- Email: [email protected]
Supplemental screening sonography in dense breasts
Radiol Clin N Am 42 (2004) 845 – 851
Supplemental screening sonography in dense breasts Wendie A. Berg, MD, PhD Breast Imaging Consultant, Study Chair ACRIN Protocol 6666, Lutherville, MD 21093, USA
There are three basic principles of screening for breast cancer. The most critical of these is that early detection and resulting treatment improve the outcome of the disease. Earlier detection often allows breast conservation and less harmful treatments. A second important principle is that healthy women are not harmed. Finally, a screening test must be practical: it must be cost-effective to screen a population in terms of quality-adjusted years of life saved. At this time, the only screening test that has been shown to reduce deaths caused by breast cancer is mammography. Supplemental screening with sonography or MR imaging after mammography can increase the rates of early detection of breast cancer in denser categories of breast tissue. Whether or not this additional breast cancer detection alters the outcome of the disease has not yet been established directly, although surrogate end points of tumor size and nodal status can guide this discussion. The degree to which healthy women are subjected to additional testing and biopsies and potentially unnecessary treatments depends on the prevalence of cancer in the healthy women. The degree to which this additional testing adversely affects women is being studied. Cost effectiveness needs to be addressed in considering widespread application of any further screening tests. This article reviews the experience to date with screening sonography in single-center studies, addresses the goals and interpretation guidelines of an ongoing multicenter randomized trial, and discusses what is needed before widespread use of this approach.
Supported by grants from the Avon Foundation and the National Institutes of Health (CA80098). E-mail address: [email protected]
Basic concepts Mammographically screen-detected cancers have a better prognosis than clinically detected cancers. Tabar et al [1] found that 50% of screen-detected cancers had good prognosis and 18% had poor prognosis, whereas 19% of clinically detected cancers had good prognosis and 47% poor prognosis. bGoodQ prognosis cancers include all ductal carcinoma in situ (DCIS), node-negative invasive cancers of small size: less than 20 mm if grade I invasive ductal, less than 15 mm if grade II, less than 10 mm if grade III, and less than 10 mm invasive lobular [1]. All tubular cancers had good or intermediate prognosis [1]. bPoorQ prognosis cancers are node-positive and larger in size, but fundamentally the same histology as those of good prognosis. It stands to reason that left undetected, good prognosis cancers will progress to those with poor prognosis. Furthermore, the prognosis and treatment of a given breast cancer depend predominantly on size and nodal status [1,2] (and receptor status): prognosis and treatment of a given cancer should be essentially independent of the method of detection. There has been recent controversy surrounding potential overdiagnosis and overtreatment of DCIS. Left untreated, most DCIS progress to invasive carcinoma, but this may occur over a period of 20 years or more [3,4]. Yen et al [5] recently analyzed the results of the Swedish two-county trial around this issue. At the first (prevalent) screen, they estimate that 37% of DCIS is nonprogressive [5]. The corresponding percentage at incidence (subsequent) screens was estimated at 4% [5], a very small percentage. This suggests that overtreatment may occur at the first (prevalent) screen with any given screening test, but is uncommon if the test is performed annually. Cancers that are new on sub-
0033-8389/04/$ – see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.rcl.2004.04.003
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sequent (incidence) screens can be considered biologically relevant. In a companion article, Duffy et al [6] conclude that most mortality reduction in the Swedish twocounty trial was caused by stage-shifting from invasive stage II or worse to invasive stage I disease and that detection of DCIS might account for 5% to 12% of all deaths averted. From these analyses, it seems that detection of stage I invasive carcinomas is the most critical benefit of screening mammography. It is reasonable to assume that this benefit accrues to other methods of screening that increase detection of stage I invasive cancers. Kerlikowske et al [7] reported results on 27,281 screening mammograms and found the sensitivity for cancer detection was 98.4% in women greater than or equal 50 years of age with fatty breasts and 83.7% in dense breasts (P = .01). In women under 50, the sensitivity was 81.8% in fatty breasts and 85.4% in dense breasts (nonsignificant), although the number of cancers was small [7]. In women under 50 with a family history of breast cancer, sensitivity decreased to 68.8% [7]. In women with dense breasts, and particularly those at increased risk because of a family or personal history of breast cancer or atypia, methods to supplement mammography are sought.
MR imaging MR imaging has been proposed as a supplemental screening examination in high-risk women. Across 11 series [8], 6524 very high-risk (detailed later) women have been screened with MR imaging with 125 (1.9%) women having cancer depicted only on MR imaging. The median size of cancers was 7 to 20 mm, and in all but one series, greater than 80% of MR imaging–only depicted cancers were node negative. Where detailed, 19 (23%) of 81 of the cancers identified were DCIS [8]. Six percent to 18% of women screened were recommended for biopsy based on MR imaging and 17% to 62% of MR imaging – prompted biopsies proved malignant. Short-interval follow-up was required in another 3% to 8% of women, but the criteria for follow-up and risk of malignancy in lesions followed have not been well studied. Liberman et al [9] report 7% of lesions followed proved malignant, and another 3% of patients had cancer develop elsewhere in their breasts during short-interval follow-up. MR imaging is limited by high cost, relative lack of availability, variable patient tolerance, and the requirement for contrast injection. It remains challenging to integrate breast MR imaging into daily breast imaging practice.
MR imaging – guided core and vacuum-assisted biopsy are becoming more widely available [10,11], but require availability of scanner time and personnel. These topics are discussed in greater detail elsewhere in this issue.
Single-center studies of screening sonography Studies of screening sonography to date have been performed in women of average risk with nonfatty breasts. Across six series totaling 42,838 examinations, 150 (0.35%) additional cancers have been identified only on sonography in 126 women (Table 1) [12 – 17]. In all but one of these studies [15], a single screening sonogram was performed, which detects prevalent cancers seen only on sonography: there is not an estimate of the rate of incident cancers seen only on subsequent annual screening sonograms. Of the 150 cancers seen only on sonography [12 – 17], 141 (94%) were invasive and 9 (6%) were DCIS. Of the 141 invasive cancers, 99 (70%) were 1 cm or smaller in size. Where staging has been detailed [14–16], 36 (90%) of 40 were stage 0 (1 of 36) or stage I (35 of 36). The detection benefit of supplemental sonography increased with increasing grades of breast density. Indeed, of the 126 women with sonographically detected cancers, 114 (90.5%) had either heterogeneously dense or extremely dense parenchyma [12 – 17]. Women at higher risk of breast cancer were twofold to threefold more likely to have a cancer seen only sonographically. When information specific to risk factors was detailed, 55 (50%) of 110 women with ultrasound-only detected cancer were at highrisk because of a personal history of breast cancer or first-degree relative with breast cancer or prior atypia [12 – 16]. In the series of Kolb et al [15], of 2914 examinations performed in women at high risk with heterogeneously dense or dense breasts, 14 (0.48%) had cancer seen only sonographically, compared with 14 (0.18%) of 7901 examinations in women not at high risk. Similarly, in the series of Crystal et al [16], cancer was found only on sonography in 4 (1.3%) of 318 women with first-degree family history or personal history of breast cancer and 3 (0.25%) of 1199 women of average risk (P < .04). For 26,753 examinations, the results of mammography are also reported [13,15,17]. Another 56 (0.22%) cancers were seen only mammographically, with 42 (75%) of the 56 caused by DCIS and 14 (25%) invasive. In the series of 8970 women evaluated by Buchberger et al [13], including 867 women with palpable or mammographic abnor-
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Table 1 Summary of studies of screening breast US, biopsies prompted by US, positive predictive value of biopsy, and prevalence of cancers seen only sonographically Investigator/Yr Gordon and Goldenberg, 1995 [12] Buchberger et al, 2000 [13]d Kaplan, 2001 [14] Kolb et al, 2002 [15] Crystal et al, 2003 [16] Leconte et al, 2003 [17] Overall
No. 12,706 8103 867d 1862 13,547f 1517 4236h 42,838
No. biopsiesa (%) c
279 (2.2) 362 (4.5) 43 (5.0) 102 (5.5) 358 (2.6) 38 (2.5)g NS 1182 (3.1)h
No. malignant(%)b
Prevalence (%)
44/279 (16) 32/362 (8.8) 8/43 (19) 6/99 (6.6) 37/358 (10) 7/38 (18) NSh 134/1171 (11.4)
44/12,706 (0.35)c 32/8103 (0.39)e 8/867 (0.9)e 6/1,862 (0.3) 37/13,547 (0.27)f 7/1517 (0.46)g 16/4,236 (0.38) 150/42,838 (0.35)
Abbrevations: NS, not stated; US, ultrasound. a Biopsies and aspiration prompted by screening sonography. b Refers to cancers seen only on breast sonography, expressed as percent of biopsies. c All women had clinical or mammographic abnormalities. Diagnosis was by fine-needle aspiration biopsy. Numbers refer to solid masses. Sixteen cancers were found in 15 women with ipsilateral cancer. d In this series, 867 women were evaluated because of palpable or mammographic abnormalities; five cancers seen only on sonography were in patients with another mammographically or clinically evident cancer. e Cancer was found only on sonography in 0.54% of women with a personal history of cancer compared with 0.26% of women with no personal history of cancer. f Includes patients described in 1998 series [9]. Number of studies, not women, because some women had more than one study. Cancer was found only on sonography in 0.48% of high-risk women compared with 0.16% of normal-risk women. g Cancer was found only on sonography in 4 (1.3%) of 318 women with first-degree family history or personal history of breast cancer and 3 (0.25%) of 1199 women of average risk; biopsies includes 17 aspirations, of which 13 yielded clear fluid. h One thousand sixteen had a personal history of breast cancer and 136 a palpable lesion (with the palpable lesions themselves excluded), although the number of cancers seen in women at high risk was not specified. Sixteen cancers were identified, but the number of biopsies induced by sonography was not specified: results of this study were not included in calculating the biopsy rate nor the malignancy rate of biopsies.
malities, mammography depicted 142 (78%) of 182 of all cancers in women with other than fatty breasts, and 162 (89%) of 182 were seen on sonography. In the series of Kolb et al [15], in women with heterogeneously dense or dense breasts, sonography alone was again more sensitive than mammography, with 60 (57%) of 105 of cancers seen mammographically and 83 (79%) of 105 seen sonographically. The combination of mammography and sonography depicted 101 (96%) of 105 of cancers in this group [15]. In all three series where results of mammography and sonography were reported [13,15,17], mammography and sonography seem complementary in that DCIS was better depicted mammographically, and small, less than 1 cm, invasive cancers were better seen sonographically in dense breasts. Invasive lobular cancer was overrepresented among cancers seen only on sonography. Summarizing results from four series where detailed histopathology was available [13,14,16,17], 17 (28%) of 61 invasive cancers seen only on sonography were lobular type. In the series of Kolb et al [15], screening sonography seemed to be especially beneficial in younger women (arbitrarily, women under 50) with
dense breasts, where mammography depicted only 21 (50%) of 42 of cancers and sonography 33 (79%) of 42. Younger age was predictive of increased prevalence of cancers seen only on sonography, independent of breast density [15]. In the single-center studies to date, the cancers found on supplemental screening sonography were almost all stage I invasive cancers. Identification of such cancers is most likely to prove beneficial in decreasing mortality from breast cancer. It will likely remain true that even with combined mammography and sonography there will be cancers that have metastasized by the time of detection and that early detection on imaging will be of no benefit. With the insensitivity of sonography to DCIS, overdiagnosis does not seem to be a major concern. Indeed, ultrasound can help identify the invasive component in lesions of DCIS and target biopsy to areas of associated mass [18]. One of the limitations of studies to date is that none of the studies were truly blinded to mammographic findings. Many performed sonography only when the mammogram is negative: any additional test can only be of benefit in this setting if it depicts anything. If performed in conjunction with mammog-
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raphy, the performance of the sonogram cannot help but be directed to areas of increased tissue density and questionable, but subthreshold mammographic abnormalities (eg, focal asymmetries, possible subtle architectural distortion). Importantly, it is not known whether or not the encouraging results of singlecenter studies are generalizable.
ACRIN Protocol 6666, screening breast ultrasound in high-risk women With the support of the AVON Foundation and the National Institutes of Health, through the American College of Radiology Imaging Network (ACRIN), a
Box 1. Summary of criteria to define high risk for ACRIN Protocol 6666, screening breast ultrasound in high-risk women (at least one of the following): 1. Known to have a mutation in BRCA1 or -2 2. Personal history of cancer (with conserved breast analyzed separately; after mastectomy, the breast reconstructed with autologous tissue will not be imaged, but the other breast will be eligible for imaging) 3. History of prior biopsy showing lobu lar carcinoma in situ 4. History of prior biopsy showing atypical ductal hyperplasia, atypical lobular hyperplasia, or atypical papillary lesion; not on chemoprevention; or any of these atypical lesions and a first-degree relative diagnosed with breast cancer under age 50 even if the patient is on chemoprevention 5. History of prior chest or mediastinal or axillary irradiation less than or equal to age 30 and at least 8 years previously 6. Lifetime risk of breast cancer by Gail [20 – 22] or Claus models of at least 25% [23,24] 7.5-year risk by Gail model of _2.5% > 8.5-year risk by Gail model of _1.7% and extremely dense > parenchyma
multicenter protocol to assess the efficacy of screening breast sonography has opened to begin enrollment (for more information, go to www.acrin.org) [19]. Twenty centers will enroll 2808 high-risk (Box 1) asymptomatic women with dense breasts for three annual screening mammograms and sonograms. Women will be randomized to initial mammography or sonography. Importantly, mammographic and sonographic interpretations will be independent, to gain true measures of the performance of sonography. A second integration interpretation will be performed. Breast sonography is highly operator dependent, requiring real-time adjustments of gain; focal zones; dynamic range; angle of insonation; pressure; patient positioning; and, most importantly, recognition of abnormalities. Because of this, all radiologist investigators performing the examinations have been specially trained in technique and interpretation criteria. A set of 70 proved breast sonogram cases was developed for this purpose, which is available through the American College of Radiology. A quality control manual has been developed with required phantom testing. Clinical images from each site will also be reviewed. The primary aim is to determine whether wholebreast bilateral screening sonography can identify cancers occult to mammography, and whether such results are generalizable across multiple centers. Issues of the accuracy of breast sonography, reliability of breast ultrasound, and risk of malignancy of solid masses classified as probably benign [25] will be addressed, as will cost-effectiveness and qualityof-life measures.
False-positives One of the advantages of sonography is that biopsy of suspicious abnormalities seen only sonographically is a relatively simple and painless procedure. Nonetheless, minimizing unnecessary patient anxiety and costs is a critical goal of any new screening procedure. Across the single-center studies [12 – 17], on average 3.1% of women screened underwent biopsy or aspiration, with 11.4% of biopsied lesions proving malignant (see Table 1).
Short-interval follow-up Another 6.6% of women required short interval follow-up based on screening sonography [12,14 – 16]. It is important to recognize that criteria continue to be refined for sonographically identified
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incidental lesions that may be able to be followed or dismissed. It is important to note that criteria are for nonpalpable lesions at this time. For a lesion to be considered bprobably benign,Q BI-RADS category 3 [26], it must meet certain criteria: 1. The risk of malignancy must be quite small. For mammography, circumscribed, nonpalpable masses of any size, on a baseline examination, have a risk of malignancy of less than 2% [27 – 29]. Stavros et al [30] found that sonographically circumscribed oval or gently lobulated, nonpalpable, hypoechoic masses had a risk of malignancy of less than 2%. This has not yet been generalized. 2. For those few malignancies that are followed, the prognosis must not be adversely affected by surveillance. 3. No suspicious findings can be present. Findings that are new or ipsilateral to a cancer have an increased likelihood of malignancy and are not generally eligible for surveillance. Uniformly hyperechoic masses are uncommon, usually caused by lipomas or focal fibrosis (atrophic breast tissue); such masses can be classified as benign in the absence of any suspicious features. Fat necrosis is often manifested as a hyperechoic mass with a tiny cystic component (seroma); with the proper history, this appearance can be considered probably benign even when palpable. At short-interval follow-up in 3 to 6 months, fat necrosis typically decreases in size, although it can develop peripheral rim calcifications. Such follow-up is appropriate to better exclude an underlying neoplasm that might have bled. Multiplicity and bilaterality have been shown to decrease the risk of malignancy for circumscribed masses seen mammographically. When at least three masses were present, at least one in each breast [31], the rate of interval cancers was 0.14% (less than agematched controls at 0.24%). Such findings were demonstrated in 1.7% of all screening examinations. It is likely, but as yet unproved, that multiple bilateral, nonpalpable, circumscribed oval hypoechoic masses identified incidentally on sonography have a similarly low rate of malignancy, as do multiple bilateral complicated cysts, particularly in the context of associated simple cysts. This requires further study. For ACRIN Protocol 6666 [19], the following nonpalpable findings are classified as probably benign on baseline screening ultrasound. These are illustrated in the ARRS 2004 Categorical Course Syllabus [25].
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1. Oval masses (parallel to the skin in orientation) hypoechoic to fat with circumscribed borders and no posterior features or minimal posterior enhancement, including multiple bilateral masses with these features if seen only sonographically 2. Hyperechoic masses with central hypoechoic to anechoic components suggesting fat necrosis 3. Complicated cysts (ie, hypoechoic oval masses with homogeneous low-level internal echoes) that otherwise meet the criteria for simple cysts (circumscribed, round, or oval with acoustic enhancement). When multiple and bilateral complicated cysts are identified in the company of simple cysts, such findings will be reevaluated in 1 year. Furthermore, complicated cysts with a mobile fluid-debris level or mobile internal echoes will be dismissed as benign. 4. Microlobulated or oval masses composed entirely of clustered microcysts, with or without layering microcalcifications (milk of calcium) 5. Probably artifactual posterior shadowing at the interface of fat lobules without any associated mass, which changes appearance on changing the angle of insonation 6. Architectural distortion believed to be caused by postsurgical scar (ie, hypoechoic areas with concave borders, with a track extending to the overlying skin scar) can be classified as probably benign or benign at the discretion of the investigator Short-interval follow-up sonography will be performed at 6, 12, and 24 months and stability recorded. Any abnormal interval change (defined as an increase in volume by more than 20% or development of suspicious features) should prompt aspiration or biopsy. Any of the previously mentioned lesions that decrease in volume by more than 20% or resolve on any follow-up will be considered benign and dismissed. It is hoped that this trial will show that such lesions conform to the criteria for surveillance outlined previously. It is possible that the rate of malignancy for such lesions will be closer to 3% to 4% by these proposed sonographic criteria [32]. Such a rate may be acceptable if short interval follow-up does not result in a worse stage distribution of the few cancers that are followed. It is incumbent for practitioners to monitor their own outcomes for any breast lesions that are followed and demonstrate that such follow-up does not adversely affect prognosis of patients. The anxiety caused by the additional testing and biopsies induced by screening sonography will be
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studied in ACRIN Protocol 6666. Costs attributed to screening sonography will also be assessed. [4]
Summary Only practitioners experienced in breast sonography should contemplate offering screening sonography at this time, with full awareness that it is not the standard of care at present [33]. Annual screening mammography beginning at age 40 (or earlier if indicated [34]) remains the only proved test to decrease a woman’s chance of dying from breast cancer. A woman with dense or heterogeneously dense breast tissue on mammography contemplating a supplemental screening sonogram in addition to mammography needs to consider the risk of a false-positive examination, possibly requiring biopsy. She needs to understand that early detection may or may not be of benefit to her if a cancer is found. Facilities and practitioners offering screening sonography should meet the equipment, experience, and continuing education criteria for accreditation by the American College of Radiology or the American Institute for Ultrasound in Medicine for performance and interpretation of breast sonography and performance of sonographically guided aspiration and core biopsy. All sites in ACRIN Protocol 6666 meet these requirements. If ACRIN Protocol 6666 confirms that sonography depicts stage I invasive cancers not seen on mammography, even in retrospect, and that the costs and risks of this additional testing are reasonable [35], then it seems appropriate to offer supplemental sonography to women with dense breasts. A randomized study with mortality as an endpoint may be unethical. In the interim, the patient and practitioner must weigh the potential risks and benefits. Ideally, interim results of screening sonography will be collected as part of appropriately designed clinical trials so that there are accurate answers for patients and physicians alike on the true benefits, risks, and proper role of screening breast sonography.
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[7]
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[10]
[11]
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[13]
[14]
[15]
[16]
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of ductal carcinoma in situ (DCIS) of the breast. Cancer Lett 1994;86:1 – 4. Feig SA. Ductal carcinoma in situ: implications for screening mammography. Radiol Clin North Am 2000; 38:653 – 68. Yen MF, Tabar L, Vitak B, Smith RA, Chen HH, Duffy SW. Quantifying the potential problem of overdiagnosis of ductal carcinoma in situ in breast cancer screening. Eur J Cancer 2003;39:1746 – 54. Duffy SW, Tabar L, Vitak B, et al. The relative contributions of screen-detected in situ and invasive breast carcinomas in reducing mortality from the disease. Eur J Cancer 2003;39:1755 – 60. Kerlikowske K, Grady D, Barclay J, Sickles EA, Ernster V. Effect of age, breast density, and family history on the sensitivity of first screening mammography. JAMA 1996;276:33 – 8. Morris EA. Screening breast MRI in high-risk women. ARRS Categorical Course Syllabus 2004;139 – 44. Liberman L, Morris EA, Benton CL, Abramson AF, Dershaw DD. Probably benign lesions at breast magnetic resonance imaging: preliminary experience in high-risk women. Cancer 2003;98:377 – 88. Perlet C, Schneider P, Amaya B, et al. MR-Guided vacuum biopsy of 206 contrast-enhancing breast lesions. Rofo Fortschr Geb Rontgenstr Neuen Bildgeb Verfahr 2002;174:88 – 95. Liberman L, Morris EA, Dershaw DD, Thornton CM, Van Zee KJ, Tan LK. Fast MRI-guided vacuumassisted breast biopsy: initial experience. AJR Am J Roentgenol 2003;181:1283 – 93. Gordon PB, Goldenberg SL. Malignant breast masses detected only by ultrasound: a retrospective review. Cancer 1995;76:626 – 30. Buchberger W, Niehoff A, Obrist P, DeKoekkoek-Doll M, Dunser M. Clinically and mammographically occult breast lesions: detection and classification with high-resolution sonography. Semin Ultrasound CT MR 2000;21:325 – 36. Kaplan SS. Clinical utility of bilateral whole-breast US in the evaluation of women with dense breast tissue. Radiology 2001;221:641 – 9. Kolb TM, Lichy J, Newhouse JH. Comparison of the performance of screening mammography, physical examination, and breast US and evaluation of factors that influence them: an analysis of 27,825 patient evaluations. Radiology 2002;225:165 – 75. Crystal P, Strano SD, Shcharynski S, Koretz MJ. Using sonography to screen women with mammographically dense breasts. AJR Am J Roentgenol 2003; 181:177 – 82. Leconte I, Feger C, Galant C, et al. Mammography and subsequent whole-breast sonography of nonpalpable breast cancers: the importance of radiologic breast density. AJR Am J Roentgenol 2003;180:1675 – 9. Soo MS, Baker JA, Rosen EL. Sonographic detection and sonographically guided biopsy of breast microcalcifications. AJR Am J Roentgenol 2003;180: 941 – 8.
W.A. Berg / Radiol Clin N Am 42 (2004) 845 – 851 [19] Berg WA. Rationale for a trial of screening breast ultrasound: American College of Radiology Imaging Network (ACRIN) 6666. AJR Am J Roentgenol 2003;180:1225 – 8. [20] Gail MH, Brinton LA, Byar DP, et al. Projecting individualized probabilities of developing breast cancer for white females who are being examined annually. J Natl Cancer Inst 1989;81:1879 – 86. [21] Gail MH, Benichou J. Validation studies on a model for breast cancer risk. J Natl Cancer Inst 1994;86: 573 – 5. [22] Gail MH, Greene MH. Gail model and breast cancer. Lancet 2000;355:1017. [23] Claus EB, Risch N, Thompson WD. The calculation of breast cancer risk for women with a first degree family history of ovarian cancer. Breast Cancer Res Treat 1993;28:115 – 20. [24] Claus EB, Risch N, Thompson WD. Autosomal dominant inheritance of early-onset breast cancer: implications for risk prediction. Cancer 1994;73:643 – 51. [25] Berg WA. Breast ultrasonography: cystic lesions and probably benign findings. ARRS Categorical Course Syllabus 2004;95 – 102. [26] American College of Radiology. Illustrated breast imaging reporting and data system (BI-RADS): ultrasound. 1st edition. Reston, VA7 American College of Radiology; 2003. [27] Sickles EA. Nonpalpable, circumscribed, noncalcified solid breast masses: likelihood of malignancy based on
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lesion size and age of patient. Radiology 1994;192: 439 – 42. Varas X, Leborgne F, Leborgne JH. Nonpalpable, probably benign lesions: role of follow-up mammography. Radiology 1992;184:409 – 14. Vizcaino I, Gadea L, Andreo L, et al. Short-term follow-up results in 795 nonpalpable probably benign lesions detected at screening mammography. Radiology 2001;219:475 – 83. Stavros AT, Thickman D, Rapp CL, Dennis MA, Parker SH, Sisney GA. Solid breast nodules: use of sonography to distinguish between benign and malignant lesions. Radiology 1995;196:123 – 34. Leung JW, Sickles EA. Multiple bilateral masses detected on screening mammography: assessment of need for recall imaging. AJR Am J Roentgenol 2000; 175:23 – 9. Rahbar G, Sie AC, Hansen GC, et al. Benign versus malignant solid breast masses: US differentiation. Radiology 1999;213:889 – 94. Kopans DB. Sonography should not be used for breast cancer screening until its efficacy has been proven scientifically. AJR Am J Roentgenol 2004;182: 489 – 91. Dershaw DD. Mammographic screening of the highrisk woman. Am J Surg 2000;180:288 – 9. Farria D, Feig SA. An introduction to economic issues in breast imaging. Radiol Clin North Am 2000;38: 825 – 42.
Supplemental screening sonography in dense breasts Wendie A. Berg, MD, PhD Breast Imaging Consultant, Study Chair ACRIN Protocol 6666, Lutherville, MD 21093, USA
There are three basic principles of screening for breast cancer. The most critical of these is that early detection and resulting treatment improve the outcome of the disease. Earlier detection often allows breast conservation and less harmful treatments. A second important principle is that healthy women are not harmed. Finally, a screening test must be practical: it must be cost-effective to screen a population in terms of quality-adjusted years of life saved. At this time, the only screening test that has been shown to reduce deaths caused by breast cancer is mammography. Supplemental screening with sonography or MR imaging after mammography can increase the rates of early detection of breast cancer in denser categories of breast tissue. Whether or not this additional breast cancer detection alters the outcome of the disease has not yet been established directly, although surrogate end points of tumor size and nodal status can guide this discussion. The degree to which healthy women are subjected to additional testing and biopsies and potentially unnecessary treatments depends on the prevalence of cancer in the healthy women. The degree to which this additional testing adversely affects women is being studied. Cost effectiveness needs to be addressed in considering widespread application of any further screening tests. This article reviews the experience to date with screening sonography in single-center studies, addresses the goals and interpretation guidelines of an ongoing multicenter randomized trial, and discusses what is needed before widespread use of this approach.
Supported by grants from the Avon Foundation and the National Institutes of Health (CA80098). E-mail address: [email protected]
Basic concepts Mammographically screen-detected cancers have a better prognosis than clinically detected cancers. Tabar et al [1] found that 50% of screen-detected cancers had good prognosis and 18% had poor prognosis, whereas 19% of clinically detected cancers had good prognosis and 47% poor prognosis. bGoodQ prognosis cancers include all ductal carcinoma in situ (DCIS), node-negative invasive cancers of small size: less than 20 mm if grade I invasive ductal, less than 15 mm if grade II, less than 10 mm if grade III, and less than 10 mm invasive lobular [1]. All tubular cancers had good or intermediate prognosis [1]. bPoorQ prognosis cancers are node-positive and larger in size, but fundamentally the same histology as those of good prognosis. It stands to reason that left undetected, good prognosis cancers will progress to those with poor prognosis. Furthermore, the prognosis and treatment of a given breast cancer depend predominantly on size and nodal status [1,2] (and receptor status): prognosis and treatment of a given cancer should be essentially independent of the method of detection. There has been recent controversy surrounding potential overdiagnosis and overtreatment of DCIS. Left untreated, most DCIS progress to invasive carcinoma, but this may occur over a period of 20 years or more [3,4]. Yen et al [5] recently analyzed the results of the Swedish two-county trial around this issue. At the first (prevalent) screen, they estimate that 37% of DCIS is nonprogressive [5]. The corresponding percentage at incidence (subsequent) screens was estimated at 4% [5], a very small percentage. This suggests that overtreatment may occur at the first (prevalent) screen with any given screening test, but is uncommon if the test is performed annually. Cancers that are new on sub-
0033-8389/04/$ – see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.rcl.2004.04.003
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sequent (incidence) screens can be considered biologically relevant. In a companion article, Duffy et al [6] conclude that most mortality reduction in the Swedish twocounty trial was caused by stage-shifting from invasive stage II or worse to invasive stage I disease and that detection of DCIS might account for 5% to 12% of all deaths averted. From these analyses, it seems that detection of stage I invasive carcinomas is the most critical benefit of screening mammography. It is reasonable to assume that this benefit accrues to other methods of screening that increase detection of stage I invasive cancers. Kerlikowske et al [7] reported results on 27,281 screening mammograms and found the sensitivity for cancer detection was 98.4% in women greater than or equal 50 years of age with fatty breasts and 83.7% in dense breasts (P = .01). In women under 50, the sensitivity was 81.8% in fatty breasts and 85.4% in dense breasts (nonsignificant), although the number of cancers was small [7]. In women under 50 with a family history of breast cancer, sensitivity decreased to 68.8% [7]. In women with dense breasts, and particularly those at increased risk because of a family or personal history of breast cancer or atypia, methods to supplement mammography are sought.
MR imaging MR imaging has been proposed as a supplemental screening examination in high-risk women. Across 11 series [8], 6524 very high-risk (detailed later) women have been screened with MR imaging with 125 (1.9%) women having cancer depicted only on MR imaging. The median size of cancers was 7 to 20 mm, and in all but one series, greater than 80% of MR imaging–only depicted cancers were node negative. Where detailed, 19 (23%) of 81 of the cancers identified were DCIS [8]. Six percent to 18% of women screened were recommended for biopsy based on MR imaging and 17% to 62% of MR imaging – prompted biopsies proved malignant. Short-interval follow-up was required in another 3% to 8% of women, but the criteria for follow-up and risk of malignancy in lesions followed have not been well studied. Liberman et al [9] report 7% of lesions followed proved malignant, and another 3% of patients had cancer develop elsewhere in their breasts during short-interval follow-up. MR imaging is limited by high cost, relative lack of availability, variable patient tolerance, and the requirement for contrast injection. It remains challenging to integrate breast MR imaging into daily breast imaging practice.
MR imaging – guided core and vacuum-assisted biopsy are becoming more widely available [10,11], but require availability of scanner time and personnel. These topics are discussed in greater detail elsewhere in this issue.
Single-center studies of screening sonography Studies of screening sonography to date have been performed in women of average risk with nonfatty breasts. Across six series totaling 42,838 examinations, 150 (0.35%) additional cancers have been identified only on sonography in 126 women (Table 1) [12 – 17]. In all but one of these studies [15], a single screening sonogram was performed, which detects prevalent cancers seen only on sonography: there is not an estimate of the rate of incident cancers seen only on subsequent annual screening sonograms. Of the 150 cancers seen only on sonography [12 – 17], 141 (94%) were invasive and 9 (6%) were DCIS. Of the 141 invasive cancers, 99 (70%) were 1 cm or smaller in size. Where staging has been detailed [14–16], 36 (90%) of 40 were stage 0 (1 of 36) or stage I (35 of 36). The detection benefit of supplemental sonography increased with increasing grades of breast density. Indeed, of the 126 women with sonographically detected cancers, 114 (90.5%) had either heterogeneously dense or extremely dense parenchyma [12 – 17]. Women at higher risk of breast cancer were twofold to threefold more likely to have a cancer seen only sonographically. When information specific to risk factors was detailed, 55 (50%) of 110 women with ultrasound-only detected cancer were at highrisk because of a personal history of breast cancer or first-degree relative with breast cancer or prior atypia [12 – 16]. In the series of Kolb et al [15], of 2914 examinations performed in women at high risk with heterogeneously dense or dense breasts, 14 (0.48%) had cancer seen only sonographically, compared with 14 (0.18%) of 7901 examinations in women not at high risk. Similarly, in the series of Crystal et al [16], cancer was found only on sonography in 4 (1.3%) of 318 women with first-degree family history or personal history of breast cancer and 3 (0.25%) of 1199 women of average risk (P < .04). For 26,753 examinations, the results of mammography are also reported [13,15,17]. Another 56 (0.22%) cancers were seen only mammographically, with 42 (75%) of the 56 caused by DCIS and 14 (25%) invasive. In the series of 8970 women evaluated by Buchberger et al [13], including 867 women with palpable or mammographic abnor-
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Table 1 Summary of studies of screening breast US, biopsies prompted by US, positive predictive value of biopsy, and prevalence of cancers seen only sonographically Investigator/Yr Gordon and Goldenberg, 1995 [12] Buchberger et al, 2000 [13]d Kaplan, 2001 [14] Kolb et al, 2002 [15] Crystal et al, 2003 [16] Leconte et al, 2003 [17] Overall
No. 12,706 8103 867d 1862 13,547f 1517 4236h 42,838
No. biopsiesa (%) c
279 (2.2) 362 (4.5) 43 (5.0) 102 (5.5) 358 (2.6) 38 (2.5)g NS 1182 (3.1)h
No. malignant(%)b
Prevalence (%)
44/279 (16) 32/362 (8.8) 8/43 (19) 6/99 (6.6) 37/358 (10) 7/38 (18) NSh 134/1171 (11.4)
44/12,706 (0.35)c 32/8103 (0.39)e 8/867 (0.9)e 6/1,862 (0.3) 37/13,547 (0.27)f 7/1517 (0.46)g 16/4,236 (0.38) 150/42,838 (0.35)
Abbrevations: NS, not stated; US, ultrasound. a Biopsies and aspiration prompted by screening sonography. b Refers to cancers seen only on breast sonography, expressed as percent of biopsies. c All women had clinical or mammographic abnormalities. Diagnosis was by fine-needle aspiration biopsy. Numbers refer to solid masses. Sixteen cancers were found in 15 women with ipsilateral cancer. d In this series, 867 women were evaluated because of palpable or mammographic abnormalities; five cancers seen only on sonography were in patients with another mammographically or clinically evident cancer. e Cancer was found only on sonography in 0.54% of women with a personal history of cancer compared with 0.26% of women with no personal history of cancer. f Includes patients described in 1998 series [9]. Number of studies, not women, because some women had more than one study. Cancer was found only on sonography in 0.48% of high-risk women compared with 0.16% of normal-risk women. g Cancer was found only on sonography in 4 (1.3%) of 318 women with first-degree family history or personal history of breast cancer and 3 (0.25%) of 1199 women of average risk; biopsies includes 17 aspirations, of which 13 yielded clear fluid. h One thousand sixteen had a personal history of breast cancer and 136 a palpable lesion (with the palpable lesions themselves excluded), although the number of cancers seen in women at high risk was not specified. Sixteen cancers were identified, but the number of biopsies induced by sonography was not specified: results of this study were not included in calculating the biopsy rate nor the malignancy rate of biopsies.
malities, mammography depicted 142 (78%) of 182 of all cancers in women with other than fatty breasts, and 162 (89%) of 182 were seen on sonography. In the series of Kolb et al [15], in women with heterogeneously dense or dense breasts, sonography alone was again more sensitive than mammography, with 60 (57%) of 105 of cancers seen mammographically and 83 (79%) of 105 seen sonographically. The combination of mammography and sonography depicted 101 (96%) of 105 of cancers in this group [15]. In all three series where results of mammography and sonography were reported [13,15,17], mammography and sonography seem complementary in that DCIS was better depicted mammographically, and small, less than 1 cm, invasive cancers were better seen sonographically in dense breasts. Invasive lobular cancer was overrepresented among cancers seen only on sonography. Summarizing results from four series where detailed histopathology was available [13,14,16,17], 17 (28%) of 61 invasive cancers seen only on sonography were lobular type. In the series of Kolb et al [15], screening sonography seemed to be especially beneficial in younger women (arbitrarily, women under 50) with
dense breasts, where mammography depicted only 21 (50%) of 42 of cancers and sonography 33 (79%) of 42. Younger age was predictive of increased prevalence of cancers seen only on sonography, independent of breast density [15]. In the single-center studies to date, the cancers found on supplemental screening sonography were almost all stage I invasive cancers. Identification of such cancers is most likely to prove beneficial in decreasing mortality from breast cancer. It will likely remain true that even with combined mammography and sonography there will be cancers that have metastasized by the time of detection and that early detection on imaging will be of no benefit. With the insensitivity of sonography to DCIS, overdiagnosis does not seem to be a major concern. Indeed, ultrasound can help identify the invasive component in lesions of DCIS and target biopsy to areas of associated mass [18]. One of the limitations of studies to date is that none of the studies were truly blinded to mammographic findings. Many performed sonography only when the mammogram is negative: any additional test can only be of benefit in this setting if it depicts anything. If performed in conjunction with mammog-
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raphy, the performance of the sonogram cannot help but be directed to areas of increased tissue density and questionable, but subthreshold mammographic abnormalities (eg, focal asymmetries, possible subtle architectural distortion). Importantly, it is not known whether or not the encouraging results of singlecenter studies are generalizable.
ACRIN Protocol 6666, screening breast ultrasound in high-risk women With the support of the AVON Foundation and the National Institutes of Health, through the American College of Radiology Imaging Network (ACRIN), a
Box 1. Summary of criteria to define high risk for ACRIN Protocol 6666, screening breast ultrasound in high-risk women (at least one of the following): 1. Known to have a mutation in BRCA1 or -2 2. Personal history of cancer (with conserved breast analyzed separately; after mastectomy, the breast reconstructed with autologous tissue will not be imaged, but the other breast will be eligible for imaging) 3. History of prior biopsy showing lobu lar carcinoma in situ 4. History of prior biopsy showing atypical ductal hyperplasia, atypical lobular hyperplasia, or atypical papillary lesion; not on chemoprevention; or any of these atypical lesions and a first-degree relative diagnosed with breast cancer under age 50 even if the patient is on chemoprevention 5. History of prior chest or mediastinal or axillary irradiation less than or equal to age 30 and at least 8 years previously 6. Lifetime risk of breast cancer by Gail [20 – 22] or Claus models of at least 25% [23,24] 7.5-year risk by Gail model of _2.5% > 8.5-year risk by Gail model of _1.7% and extremely dense > parenchyma
multicenter protocol to assess the efficacy of screening breast sonography has opened to begin enrollment (for more information, go to www.acrin.org) [19]. Twenty centers will enroll 2808 high-risk (Box 1) asymptomatic women with dense breasts for three annual screening mammograms and sonograms. Women will be randomized to initial mammography or sonography. Importantly, mammographic and sonographic interpretations will be independent, to gain true measures of the performance of sonography. A second integration interpretation will be performed. Breast sonography is highly operator dependent, requiring real-time adjustments of gain; focal zones; dynamic range; angle of insonation; pressure; patient positioning; and, most importantly, recognition of abnormalities. Because of this, all radiologist investigators performing the examinations have been specially trained in technique and interpretation criteria. A set of 70 proved breast sonogram cases was developed for this purpose, which is available through the American College of Radiology. A quality control manual has been developed with required phantom testing. Clinical images from each site will also be reviewed. The primary aim is to determine whether wholebreast bilateral screening sonography can identify cancers occult to mammography, and whether such results are generalizable across multiple centers. Issues of the accuracy of breast sonography, reliability of breast ultrasound, and risk of malignancy of solid masses classified as probably benign [25] will be addressed, as will cost-effectiveness and qualityof-life measures.
False-positives One of the advantages of sonography is that biopsy of suspicious abnormalities seen only sonographically is a relatively simple and painless procedure. Nonetheless, minimizing unnecessary patient anxiety and costs is a critical goal of any new screening procedure. Across the single-center studies [12 – 17], on average 3.1% of women screened underwent biopsy or aspiration, with 11.4% of biopsied lesions proving malignant (see Table 1).
Short-interval follow-up Another 6.6% of women required short interval follow-up based on screening sonography [12,14 – 16]. It is important to recognize that criteria continue to be refined for sonographically identified
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incidental lesions that may be able to be followed or dismissed. It is important to note that criteria are for nonpalpable lesions at this time. For a lesion to be considered bprobably benign,Q BI-RADS category 3 [26], it must meet certain criteria: 1. The risk of malignancy must be quite small. For mammography, circumscribed, nonpalpable masses of any size, on a baseline examination, have a risk of malignancy of less than 2% [27 – 29]. Stavros et al [30] found that sonographically circumscribed oval or gently lobulated, nonpalpable, hypoechoic masses had a risk of malignancy of less than 2%. This has not yet been generalized. 2. For those few malignancies that are followed, the prognosis must not be adversely affected by surveillance. 3. No suspicious findings can be present. Findings that are new or ipsilateral to a cancer have an increased likelihood of malignancy and are not generally eligible for surveillance. Uniformly hyperechoic masses are uncommon, usually caused by lipomas or focal fibrosis (atrophic breast tissue); such masses can be classified as benign in the absence of any suspicious features. Fat necrosis is often manifested as a hyperechoic mass with a tiny cystic component (seroma); with the proper history, this appearance can be considered probably benign even when palpable. At short-interval follow-up in 3 to 6 months, fat necrosis typically decreases in size, although it can develop peripheral rim calcifications. Such follow-up is appropriate to better exclude an underlying neoplasm that might have bled. Multiplicity and bilaterality have been shown to decrease the risk of malignancy for circumscribed masses seen mammographically. When at least three masses were present, at least one in each breast [31], the rate of interval cancers was 0.14% (less than agematched controls at 0.24%). Such findings were demonstrated in 1.7% of all screening examinations. It is likely, but as yet unproved, that multiple bilateral, nonpalpable, circumscribed oval hypoechoic masses identified incidentally on sonography have a similarly low rate of malignancy, as do multiple bilateral complicated cysts, particularly in the context of associated simple cysts. This requires further study. For ACRIN Protocol 6666 [19], the following nonpalpable findings are classified as probably benign on baseline screening ultrasound. These are illustrated in the ARRS 2004 Categorical Course Syllabus [25].
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1. Oval masses (parallel to the skin in orientation) hypoechoic to fat with circumscribed borders and no posterior features or minimal posterior enhancement, including multiple bilateral masses with these features if seen only sonographically 2. Hyperechoic masses with central hypoechoic to anechoic components suggesting fat necrosis 3. Complicated cysts (ie, hypoechoic oval masses with homogeneous low-level internal echoes) that otherwise meet the criteria for simple cysts (circumscribed, round, or oval with acoustic enhancement). When multiple and bilateral complicated cysts are identified in the company of simple cysts, such findings will be reevaluated in 1 year. Furthermore, complicated cysts with a mobile fluid-debris level or mobile internal echoes will be dismissed as benign. 4. Microlobulated or oval masses composed entirely of clustered microcysts, with or without layering microcalcifications (milk of calcium) 5. Probably artifactual posterior shadowing at the interface of fat lobules without any associated mass, which changes appearance on changing the angle of insonation 6. Architectural distortion believed to be caused by postsurgical scar (ie, hypoechoic areas with concave borders, with a track extending to the overlying skin scar) can be classified as probably benign or benign at the discretion of the investigator Short-interval follow-up sonography will be performed at 6, 12, and 24 months and stability recorded. Any abnormal interval change (defined as an increase in volume by more than 20% or development of suspicious features) should prompt aspiration or biopsy. Any of the previously mentioned lesions that decrease in volume by more than 20% or resolve on any follow-up will be considered benign and dismissed. It is hoped that this trial will show that such lesions conform to the criteria for surveillance outlined previously. It is possible that the rate of malignancy for such lesions will be closer to 3% to 4% by these proposed sonographic criteria [32]. Such a rate may be acceptable if short interval follow-up does not result in a worse stage distribution of the few cancers that are followed. It is incumbent for practitioners to monitor their own outcomes for any breast lesions that are followed and demonstrate that such follow-up does not adversely affect prognosis of patients. The anxiety caused by the additional testing and biopsies induced by screening sonography will be
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studied in ACRIN Protocol 6666. Costs attributed to screening sonography will also be assessed. [4]
Summary Only practitioners experienced in breast sonography should contemplate offering screening sonography at this time, with full awareness that it is not the standard of care at present [33]. Annual screening mammography beginning at age 40 (or earlier if indicated [34]) remains the only proved test to decrease a woman’s chance of dying from breast cancer. A woman with dense or heterogeneously dense breast tissue on mammography contemplating a supplemental screening sonogram in addition to mammography needs to consider the risk of a false-positive examination, possibly requiring biopsy. She needs to understand that early detection may or may not be of benefit to her if a cancer is found. Facilities and practitioners offering screening sonography should meet the equipment, experience, and continuing education criteria for accreditation by the American College of Radiology or the American Institute for Ultrasound in Medicine for performance and interpretation of breast sonography and performance of sonographically guided aspiration and core biopsy. All sites in ACRIN Protocol 6666 meet these requirements. If ACRIN Protocol 6666 confirms that sonography depicts stage I invasive cancers not seen on mammography, even in retrospect, and that the costs and risks of this additional testing are reasonable [35], then it seems appropriate to offer supplemental sonography to women with dense breasts. A randomized study with mortality as an endpoint may be unethical. In the interim, the patient and practitioner must weigh the potential risks and benefits. Ideally, interim results of screening sonography will be collected as part of appropriately designed clinical trials so that there are accurate answers for patients and physicians alike on the true benefits, risks, and proper role of screening breast sonography.
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