equipment and staff performing breast ultrasound have adapted the US BI-RADS criteria [912].

                  International guidelines recommend that breast ultrasound be used as a supplemental examination but not as a primary method for screening of breast cancer [1317].

                  Screening for breast cancer focuses on detecting occult cancer at an early stage with tumor size preferably smaller than 1 cm, negative lymph node status and with no evidence of distant spread [18]. Mammography has been established as the primary method for screening. Some 35%-45% of non-palpable cancers are detected as microcalcifications in mammographic studies [19]. These microcalcifications can sometimes be visualized by modern ultrasound equipment, but cannot be reliably identified as such without knowledge of mammography [20, 21]. However, not every carcinoma is detected in breast cancer screening. Breast density is one of the factors leading to false-negative findings in mammography [2225]. Furthermore, mammographically dense breast tissue has been identified as an independent marker strongly associated with breast cancer risk and in particular with higher risk of interval cancer, i.e. cancer detected between screening tests [2628]. Epidemiological studies have confirmed that individuals at varying risks according to the appearance of dense breast tissue in mammograms can be identified, and there is strong evidence for influence by genetic variants [29, 30].

                  This systematic review examines two issues: First, can a supplemental breast ultrasound examination performed as a second-line screening procedure after negative mammography improve the early detection rate of breast cancer in asymptomatic women with dense breast tissue? Second, what potential risks does this involve for the women examined?


                  The aim was to identify studies that provide reliable information on the benefit (positive effects of intervention) and the potential risks (negative effects of intervention) of supplemental breast ultrasound in breast cancer screening. The criteria for inclusion or exclusion of studies were established prospectively before actually running a systematic search of the literature.

                  The study populations included asymptomatic primarily healthy women who took part in mammographic screening. The evaluation was not limited to women who had been invited within the framework of an organized mammography screening program.

                  The value of the intervention 'Doppler sonography of the breast or axilla' was not included in the questions studied. Histological confirmation or adequate follow-up were taken as standards of reference.

                  The Oxford Classification for diagnostic studies was used, and publication quality was reported separately when assessing the studies from a methodological perspective [31].

                  Criteria for inclusion and exclusion

                  In order to ensure evaluability and comparability, the studies were required to contain the following information to be included in the present analysis:

                  - breast density according to the BI-RADS ACR categories and/or quantification; ACR 1: almost entirely fat (low density, up to 25% mammary gland parenchyma), ACR 2: scattered fibroglandular densities (average density, 26-50% gland parenchyma), ACR 3: heterogeneously dense (high density, 51%-75% gland parenchyma), ACR 4: extremely dense (very high density, more than 75% gland parenchyma) [8].

                  For inclusion, all of the following criteria were required to be satisfied:

                  1. 1.

                    study/review deals with the questions under investigation

                  2. 2.

                    adequate type of study

                  3. 3.

                    adequate study population

                  4. 4.

                    intervention complies with technical standards (transducer frequency > 5 MHz)

                  5. 5.

                    required data are provided


                  Publications were excluded if any of the following criteria were met:

                  1. 1.

                    redundancy: multiple publications of the same data

                  2. 2.

                    methods: case reports, expert opinions, or poor-quality case-control studies


                  Literature search

                  The systematic literature search covered the period from January 1st, 2000 up to August 30th, 2008 in the following databases:

                  1. 1.

                    PubMed (Internet portal of the National Library of Medicine) http://​www.​ncbi.​nlm.​nih.​gov/​sites/​entrez?​db=​pubmed

                  2. 2.

                    Database of Abstracts of Reviews of Effects (DARE), of the Centre for Reviews and Dissemination (CRD) http://​www.​york.​ac.​uk/​inst/​crd/​crddatabases.​htm#DARE

                  3. 3.

                    Cochrane-database 'Cochrane Reviews' and 'Clinical Trials' http://​www3.​interscience.​wiley.​com/​cgi-bin/​mrwhome/​106568753/​HOME


                  The following search words were used:

                  PubMed: screening AND (mammography OR mammogram) AND breast neoplasms

                  AND (ultrasonography, mammary OR breast echography)

                  Cochrane und DARE: mammography screening AND ultrasound

                  The abstracts found were checked for relevance of content. Abstracts that did not prove to be relevant were excluded. Full-text versions of the abstracts deemed to contain relevant information were checked as to the criteria for inclusion and exclusion. The reasons for excluding a full text were given in each case.

                  Target values and their definition

                  Since none of the identified studies addressed the mortality rate or the difference in mortality rate contributed by supplemental breast ultrasound, surrogate parameters, namely the assessment criteria of diagnostic tests, the additional relative and absolute rates of detected cancers compared to mammography and tumor size and lymph node negative status were used as target values. Negative predictive value, sensitivity and specificity of breast ultrasound were only computed if the follow-up period continued as long as the screening interval, thus permitting the identification of false-negative findings.

                  The risk of adverse impacts for the women examined was quantified using the number of biopsies performed due to breast ultrasound findings. The positive predictive value for biopsies with malignant histological findings characterizes the number of unnecessary biopsies induced by false positives.


                  The results of the literature search are represented in in Figure 1. and the details on the excluded studies are presented in Additional file 1 [3247]. Six cohort studies conforming to the inclusion criteria are discussed in detail (Additional file 2, Part 1; Additional file 3, Part II).
                  Figure 1

                  Search strategy and search results. Flow diagram of search strategy and search results.

                  Quality of studies and publications

                  It could be inferred from the information given in five of the six studies that women had been enrolled consecutively. The reference standard, i.e. histological confirmation of the findings, was applied in all studies for those results classified as malignant or suspicious or indeterminate.

                  Only Kolb et al., 2002 [48] reported a follow-up period of at least one year (up to the next screening exam) for all benign, but not for the negative findings. Kaplan, 2001 [49] mentioned a follow-up period for a part of the results classified as benign. None of the other studies provided any information on follow-up.

                  Due to non-consecutive inclusion of patients and/or an inconsistently applied reference standard, all studies were ultimately assigned to the level of evidence category 3b [31].

                  As for publication quality, it is worth noting that false positives were expressed in such a way that the positive predictive values for ultrasound examination and the biopsy rate could be calculated in only five of the six studies. Information on mean or median age was lacking in one study, while the relative rate of cancers detected by procedures done as a complement to mammography was reported in five of the six studies.

                  Group of women examined

                  The systematic search yielded studies in which breast ultrasound was used as a supplemental examination following mammographic interpretation. Moreover, of the group of asymptomatic women with negative mammographic results, women with breast tissue density (ACR 2-4) went on to be examined by ultrasound. The only exception is the study performed by Leconte et al., 2003 [50], where 3% had palpable findings (Additional file 2, Part I).

                  The fraction of these women relative to all women screened within the specified period was reported in two studies at 36% (Kaplan, 2001 [49]) and 35.8% (Corsetti et al., 2008 [51]). The size of the study populations ranged from n = 1517 to n = 13547, with mean n = 5118.

                  Age distribution

                  The median age was reported in four studies, ranging from 47.6 years to 60.7 years, with overall age ranges of more than 30 years in each study. One study provided information on mean age (52 years) [51] and one study just reported age ranges from 35-87 years (Kaplan., 2001 [49]).

                  Cancer diagnosis according to breast density categories

                  Two studies analyzed mammographic results of breasts in categories ACR 3 to ACR 4 [51, 49], and the other studies evaluated the mammograms of ACR 2 to ACR 4 breast tissue [48, 50, 52, 53].

                  Women with breasts of types ACR 3 or ACR 4 proved to have the highest proportion of breast cancers diagnosed by ultrasound screening.

                  Leconte et al. [50] diagnosed 16 carcinomas in all; 11 of which were detected in ACR 3 and ACR 4 breast tissue and five in women with breasts in categories ACR 1 and 2. Buchberger et al. [53] diagnosed 36 malignancies in breast tissue of ACR types 3 and 4 (0.3% cancer detection rate ACR 3, 1.1% cancer detection rate in ACR 4), while two carcinomas were found in the ACR category 2 breasts (0.4%). Crystal et al. [52] found no carcinomas in ACR-2 women, and 0.4% and 0.3% in breast-density categories ACR 3 and ACR 4, respectively. Kaplan [49] diagnosed cancer at the rate of 0.11% in ACR 2 breast tissue and 0.27% and 0.25% in ACR categories 3 and 4, in the one series where technologists performed the screening ultrasound.

                  Percentage of carcinomas identified in breast ultrasound

                  The relative percentage of carcinomas found in supplemental breast ultrasound examinations as a fraction of the total number of detected cancers was reported in four studies, with a mean percentage of 22.5% (15%-34%) [53, 51, 48, 50]. The percentage as a fraction of the total population screened was calculated from all studies, with a mean value of 0.32% (0.23%-0.41%).

                  Tumor size and stage (invasive/noninvasive and lymph node status)

                  The mean size of the detected carcinomas was 9.9 mm (median size range 9.0 mm to 11.0 mm) in five of the six studies [53, 52, 49, 48, 50]. The mean percentage of invasive cancer detected was 94% (81%-100%) compared to noninvasive cancer (ductal carcinoma in situ, DCIS) with a mean of 6% (0%-19%) in all studies. Lymph node status was reported in four studies with negative lymph nodes in 90% (86%-100%) [51, 52, 49, 48].

                  Quality of testing

                  The positive predictive value with regard to the detection of additional malignancies for ultrasound prompted biopsies was reported or was able to be inferred from the given data in four of the six studies. The mean positive predictive value was 15% (2%-28%) [53, 52, 49, 48]. In other words, the percentage of positively classified findings for which no carcinoma was subsequently found ranged from 72% to 98%. This large variation of positive predictive values can mainly be attributed to the application of different sonographic criteria for malignancy and different assessment categories (see next section). Only one study reported that all findings classified as benign were followed up in the interval between two screenings (Kolb et al., 2002 [48]). However, Kolb et al. [48] do not mention a follow-up for those patients with negative results. Kolb states a sensitivity of 75.3%, a specifity of 96.8% and a negative predictive value of 99.7% [48].

                  Assessment categories for breast ultrasound

                  The positive predictive value of detecting carcinomas by breast ultrasound mainly derives from the sonographic assessment criteria and categories applied. Overall, the range is still low relative to mammography.

                  Kaplan, 2001 [49] used a two-armed categorization approach, namely a simple subdivision into negative and positive. All positive results were considered to be potentially suspicious. In contrast to the other studies, Kaplan [49] also deemed cysts positive if they exceeded a size of 1 cm. The author had a low positive predictive value of 2% [49]. Three studies (Buchberger et al., 2000 [53]; Kolb et al., 2002 [48] and Leconte et al., 2003 [50]) subdivided their findings into three categories, but applied different definitions of these categories. Categories 1, 2 and 3 were called 'normal', 'benign', and 'suspicious' (Kolb et al. [48]) or 'benign', 'indeterminate' and 'malignant' (Buchberger et al. [53]). These authors found positive predictive values of biopsy of 10.3% (Kolb et al. [48]) and 28% (Buchberger et al. [53]). The values for Leconte's study could not be ascertained [50]. Crystal et al., 2003 [52] used four arms of classification, thereby reaching a positive predictive value for malignancy of 20%. Other than Buchberger et al., Crystal et al. included the 'indeterminate' findings in their calculation of suspicious findings. Only one study used the five categories proscribed by the BI-RADS classification for breast ultrasound scans (Corsetti et al., 2008 [51]). In this study, however, the positive predictive value could not be determined.

                  Rate of biopsies as a result of breast ultrasound

                  The rate of biopsies resulting from suspicious findings detected by breast ultrasound ranged from 2.3% (Crystal et al. [52]) to 4.7% (Corsetti et al., 2008 [51]) as a fraction of the total population of women screened. The positive predictive value of biopsies ranged from 8.4% to 13.7%. The difference compared to the positive predictive value of the breast ultrasound categorization may be explained by the fact that biopsies were sometimes also performed when findings were classified as 'indeterminate'. Clinically speaking, this means that 86.3% up to 91.6% of the invasive interventions done to confirm the diagnosis did not lead to a diagnosis of cancer.


                  Methodological aspects

                  Despite choosing a sensitive search strategy and a very broad definition of "breast cancer screening", only few single-center cohort studies analyzing breast ultrasound in the framework of breast cancer screening could be identified. All of these studies, however, were planned and conducted prospectively. The study populations were characterized by wide age ranges. For this reason, the results cannot be directly applied to women asked to participate in an organized population-based mammography screening program while aged between 50 and 69 years.

                  Since the studies applied different assessment criteria and classifications with regard to ultrasound morphology, their results are comparable only to a limited extent. As most studies lacked the requisite follow-up needed for computing sensitivity, specificity and negative predictive value, a comprehensive appraisal of the test quality of the intervention breast ultrasound could not be undertaken. None of the studies of US in breast screening were RCTs; therefore studies were not designed to provide evidence on screening benefit in terms of mortality reduction.

                  Discussion of content

                  The effectiveness of breast ultrasound as a screening tool was mainly studied in women with breast tissue of the categories ACR 2 to ACR 4 and invariably only after previous mammography screening had yielded a negative result. Women with dense breasts run a four- to six-fold higher risk of developing breast cancer than other women [26, 27]. The results revealed that supplemental breast ultrasound after negative mammographic screening permits the diagnosis of primarily invasive carcinomas in this risk group of women in an absolute mean of 0.32% of the cases. For comparative purposes: In population-based screening using mammography alone a mean of 0.4%-0.9% of all women screened were diagnosed with cancer [54].

                  The majority of cancers were detected in breast tissue of ACR types 3 and 4. According to these studies, the mean size of the cancers diagnosed additionally by breast ultrasound was not larger than the size of those visualized in mammography screening.

                  Berg (2004 [39]) reported similar results in a review of the application of breast ultrasound in women with dense breasts. The review was excluded because no systematic search strategy was specified, but Berg analyzed five of the six studies identified (Buchberger et al. [53]; Kaplan [49]; Kolb et al. [48]; Crystal et al. [52]; and Leconte et al. [50]) and, in addition, a study by Gordon et al., 1995 [55]. She calculated a pooled value for the additional detection of cancers in the study populations of 0.35% and reported that 94% of the cancers detected in breast ultrasound were invasive with a mean diameter of 9-11 mm [39]. More than 90% of the women in whom cancer was detected by breast ultrasound had breast density corresponding to ACR categories 3 or 4 [39].

                  Hence, the contribution of supplemental breast ultrasound for the detection of breast cancer is primarily relevant for women with ACR 3 or ACR 4 tissue density. The question of whether improved detection of carcinomas leads to decreased breast cancer mortality cannot be answered on the basis of the available studies, although mathematical models allow to relate tumor size, lymph node involvement and death rates [18, 56, 57].

                  Concerning possible adverse impacts of additional breast ultrasound, the biopsy rates in the evaluated studies of 2.3%-4.7% were significantly higher than the biopsy rates of about 1%-2% resulting from mammographic screenings [5860]. Moreover, the positive predictive value of biopsies (mean 10.3%) was significantly lower than that of mammography screening (mean approximately 38%) [5961], i.e. three times more women need to undergo a biopsy per carcinoma detected. Although findings visualized by ultrasound examination can easily be biopsied in a minimally-invasive procedure, risk assessment should still take into consideration the psychological strain that women experience before and during biopsy performed because of a false-positive ultrasound result [62, 63].

                  The heterogeneous nature of the assessment criteria for breast ultrasound examinations, which in turn influence biopsy rates, is quite striking. Due to this heterogeneity, comparability of the studies is limited, and the effect of differences in experience of examiners is difficult to quantify. Since few studies included adequate follow-up of subjects with negative or benign findings, the false-negative rate in women with high breast density -- and hence the proportion of cancers missed by mammography and also missed by the addition of breast ultrasound in this group -- cannot be reliably estimated.

                  In 2003, Berg [61] initiated a prospective multicenter trial, randomized to the sequence of performance of mammography and ultrasound in women with intermediate and high breast cancer risk. Adding a single screening ultrasound to mammography yielded additional 1.1 to 7.2 cancers per 1000 high-risk women, but also substantially increased the number of false positives [37]. The study provided evidence for the importance of supplemental breast ultrasound screening. Furthrmore the standardized scanning and interpretive criteria proved to be practicable for independent performance and intrepretation and could be used for further implementation. However, in view of the selected study cohort the results cannot be applied directly to a population-based screening program for asymptomatic women aged 50-69 years without personal history evaluation prior performing mammography.


                  As far as the transferability of the findings to a population-based mamographic screening program for women aged 50-69 years as currently practiced in many countries is concerned, one can conclude the following:

                  1. 1.

                    The reviewed studies provided limited evidence that within the framework of screening for breast cancer, an additional ultrasound examination after a negative mammogram is useful for the detection of primarily invasive cancers in women with mammographically dense breast tissue (ACR types 3 and 4, with more than 50% parenchymal gland), with the mean size of invasive cancers thus identified being 9.9 mm and in 90% with negative lymph node status.

                  2. 2.

                    As for adverse impacts resulting from the breast ultrasound intervention, three times more women need to undergo a biopsy per carcinoma detected by supplemental ultrasound compared to cancers detected by mammography screening alone.

                  3. 3.

                    Since the study populations were characterized by very broad age ranges and invariably also included younger women, the impact in an organized population-based mammography screening program, including only women in the age group of 50 to 69 years, could be reduced.

                  4. 4.

                    There is a need for prospective validating studies of risk-adjusted, second-line, supplemental breast ultrasound screening in women with dense breast tissue (ACR types 3 and 4), performed within the framework of established population-based mammography-screening-programs.

                  5. 5.

                    Validating studies should not only state the positive predictive value, but also the sensitivity, specificity and negative predictive value for breast ultrasound. Quality of performance standards and a uniform assessment system, such as the ultrasound BI-RADS™ categories, should be applied, so that the precise reasons for the biopsies can be given and explained accurately.

                  6. 6.

                    In analogy to the quality assurance assessments of established mammography screening programs, performance indicators and surrogate end points, such as tumor size, lymph node status are effective and accurate, and should be used for health care outcomes analyses. Beside lethality, issues such as quality of life and health care costs are of importance.




                  American College of Radiology


                  Atypical ductal hyperplasia


                  Area under ROC curve


                  Breast Imaging Reporting and DataSystem™


                  confidence interval


                  Database of Abstracts of Reviews of Effects


                  German Association for Ultrasound in Medicine


                  lobular carcinoma in situ


                  lobular neoplasia




                  positive predictive value


                  receiver operating characteristic (sensitivity vs. specificity)



                  Supported by a grant from the German Cancer Aid and the German Society of Senology, Funding Code: 107374 within the project: Update of the Guideline: Early Detection of Breast Cancer in Germany - Model Project for the Updating of Stage-3-Guidelines in Germany 2008. The study is part of the evidence report 2007, Version 1.00 edn. Ärztliches Zentrum für Qualität in der Medizin (ÄZQ), Band 31, http://​www.​aezq.​de/​publikationen0in​dex/​schriftenreihe/​view), Berlin. The study sponsor had no role in the design of the review; the collection, analysis and interpretation of the data; the writing of the manuscript; or the decision to submit the manuscript for publication.

                  Authors’ Affiliations

                  Agency for Quality in Medicine
                  Department of Gynecology, Gynecological Endocrinology and Oncology, University of Marburg
                  Department of Gynecology and Obstetrics, University of Tuebingen
                  Department of Gynecology and Obstetrics, University of Cologne
                  Women's hospital, Franziskus-Hospital
                  German Clinic for Diagnostics
                  Agency for Quality in Medicine
                  Department of Gynecology, Gynecological Endocrinology and Oncology, University of Marburg


                  1. Bassett L, Kimme-Smith C: Breast sonography. Am J Radiol 1991, 156: 449–456.
                  2. Jackson VP: The role of US in breast imaging. Radiology 1990, 177: 305.PubMed
                  3. Parker SH, Jobe WE, Dennis MA, Stavros AT, Johnson KK, Yakes WF, Truell JE, Price JG, Korzt AB, Clark DG: US-guided automated large core breast biopsy. Radiology 1993, 187: 507–511.PubMed
                  4. Stavros A, Thickman D, Rapp C, Dennis M, Parker S, Sisney G: Solid breast nodules:use of sonography to distinguish between benign and malignant lesions. Radiology 1995, 196: 123–127.PubMed
                  5. Skaane P, Engedal K: Analysis of sonographic features in the differentiation of fibroadenomas and invasive ductal carcinoma. AJR 1998, 170: 109–114.PubMed
                  6. Rahbar G, Sie A, Hansen G, Prince J, Melany M, Reynolds H, Jackson V, Syre J, Bassett L: Benign versus malignant solid breast masses: us differentiation. Radiology 1999, 213: 889–894.PubMed
                  7. Mendelson EB, Baum JK, Berg W, Merritt C, Rubin E: Breast Imaging Reporting and Data System BIRADS: Ultrasound. Reston VA: American College of Radiology 2003.
                  8. D'Orsi D, Bassett L, Berg W, et al.: Breast Imaging Reporting and Data System, BI-RADS:Mammography Reston VA: American College of Radiology 2003.
                  9. Madjar H, Mundinger A, Degenhardt F, Duda V, Hackelöer B, Osmers R: Qualitätskontrolle in der Mamma-Sonographie. Ultraschall in Med 2003, 24: 190–194.View Article
                  10. Madjar H, Ohlinger R, Mundinger A, Watermann D, Frenz J, Bader W, Schulz-Wendlandt R, Degenhardt F: BI-RADS analoge DEGUM Kriterien von Ultraschallbefunden der Brust - Konsensus des Arbeitskreises Mammosonographie der DEGUM. Ultraschall in Med 2006, 27: 374–379.View Article
                  11. Amercan College of Radiology: ACR Practice guideline for the performance of breast ultrasound examination. American College of Radiology. ACR practice guideline Res. 34 2007, 569–573.
                  12. Quality Determinants Working Group: Quality determinants of organized breast cancer screening programs Minister of Public Works and Government Services Canada, Ottawa, Ontario 2003.
                  13. Albert US, Schulz K, the members of the Guideline Steering Committee and the Chairs of the Task Force Groups: Short version of the guideline - Early Detection of Breast Cancer in Germany. An evidence-, consensus- and outcome-based Guideline according to the German Association of the Scientific Medical Societies and the German Agency for Quality in Medcine. J Cancer Res Clin Oncol 2004, 130: 527–536.View ArticlePubMed
                  14. Smith R, Saslow D, Sawyer K, Burke W, Costanza M, Evans W, Foster R, Hendrick E Jr, Eyre H, Sener S: American Cancer Society guidelines for breast cancer screening. Update 2003. CA Cancer Journal of Clinicans 2003, 53: 141–169.View Article
                  15. SIGN Scottish Intecollegiate Guideline Network: SIGN Scottish Intecollegiate Guideline Network. Management of breast cancer in women Edinburgh: SIGN 2005.
                  16. NCCN National Comprehensive Cancer Network: Breast cancer screening and diagnosis guidelines USA: NCCN Clinical Practice Guidelines in Oncology 2007.
                  17. Albert US, Altland H, Duda V, Engel J, Geraedts M, Heywang-Köbrunner S, Hölzel D, Kalbheim E, Koller M, König K, et al.: 2008 update of the guideline early detection of breast cancer in Germany. J Cancer Res Clin Oncol 2009, 135: 339–354.View ArticlePubMed
                  18. Michaelson J, Silverstein M, Sgroi D, Cheongsiatmy J, Taghian A, Powell S, Hughes K, Comegno A, Tanabe K, Smith B: The effect of tumor size and lymph node status on breast cancer lethality. Cancer 2003, 98: 2133–2143.View ArticlePubMed
                  19. Sickles E: Mammographic detectability of breast mircrocalcification. AJR 1982, 139: 913–918.PubMed
                  20. Soo M, Baker J, Rosen E: Sonographic detection and sonographically guided biopsy of breast calcification. AJR 2003, 180: 941–948.PubMed
                  21. Cheung Y, Wan Y, Chen S, Lui K, Ng S, Yeow K, Lee K, Hsueh S: Sonographic evaluation of mammographic detected microcalcification without a mass prior to stereotactic core needle biopsy. J Clin Ultrasound 2003, 30: 323–331.View Article
                  22. Ma I, Fishell F, Wright B, Hanna W, Allan S, Boyd N: Case-control study of factors associated with failure to detect breast cancer by mammography. J Natl Cancer Inst 1992, 84: 781–785.View ArticlePubMed
                  23. Mandelson MT, Oestreicher N, Porter PL: Breast density as a predictor of mammographic detection: comparison of interval- and screen-detected cancers. J Natl Cancer Inst 2000, 92: 1081–1087.View ArticlePubMed
                  24. Roubidoux M, Bailey J, Wray L, Helvie M: Invasive cancers detected after breast cancer screening yielded a negative result: relationship of mammographic density to tumor prognostic factors. Radiology 2004, 230: 42–48.View ArticlePubMed
                  25. Porter G, Evans A, Cornford E, Burrell H, James J, Lee A, Chakrabarti J: Influence of mammographic parenchym pattern in screening -detected and interval invasive breast cancers on pathologic features, mammographic features and patient survival. Am J Roentgenol 2007, 188: 676–683.View Article
                  26. McCormack V, dos Santos Silva I: Breast density and parenchymal patterns as markers of breast cancer risk: a meta analysis. Cancer Epidemiology Biomarkers and Prevention 2006, 15: 1159–1169.View Article
                  27. Boyd N, Gua H, Martin I, Sun L, Stone J, Fishell E, Jong R, Hislop G, Chiarelli A, Minkin S, et al.: Mammographic density and the risk and detection of breast cancer. N Eng J Med 2007, 356: 227–236.View Article
                  28. Kerlikowske K, Ichikawa L, Miglioretti D, Buist D, Vacek P, Smith-Bindman R, Yankaskas B, Carney P, Ballard-Barbash R: Longitudinal measurement of clinical mammographic breast density to improve estimation of breast cancer risk. National Institutes of Health Breast Cancer Consortium. J Natl Cancer Inst 2007, 99: 386–395.View ArticlePubMed
                  29. Vachon C, Sellers T, Carlson E, Cunningham J, Hilker C, Smalley R, Schais D, Kelemen L, Couch F, Pankratz V: Strong evidence of a genetic determinant for mammographic density, a major risk factor of breast cancer. Cancer Research 2007, 67: 8412–8418.View ArticlePubMed
                  30. Martin L, Boyd N: Potentials mechanisms of breast cancer risk associated with mammographic density:hypotheses based on epidemiological evidence. Breast Cancer Res 2008, 10: 201.View ArticlePubMed
                  31. Ball C, Sackett D, Philipps B, Haynes B, Straus S, Dawes M: Oxford-Centre for Evidence-based Medicine Levels of Evidence (2001). [http://​www.​cebm.​net/​index.​aspx?​o=​1025] 2001.
                  32. Geller B, Vacek P, Skelly J, Harvey S: The use of additional imaging increased specificity and decreased sensitivity in screening mammography. J Clin Epidemiol 2005, 58: 942–950.View ArticlePubMed
                  33. O'Driscoll D, Warren R, Mackay J, Britton P, Day N: Screening with breast ultrasound in a population at moderate risk due to family history. J Med Screen 2001, 8: 106–109.View ArticlePubMed
                  34. Ohlinger R, Heyer H, Thomas A, Paepke S, Warm H, Klug U, Frese H, Schulz K, Schimming A, Schwesinger G, et al.: Non-palpable breast lesions in asymptomatic women: diagnostic value of initial ultrasonography and comparison with mammography. Anticancer Res 2006, 26: 3943–3955.PubMed
                  35. Corsetti V, Ferrari A, Ghirardi M, Bergonzini R, Bellarosa S, Angelini O, Bani C, Ciatto S: Role of ultrasonography in detecting mammographically occult breast carcinoma in women with dense breasts. Radiol Med (Torino) 2006, 111: 440–448.View Article
                  36. Brancato B, Binardi R, Catarazi S, Iacconi C, Rissso G, Taschini R, Ciatto S: Negligible advantages and excess costs of routine addition of breast ultrasonography to mammography in dense breast. Tumori 2007, 93: 526–566.
                  37. Berg W, Blume J, Cormack J, Mendelson E, Lehrer D, Böhm-Vélez M, Pisano E, Jong R, Evans W, Morton M, et al.: Combined Screening with ultrasound and mammography vs mamography alone in women at elevated risk of breast cancer. JAMA 2008, 299: 2151–2163.View ArticlePubMed
                  38. Hou M, Chuang H, Ou-Yang F, Wang V, Huang C, Fan H, Chung C, Wang J, Hsieh J, Liu G, et al.: Comparision of breast mammography, sonography and physical exmination for screening women at high risk of breast cancer in Taiwan. Ultrasound Med Biol 2002, 28: 415–420.View ArticlePubMed
                  39. Berg W: Supplemental screening sonography in dense breast. Radiol Clin North Am 2004, 42: 845–851.View ArticlePubMed
                  40. Delorme S: Mammasonographie und Magnetresonanz-Mammographie als ergänzende Methoden im Mammographiescreening. Radiologe 2001, 41: 371–378.View ArticlePubMed
                  41. Elmore J, Armstrong K, Lehmann C, Fletcher S: Screening for breast cancer. JAMA 2005, 293: 1245–1256.View ArticlePubMed
                  42. Gordon P: Ultrasound for breast cancer screening and staging. Radiol Clin North Am 2002, 40: 431–441.View ArticlePubMed
                  43. Metha T: Current uses of ultrasound in the evaluation of the breast. Radiol Clin North Am 2003, 41: 841–856.View Article
                  44. Smith J, Andreopoulou E: An overview of the status of imaging screening technology for breast cancer. Ann Oncol 2004, 15 (Suppl 1) : I18-I26.View ArticlePubMed
                  45. Zonderland H: The role of ultrasound in the diagnosis of breast cancer. Semin Ultrasound CT MR 2000, 21: 317–324.View ArticlePubMed
                  46. Villeirs G: Is there a role for sonography in breast cancer screening? JBR-BTR 2007, 90: 155–158.PubMed
                  47. Nemec C, Listinsky J, Rim A: How should we screen for breast cancer? Mammography, ultrasound, MRI. Cleve Clin J Med 2007, 74: 897–904.View ArticlePubMed
                  48. Kolb T, Lichy J, Newhouse J: Comparison of the performance of screening mammography, physical examination an breast US and evaluation of factors that influence them: an analysis of 27,825 patient evaluations. Radiology 2002, 225: 165–175.View ArticlePubMed
                  49. Kaplan S: Clinical utility of bilateral whole-breast US in the evaluation of women with dense breast tissue. Radiology 2001, 221: 641–649.View ArticlePubMed
                  50. Leconte I, Feger C, Galant C, Berliere M, Berg B, D'Hoore W, Maldague B: Mammography and subsequent whole-breast sonography of nonpalpable breast cancers: the importance of radiologic breast density. AJR Am J Roentgenol 2003, 180: 1675–1679.PubMed
                  51. Corsetti V, Houssami N, Ferrari A, Ghirardi M, Bellarosa S, Angelli O, Bani C, Sardo P, Remida G, Galligioni E, et al.: Breast screening with ultrasound in women with mammography-negative dense breasts:evidence on incremental cancer detection and false positives, and associated costs. Eur J Cancer 2008, 44: 539–544.PubMed
                  52. Crystal P, Strano S, Shcharynski S, Koretz M: Using sonography to screen women with mammographically dense breasts. AJR Am J Roentgenol 2003, 181: 177–182.PubMed
                  53. Buchberger W, Niehoff A, Obrist P, Koekkoek-Doll P, Dunser M: Clinically and mammographically occult breast lesions: detection and classification with high-resolution sonography. Semin Ultrasound CT MR 2000, 21: 325–336.View ArticlePubMed
                  54. Gotzsche PC, Nielsen M: Screening for breast cancer with mammography. Cochrane Database of Systematic Reviews 2006, CD001877.
                  55. Gordon PB, Goldenberg SL, Chan NHL: Malignant breast masses detected only by ultrasound: a retrospective review. Cancer 1995, 76: 626–630.View ArticlePubMed
                  56. Michaelson J, Satija S, Kopan D, Moore R, Silverstein M, Comegno A, Hughes K, Taghian A, Powell S, Smith B: Gauging the impact of breast carcinoma screening in terms of tumor size and death rate. Cancer 2003, 96: 2114–2124.View Article
                  57. Verschraegen C, Vinh-Hung V, Cserni G, Gordon R, Royce M, Vlastos G, Tai P, Storme G: Modeling the effect of tumor size and early breast cancer. Annals of Surgery 2005, 241: 309–318.View ArticlePubMed
                  58. Kwek B, Lau T, Ng F, Gao F: Non-consensual double reading in the Singapore Breast Screening Project: benefits and limitations. Ann Acad Med Singapore 2003, 32: 438–441.PubMed
                  59. Morton M, Whaley D, Brandt K, Amrami K: Screening mammograms: interpretation with computer-aided detection--prospective evaluation. Radiology 2006, 239: 375–383.View ArticlePubMed
                  60. Cupples T, Cunningham J, Reynolds JJ: Impact of computer-aided detection in a regional screening mammography program. AJR Am J Roentgenol 2005, 185: 944–950.View ArticlePubMed
                  61. Berg W: Rationale for a trial of screening breast ultrasound: American College of Radiology Imaging Network (ACRIN) 6666. AJR 2003, 180: 1225–1228.PubMed
                  62. Brett J, Bankhead C, Henderson B, Watson E, Austoker J: The psychological impact of mammographic screening. A systematic review. Psycho-Oncology 2005, 14: 917–938.View ArticlePubMed
                  63. Rimer B, Bluman LG: The psychosocial consequences of mammography. J Natl Cancer Inst Monogr 2002, 22: 131–138.
                  64. Pre-publication history

                    1. The pre-publication history for this paper can be accessed here:http://​www.​biomedcentral.​com/​1471-2407/​9/​335/​prepub


                  © Nothacker et al. 2009

                  This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://​creativecommons.​org/​licenses/​by/​2.​0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.