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SUCCESSFUL METHODS TO REDUCE FALSE-POSITIVE MAMMOGRAPHY INTERPRETATIONS
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SUCCESSFUL METHODS TO REDUCE FALSE-POSITIVE MAMMOGRAPHY INTERPRETATIONS Edward A. Sickles, MD
There is now solid scientific evidence, derived from several randomized controlled trials, of a statistically significant breast cancer mortality reduction for women age 40 and older who undergo routine screening mammography.” 6, 21 Because of the convincing nature of this evidence, the remaining controversy about the widespread use of screening has, for the most part, shifted to concerns about the risks (harms) of mammography, concentrating on the morbidity and economic costs of false-positive cases.3,13* l4 It is beyond the scope of this article to join in the debate. Rather, the aim herein is to discuss several already demonstrated methods that permit radiologists safely and effectively to reduce the frequency of false-positive mammography interpretations. In my opinion, the widespread implementation of these successful methods currently represents the best argument in defense of mammography that can be advanced by the radiology community. One must remember that the primary goal of mammography is to detect nonpalpable, favorable-prognosis cancer; it is not to have relatively few false-positive cases. As a first priority, the radiologist should strive to achieve a high cancer detection rate, with the
great majority of cancers being nonpalpable and early in stage. Only once such a level of success is demonstrated should one attempt to reduce the rate of false-positive interpretations. In other words, first establish the benefit and then attempt to minimize the harms (while maintaining an acceptable level of benefit). Because any strategy designed to reduce the frequency of false-positive cases requires examinations otherwise interpreted as positive to instead be read as negative, and because this leads to a reduction in the number of true-positive cases if any cancers are thereby overlooked, it is clear that successful approaches to reducing false-positive interpretations achieve this goal only if there is no more than a minor decrease in the early detection of favorable-prognosis cancers. Any initially overlooked cancers should still be of good prognosis when ultimately detected, demonstrating favorable clinical outcomes after treatment. FALSE-POSITIVE INTERPRETATIONS
A false-positive case is one that is interpreted as positive but actually found to be nega-
From the Breast Imaging Section, Department of Radiology, University of California Medical Center, San Francisco, California
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tive. In the context of mammography, found to be negative is defined as the absence of a tissue diagnosis of cancer (invasive carcinoma or ductal carcinoma in situ [DCIS]) within a given time period after examination, the time period being equivalent to the standard interval between screening examinations. This time period is 1 year in the United States, where screening mammography is widely recommended at yearly intervals for all women beginning at age 40.’. 16, 23 There are two definitions of interpreted as positive, one for screening mammography, the other for diagnostic mammography. For screening mammography, which is limited to a craniocaudal and mediolateral oblique view of each breast, a positive case is any examination for which prompt additional work-up is recommended. This includes not only the relatively few examinations with findings already judged to be sufficiently suspicious for malignancy so as to justify tissue diagnosis (BI-RADS assessment categories 4 and 5), but also the larger subset of examinations with findings that are incompletely evaluated at screening and require additional imaging assessment (BI-RADS category 0). The outcome parameter that tracks positive cases at screening is the recall rate.* For diagnostic mammography, which includes whatever supplementary mammographic views are needed to solve a patient’s particular imaging problems, a positive case is defined as an examination for which tissue diagnosis is recommended. To track positive cases for diagnostic mammography, one obtains follow-up data on BI-RADS category 4 and 5 (but not category 0) assessments. There are two principal false-positive scenarios concerning mammography interpretation. First is the recommendation to perform additional imaging (recall examination), *Some mammography practices interpret screening examinations while women are still on site, so that many detected abnormalities for which recall otherwise would be recommended are worked-up immediately; in such cases, there is no need for formal screening interpretation, and only diagnostic (final) assessments are made. Some other practices do not make formal interpretations for recalled screening examinations, but rather recall each woman directly and wait until the imaging work-up is completed to render a single (final) assessment. In both such situations, although BI-RADS category 0 assessments are not formally made for screening-detected abnormalities, the screening components of these examinations nonetheless should be considered to be positive, independent of the assessments made for the diagnostic examinations.
based on screening-detected findings, for which cancer ultimately is not identified. Second is the recommendation to perform tissue diagnosis procedures, to assess unresolved abnormalities further following a complete breast imaging work-up, for which cancer is not found . Successful methods to reduce the recall rate for screening mammography (without substantially reducing the rate of detecting favorable-prognosis cancer) involve (1) obtaining previous mammograms for comparison at the time of initial image interpretation, (2) confidently and correctly identifying some summation artifacts from the two standard screening views of each breast, and ( 3 ) learning to ignore subtle mammographic findings of doubtful significance. Successful methods to reduce the rate of benign tissue diagnosis after full breast imaging work-up involve (1) confidently and correctly identifying the as yet unrecognized summation artifacts by properly tailoring the diagnostic mammography examination, and (2) substituting management by periodic mammographic surveillance in place of tissue diagnosis for probably benign findings (BI-RADS category 3 assessments). COMPARISON WITH PREVIOUS MAMMOGRAMS AT TIME OF INITIAL SCREENING INTERPRETATION
The recall rate for screening mammography is highly dependent on whether examinations are interpreted with or without comparison films from previous screening examinations. Indeed, one can expect a significant (approximately 50%) reduction in the recall rate, with no accompanying reduction in the detection of nonpalpable early stage cancers, when screening examinations are interpreted in comparison with recent previous screening mammograms.7,9,17,24,27-29,37.43,44,48 1n my own practice at the University of California at San Francisco (UCSF), based on data for 118,783 consecutive screening mammography examinations, the recall rate is 7.4% for examinations interpreted without the benefit of previous films, versus 3.2% for examinations interpreted in comparison with previous UCSF screening mammograms. One factor that helps to explain this disparity is that some lesions detected at initial screening are excised, so that fewer abnormalities are still present at subsequent screening
SUCCESSFUL METHODS TO REDUCE FALSE-POSITIVE MAMMOGRAPHY INTERPRETATIONS
to be available for recall. In addition, some other lesions detected at initial screening undergo percutaneous tissue sampling yielding benign diagnoses that are concordant with imaging findings, so that although portions of these lesions remain, they do not prompt recall on subsequent screening because they are now known to be benign. There also are two major reasons why mammographic findings that otherwise might prompt recall at current screening do not do so, simply because previous films are available for comparison. (1) The previous films include those from a recall examination already performed for the given mammographic finding, in which the recall examination itself demonstrates confidently benign features, thereby eliminating any further concern at subsequent screening. (2) The findings seen currently are just above the threshold for recall, but demonstration of stability in comparison with previous films reduces the level of concern below the threshold for recall. On the basis of these various observations, it is clear that one successful method to reduce the recall rate for screening mammography substantially is to implement policies that maximize the availability of previous mammograms at the time of image interpretation. Radiology practices should develop procedures to facilitate the reliable retrieval of their own previous films in the interval between when a woman makes a screening mammography appointment and when the films from that examination are interpreted. Primary care providers and women themselves must be more effectively educated to the advantage of deferring screening mammography examinations until they first obtain previous mammograms from different radiology facilitie~.~~ CONFIDENTLY AND CORRECTLY IDENTIFYING SUMMATION ARTIFACTS
It is not at all unusual for potentially abnormal findings to be identified at screening mammography on only one of the two standard-projection images. The great majority of these findings represent superimposition of normal structures (summation artifact); relatively few eventually are found to be malignant. Several imaging approaches have been described to distinguish summation artifacts
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from more important lesions in these cases, principally involving additional mammography using nonstandard projections, such as off-angle views, roll views, and 90-degree lateral views, and spot-compression and magnification tecKques.4, 8, 11. 12. 15. 22, 25. 31. 39, 42 Based on a recent large-scale UCSF study, there is emerging evidence that one can (1) reliably characterize many summation artifacts simply by enlightened screening mammography interpretation, thereby reducing the recall rate; and (2) characterize the remainder of summation artifacts by obtaining tailored diagnostic mammographic views at the time of recall examination, thereby averting benign biopsy or short-term interval follow-up.33 The UCSF study involved consecutive mammography screening examinations for which radiologists prospectively identified a variety of potentially abnormal findings seen only on one of the two standard screening views. The study catalogued the frequency of occurrence of examinations with one-viewonly findings, the mammographic features of the findings, whether recall for additional imaging work-up was recommended, and the final assessment after imaging was complete. For examinations with screening-detected findings undergoing tissue sampling, pathologic diagnosis was recorded, cancer being defined as invasive carcinoma or DCIS. To identify breast cancers among the remaining examinations with one-view-only findings, computer linkage of these cases was performed with the data stored in a regional tumor registry, the linkage taking place a minimum of 2 years after screening was done. There were 61,273 screening examinations reviewed in the UCSF study. One-view-only findings were identified on 2023 examinations, representing 3.3% of these cases. This amounts to 1 in approximately every 30 examinations, so that a moderately busy mammography screening practice can expect to encounter one-view-only findings on a daily basis. The great majority of these findings were noncalcified densities, with relatively small percentages of cases representing areas of possible architectural distortion and microcalcifications. Of the 2023 one-view-only findings, 1086 (53.7%) were interpreted as representing superimposition of normal structures simply on the basis of the standard two-view screening examination. Each of these cases presented as a one-view-only noncalcified density or area of architectural distortion at screening mam-
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mography. Of the remaining 937 cases, for which recall imaging was requested and performed, an additional 587 cases (also noncalcified densities or areas of architectural distortion) were found to represent superimposition of normal structures. Summation artifact accounted for 1673 (82.7%) of the 2023 one-view-only cases. These assessments indicating the presence of summation artifact indeed were highly accurate, despite the lack of confirmation by tissue diagnosis, because none of the cases were eventually found to involve breast carcinoma, either at subsequent routine mammography screening (if done), or by linkage with the regional tumor registry. As shown in the UCSF study, it is possible to recognize a large percentage of summation artifacts simply by careful analysis of the two standard-projection screening images. By eliminating recall for these 1086 UCSF cases, the total number of recalled cases during the study period decreased from 4310 to 3224, thereby decreasing the recall rate by slightly more than one third (from 6.8% to 5.1%), without overlooking any cancers. The fact that this (UCSF) approach to screening mammography interpretation is not in widespread use indicates a great opportunity for largescale reduction in recall rates. It is unknown, however, to what degree the success achieved at UCSF can be transferred to other screening mammography practices. As applies to the introduction of any new interpretive approach, one should exercise caution in implementation. A simple and safe method is to attempt the UCSF approach but still recommend recall, and then determine performance by assessing outcomes at recall examination, putting the approach into practice only after success has been demonstrated. It also is important for radiologists to develop sufficient skills to make the diagnosis of summation artifact using additional imaging after recall from screening. In the UCSF study, had all 1673 cases interpreted as summation artifact actually received a recommendation for tissue diagnosis (fine-needle aspiration biopsy, core biopsy, or surgical biopsy), the number of requested biopsies during the study period would have increased from 932 to 2605, without any increase in the 328 cancers discovered, thereby decreasing the cancer rate for positive diagnostic interpretations from 35.2% to an unacceptably low rate of 12.6%.
IGNORING SUBTLE MAMMOGRAPHIC FINDINGS OF DOUBTFUL SIGNIFICANCE Most radiologists are aware that 25% to 75% of breast cancers detected at mammography screening are visible in retrospect on at least one previous mammography examinat i ~ n ,19,~ 26, , 46 usually as subtle findings below traditional thresholds for recall imaging or biopsy. The genuine desire to identify breast cancer at its earliest detectable stage, and the fear of malpractice exposure if such subthreshold findings are ignored, causes many radiologists to request recall examinations for mammographic findings that have an exceedingly low likelihood of malignancy. One consequence of adopting this approach is an increase in false-positive interpretations. Another study was recently published from UCSF that demonstrated the radiographic and clinical outcomes for such findings, which were described as being of "doubtful" mammographic signifi~ance.~~ In this study, selected subthreshold findings were identified prospectively at routine screening, circled with wax crayon directly on the films, but the examinations were interpreted as negative or benign (BI-RADS category 1 or 2), with no recommendation for further imaging evaluation or tissue diagnosis. Circled findings displayed a variety of mammographic features, including loosely grouped calcifications, small low-opacity partially circumscribed densities, poorly defined asymmetric densities, and larger areas of asymmetric breast tissue. These findings were judged to be benign for several different reasons, including substantial variation in appearance on the two standard mammographic views; presence of similar benign-appearing findings elsewhere (especially if multiple and bilateral); and lack of suspicious associated features. The hallmark of the doubtful finding, however, was the assessment that it appeared sufficiently benign so as to permit repeat mammography in 1 year rather than further work-up. In the UCSF study on doubtful findings, 5514 consecutive screening examinations were reviewed for which a previous negative or benign screening examination was available for comparison. There were 543 wax crayon circles present on 382 of the previous examinations, marking doubtful findings for which the radiographic and clinical outcomes were then determined. The mean follow-up
SUCCESSFUL METHODS TO REDUCE FALSE-POSITIVE MAMMOGRAPHY INTERPRETATIONS
interval was 2.5 years. At subsequent mammography screening, 74% of the doubtful findings were unchanged; 21% had decreased in visibility or disappeared entirely; 4% were so slightly more prominent that the apparent changes were judged to be caused by differences in imaging technique; and 1% (six cases) had increased sufficiently to prompt recall examination. After full diagnostic imaging evaluation, three lesions underwent biopsy, with the diagnosis of only one malignancy, a low-grade cribriform DCIS that had changed only after 4 years of stability as a doubtful finding. This lesion then was completely excised and almost certainly cured by that treatment. After completion of case accrual, 1 year after the most recent subsequent screening examination, linkage of all study cases with the regional tumor registry failed to identify any other cases of breast cancer. Among 543 doubtful findings in 382 women, only one proved to be malignant, still favorable in prognosis when ultimately detected. This represented a cancer frequency of 0.2% per finding and 0.3% per woman screened, rates so low that they are essentially identical to the cancer incidence rate in an asymptomatic population. These results were interpreted as suggesting that prospective identification of mammographic findings below conventional thresholds for abnormality is not an effective method for detecting clinically occult breast cancer. The observations that virtually all doubtful mammographic findings are benign, and that subthreshold precursors of malignancy are difficult if not impossible to detect prospectively at mammography screening, indicate that recall or biopsy of such findings has little if any clinical use. To reduce false-positive screening interpretations substantially without meaningfully affecting the cancer detection rate, radiologists should learn to ignore such doubtful mammographic findings. MAMMOGRAPHIC SURVEILLANCE FOR PROBABLY BENIGN LESIONS
It is important to distinguish probably benign lesions from the doubtful findings described in the previous section of this article. Doubtful findings are so very unlikely to be malignant that they can safely be ignored. In contrast, probably benign lesions (BI-RADS category 3) usually are managed by periodic mammographic surveillance. Unlike doubtful
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findings, probably benign lesions have much less subtle mammographic features (e.g., circumscribed noncalcified mass, clustered round microcalcifications,and focal asymmetric density), prompting additional imaging to supplement that provided by the standard two-view-per-breast screening mammography examination. Ultrasonography is done for the circumscribed noncalcified mass, to establish or exclude the diagnosis of simple benign cyst, and to look for suspicious sonographic features that prompt a tissue diagnosis. Solid masses, densities, and lesions involving microcalcifications all benefit from fine-detail mammographic imaging, especially spot-compression magnification mammography, to portray the shapes and marginal characteristics of these lesions more clearly and also to serve as a baseline in case additional fine-detail images are obtained subsequently during the course of mammographic follow-up.40 The strongest evidence suggesting the use of noninterventional management for probably benign lesions comes from two longitudinal studies of prospectively identified, consecutive cases, collectively involving more than 80,000 mammography examination^.^^ In these studies from UCSF36,38 and from the Hospital Pereira Rossell in Montevideo, Uruand in other smaller and less wellcontrolled investigations, the frequency of cancer among probably benign lesions has 49 Indepenranged from 0.5% to 1.7%.1°, dent demonstration that probably benign lesions have such a low likelihood of malignancy justifies the now widespread practice of managing these lesions with periodic mammographic surveillance. The purpose of this approach is to avert the morbidity and substantial cost of tissue diagnosis (fine-needle aspiration, core, or surgical biopsy) for lesions that almost always are benign. It also has been shown that careful mammographic surveillance (1) likely identifies by interval change those few lesions that actually are malignant, and (2) does so while the tumors still have a favorable prognosis. Among the presenting mammographic features of the cancers that were detected during the course of mammography surveillance in the UCSF and Montevideo studies, 23 cancers presented as solitary circumscribed noncalcified solid masses (among 1692 such cases), indicating a positive predictive value of 1.4% for this mammographic feature.35The remaining types of probably benign lesions
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each had a positive predictive value of less than 1%.The positive predictive value for all probably benign lesions combined was 0.7%. The findings of the UCSF and Montevideo studies indicated that mammographic surveillance of probably benign lesions correctly identifies almost all of those lesions that are malignant, likely while the tumors remain curable.35Indeed, 31 of the 33 cancers in these studies underwent biopsy because mammography showed interval progression, before the development of palpable findings. In addition, prognostic factors were very favorable for the 33 malignancies. Four of the cancers were DCIS, and all but two of the invasive cancers were T1 lesions (2 cm or less in greatest dimension). Only 12% (4 of 33) of the cancers had axillary lymph node metastasis. All of the 24 UCSF cancer patients have been free of recurrent tumor after a median followup period of more than 7 years; only one of the nine patients in the Montevideo series has shown evidence of recurrence (distant metastasis from a TlNO cancer) after an average follow-up of 23 months. These various indicators of good prognosis are similar in fact to those found in large-scale screening programs using modern m a m m ~ g r a p h y .47, ~ ~48, There does not appear to be a clinically significant delay in diagnosis of cancer because of periodic mammographic follow-up of those few probably benign lesions that actually are malignant. Results of the UCSF and Montevideo studies also show that the use of a less aggressive management approach for probably benign lesions (i.e., periodic mammographic surveillance) should produce an increase in the biopsy yield of cancer from the current United States average of 20% to 30% up to approximately 40%, without a substantial reduction in the detection of small cancers. During the periods of case accrual in the UCSF and Montevideo studies, the biopsy yield of cancer for nonpalpable lesions read as suspicious for malignancy indeed was 38% and 47%’ respectively. These results were obtained during the same periods in which only 0.5% and 1.7% of probably benign interpretations eventually proved to represent malignant lesions. An as yet unresolved issue concerning probably benign lesions is whether to use patient age and lesion size (for circumscribed noncalcified masses) as additional criteria in choosing between the management alternatives of mammographic follow-up and immediate tissue diagnosis. The UCSF study has
provided what so far is the only objective evidence on the validity of using age and size threshold^.^^ These data indicated trends showing a slightly increased likelihood of malignancy among older women and for larger masses, but the differences among age and size subgroups were very small and did not approach statistical significance. More important, neither age nor size criteria permitted identification of masses that have so high a probability of malignancy as to justify immediate biopsy. Even the most likely malignant subgroup, involving women age 50 and older, contained 60 benign masses for each cancer. Results also showed that neither age nor size criteria defined subgroups that selectively permit diagnosis while more cancers remain curable: (1) the vast majority of cancers were stage 0 or stage 1 tumors, despite diagnosis 6 months to 3 years after initial detection, regardless of age or size; (2) the few stage 2 cancers did not show a predilection for earlier identification on the basis of either age or size; and (3) none of the women with cancer in the entire study showed evidence of local, regional, or systemic tumor recurrence. Overall results of this study suggest that probably benign masses should be managed with periodic mammographic surveillance regardless of patient age or lesion size. This conclusion would be strengthened by publication of similar results from at least one more prospectively derived, consecutive case series. By providing such strong evidence, more radiologists would likely abandon the use of age and size criteria to guide management decisions; by subjecting all (rather than just some) circumscribed noncalcified masses to periodic follow-up, the number of recommended biopsies for truly benign lesions would decrease substantially, without a meaningful decrease in the number of favorable-prognosis cancers, thereby reducing the false-positive rate for diagnostic mammography. The other controversial issue concerning probably benign lesions involves the specific details of the follow-up protocol used for periodic mammographic surveillance. There is considerable diversity of opinion among radiologists about the proper timing, frequency, and duration of follow-up for probably benign lesions, probably because of the lack of consensus in published reports.20,36* 38, 47 The features common to most suggested protocols are (1) repeat mammography of the ipsilateral
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breast at 4 to 6 months, (2) bilateral mammography 6 months later, and (3) one to three more annual bilateral mammography examinations. The UCSF experience, recently updated to involve 36 cancers diagnosed during a 3-year surveillance period of 7484 probably benign lesions, has provided the only published data on the relative efficacy of the specific component examinations of follow-up.34 Twenty-four (67%) of the 36 cancers were found at 1-year or 2-year follow-up, examinations that would have been performed anyway for routine screening, given the current (annual) screening guidelines in the United States.', 16, 23 There is general agreement that both 1-year and 2-year follow-up examinations are efficacious. Debate has concentrated on the value of the single short-interval follow-up examination (done at 6 months in the UCSF study), at which only 6 (17%) of 36 cancers were identified. The principal argument against 6month follow-up is that the resultant added cost and anxiety affecting all women with probably benign lesions does not justify the benefit of earlier diagnosis of relatively few cancers.3oThe principal argument in favor of retaining the 6-month follow-up examination is to achieve earlier diagnosis of the most rapidly growing, aggressive cancers among probably benign lesions, while they are demonstrated to still have good prognosis. This latter argument is based on several points: (1) four (80%) of the five stage 2 cancers in the updated UCSF series were found before 1year follow-up examination; (2) none of these cancers has yet recurred locally, regionally, or systemically (mean follow-up, 9.3 years); (3) although the detection rate of probably benign cancers at 6-month follow-up is only 0.1%, this rate is not much smaller than what is considered acceptable for incidence screening mammography, and probably benign cancers grow more rapidly than those usually detected at screening; and (4) there is considerable indirect evidence that the added anxiety imparted by the request for 6-month follow-up, although slight, has the benefit of increasing patient compliance with recommendations for the generally accepted 1-year and 2-year follow-up examination^.^^ SUMMARY
Several approaches to mammographic interpretation and breast imaging management
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have been developed that substantially reduce the frequency of false-positive cases, involving both recall examinations and biopsies, without meaningfully reducing the detection of nonpalpable favorable-prognosis cancers. By applying these approaches successfully, on a nationwide scale, radiologists should be able to demonstrate convincingly that the benefits of mammography far outweigh the risks of false-positive interpretations. The challenge we face is to learn to use the approaches effectively, thereby achieving widespread use. References 1. American Medical Association Council on Scientific Affairs: Mammographic screening for asymptomatic women. CSA Report 16(A-99):15, 1999 2. Anderson I, Janzon L: Reduced breast cancer mortality in women under age 50: Updated results from the Malmo mammographic screening program. Monogr Natl Cancer Inst 22:63, 1997 3. Beam CA, Layde PM, Sullivan DC: Variability in the interpretation of screening mammograms by US radiologists: Findings from a national sample. Arch Intern Med 156:209, 1996 4. Berkowitz JE, Gatewood OMB, Gaylor BW Equivocal mammographic findings: Evaluation with spot compression. Radiology 171:369, 1989 5. Bird RE, Wallace TW, Yankaskas BC: Analysis of cancers missed at screening mammography.. Radiology 184:613, 1992 6. Bjurstam N, Bjorneld L, Duffy SW, et al: The Gothenburg breast screening trial: First results on mortality, incidence, and mode of detection for women ages 3 9 4 9 years at randomization. Cancer 80:2091, 1997 7. Blanks RG, Wallis MG, Moss SM: A comparison of cancer detection rates achieved by breast cancer screening programmes by number of readers, for one and two view mammography: Results from the UK National Health Service breast screening programme. J Med Screen 5:195, 1998 8. Brenner RJ: Asymmetries of the breast: Extended use of the rolled projection. Appl Radiol 215, 1998 9. Callaway MP, Boggis CRM, Astley SA, et al: The influence of previous films on screening mammographic interpretation and detection of breast carcinoma. Clin Radiol 52:527, 1997 10. de Waal JC: Periodic mammographic follow-up of probably benign lesions-[letter]. Radiology 181:608, 1991 11. Eklund G W Tailoring the mammographic examination. In Kapans DB, Mendelson EB, (eds). RSNA Categorical Course in Breast Imaging. Oak Brook, IL, Radiological Society of North America, 1995, p 117 12. Eklund GW, Cardenosa C: The art of mammographic positioning. Radiol Clin North Am 30:21, 1992 13. Elmore JG, Barton MB, Moceri VM, et al: Ten-year risk of false positive screening mammograms and clinical breast examinations. N Engl J Med 338:1089, 1998 14. Elmore JG, Wells CK, Lee CH, et al: Variability in radiologist's interpretations of mammograms. N Engl IMed 331:1493. 1994
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15. Feig SA: Importance of mammographic views to diagnostic accuracy. AJR Am J Roentgenol 151:40, 1988 16. Feig SA, DOrsi CJ, Hendrick RE, et al: American College of Radiology guidelines for breast cancer screening. AJR Am J Roentgenol 171:29, 1998 17. Frankel SD, Sickles EA, Curpen BN, et al: Initial versus subsequent screening mammography: Comparison of findings and their prognostic significance. AIR Am J Roentgenol 164:1107, 1995 18. Hall FM, Storella JM, Silverstone DZ, et al: Nonpalpable breast lesions: Recommendations for biopsy based on suspicion of carcinoma at mammography. Radiology 167:353, 1988 19. Harvey JA, Fajardo LL, Innis CA: Previous mammograms in patients with impalpable breast carcinoma: Retrospective vs blinded interpretation. AJR Am J Roentgenol 161:1167, 1993 20. Helvie MA, Pennes DR, Rebner M, et al: Mammographic follow-up of low suspicion lesions: Compliance rate and diagnostic yield. Radiology 178:155, 1991 21. Hendrick RE, Smith RA, Rutledge JH 111, et al: Benefit of screening mammography in women aged 40-49: A new meta-analysis of randomized controlled trials. Monogr Natl Cancer Inst 22:87, 1997 22. Kopans DB: Breast Imaging, ed 2. Philadelphia, Lippincott-Raven, 1998 23. Leitch AM, Dodd GD, Costanza M, et al: American Cancer Society guidelines for the early detection of breast cancer: Update 1997. CA Cancer J Clin 47150, 1997 24. Libstug AR, Moravan V, Aitken SE: Results from the Ontario breast screening program, 1990-1995. J Med Screen 5:73, 1998 25. Logan WW, Janus J: Use of special mammographic views to maximize radiographic information. Radiol Clin North Am 25:953, 1987 26. Martin JE, Moskowitz M, Milbrath J R Breast cancer missed by mammography. AJR Am J Roentgenol 132:737, 1979 27. May DS, Lee NC, Nadel MR, et al: The national breast and cervical cancer early detection program: Report on the first 4 years of mammography provided to medically underserved women. AJR Am J Roentgenol 170:97, 1998 28. Pamilo M, Anttinen I, Soiva M, et al: Mammography screening: Reasons for recall and the influence of experience on recall in the Finnish system. Clin Radiol 41:384, 1990 29. Robinson JI, Crane CEB, King JM, et al: The South Australian breast x-ray service: Results from a statewide mammographic screening programme. Br J Cancer 73:837, 1996 30. Rubin E: Six-month follow-up: an alternative view [editorial]. Radiology 213:15, 1999 31. Sickles EA: Combining spot compression and other special views to maximize mammographic information [letter]. Radiology 173:571, 1989 32. Sickles EA: False positive rate of screening mammography [letter]. N Engl J Med 339:561, 1998 33. Sickles EA: Findings at mammographic screening on
only one standard projection: Outcomes analysis. Radiology 208:471, 1998 34. Sickles EA: Probably benign breast lesions: when should follow-up be recommended and what is the optimal follow-up protocol [editorial]? Radiology 213:11, 1999 35. Sickles EA: Management of probably benign breast lesions. Radiol Clin North Am 33:1123, 1995 36. Sickles EA: Nonpalpable, circumscribed, noncalcified solid breast masses: Likelihood of malignancy based on lesion size and age of patient. Radiology 192:439, 1994 37. Sickles EA, Ominsky SH, Sollitto RA, et al: Medical audit of a rapid-throughput mammography screening practice: Methodology and results of 27,114 examinations. Radiology 175:323, 1990 38. Sickles EA: Periodic mammographic follow-up of probably benign lesions: Results in 3,184 consecutive cases. Radiology 179:463, 1991 39. Sickles EA: Practical solutions to common mammographic problems: Tailoring the examination. AJR Am J Roentgenol 151:31, 1988 40. Sickles EA: Probably benign breast nodules: Followup of all cases requires initial full problem-solving imaging [editorial]. Radiology 194:305, 1995 41. Sickles EA: Quality assurance: How to audit your own mammography practice. Radiol Clin North Am 30265, 1992 42. Sickles EA: Triangulating the location of a lesion by using the oblique view. In Sickles EA, Destouet JM, Eklund GW, et a1 (eds): Breast Disease (Second Series): Test and Syllabus. Reston, VA, American College of Radiology, 1993, p 2 43. Tabir L, Fagerberg G, Duffy SW, et al: Update of the Swedish two-county program of mammographic screening for breast cancer. Radiol Clin North Am 30:187, 1992 44. Tabir L, Gad A, Holmberg L, et al: Significant reduction in advanced breast cancer: Results of the first seven years of mammography screening in Kopparberg, Sweden. Diagn I p a g Clin Med 54:158, 1985 45. Thurfjell EL, Lindgren J A Population-based mammography screening in Swedish clinical practice: Prevalence and incidence screening in Uppsala County. Radiology 193:351, 1994 46. Van Dijck JAAM, Verbeek ALM, Hendriks JHCL, et al: The current detectability of breast cancer in a mammographic screening program. Cancer 72:1933, 1993 47. Varas X, Leborgne F, Leborgne JH: Nonpalpable probably benign lesions: Role of follow-up mammography. Radiology 184:409, 1992 48. Warren Burhenne LJ, Burhenne HJ, Kan L: Qualityoriented mass mammography screening. Radiology 194:185, 1995 49. Wolfe JN, Buck KA, Salane M, et al: Xeroradiography of the breast: Overview of 21,057 consecutive cases. Radiology 165:305, 1987 50. Wolverton DE, Sickles E A Clinical outcome of doubtful mammographic findings. AJR Am J Roentgenol 1671041, 1996 Address reprint requests to
Edward A. Sickles, MD 2330 Post Street Room 180 San Francisco, CA 94115
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SUCCESSFUL METHODS TO REDUCE FALSE-POSITIVE MAMMOGRAPHY INTERPRETATIONS Edward A. Sickles, MD
There is now solid scientific evidence, derived from several randomized controlled trials, of a statistically significant breast cancer mortality reduction for women age 40 and older who undergo routine screening mammography.” 6, 21 Because of the convincing nature of this evidence, the remaining controversy about the widespread use of screening has, for the most part, shifted to concerns about the risks (harms) of mammography, concentrating on the morbidity and economic costs of false-positive cases.3,13* l4 It is beyond the scope of this article to join in the debate. Rather, the aim herein is to discuss several already demonstrated methods that permit radiologists safely and effectively to reduce the frequency of false-positive mammography interpretations. In my opinion, the widespread implementation of these successful methods currently represents the best argument in defense of mammography that can be advanced by the radiology community. One must remember that the primary goal of mammography is to detect nonpalpable, favorable-prognosis cancer; it is not to have relatively few false-positive cases. As a first priority, the radiologist should strive to achieve a high cancer detection rate, with the
great majority of cancers being nonpalpable and early in stage. Only once such a level of success is demonstrated should one attempt to reduce the rate of false-positive interpretations. In other words, first establish the benefit and then attempt to minimize the harms (while maintaining an acceptable level of benefit). Because any strategy designed to reduce the frequency of false-positive cases requires examinations otherwise interpreted as positive to instead be read as negative, and because this leads to a reduction in the number of true-positive cases if any cancers are thereby overlooked, it is clear that successful approaches to reducing false-positive interpretations achieve this goal only if there is no more than a minor decrease in the early detection of favorable-prognosis cancers. Any initially overlooked cancers should still be of good prognosis when ultimately detected, demonstrating favorable clinical outcomes after treatment. FALSE-POSITIVE INTERPRETATIONS
A false-positive case is one that is interpreted as positive but actually found to be nega-
From the Breast Imaging Section, Department of Radiology, University of California Medical Center, San Francisco, California
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tive. In the context of mammography, found to be negative is defined as the absence of a tissue diagnosis of cancer (invasive carcinoma or ductal carcinoma in situ [DCIS]) within a given time period after examination, the time period being equivalent to the standard interval between screening examinations. This time period is 1 year in the United States, where screening mammography is widely recommended at yearly intervals for all women beginning at age 40.’. 16, 23 There are two definitions of interpreted as positive, one for screening mammography, the other for diagnostic mammography. For screening mammography, which is limited to a craniocaudal and mediolateral oblique view of each breast, a positive case is any examination for which prompt additional work-up is recommended. This includes not only the relatively few examinations with findings already judged to be sufficiently suspicious for malignancy so as to justify tissue diagnosis (BI-RADS assessment categories 4 and 5), but also the larger subset of examinations with findings that are incompletely evaluated at screening and require additional imaging assessment (BI-RADS category 0). The outcome parameter that tracks positive cases at screening is the recall rate.* For diagnostic mammography, which includes whatever supplementary mammographic views are needed to solve a patient’s particular imaging problems, a positive case is defined as an examination for which tissue diagnosis is recommended. To track positive cases for diagnostic mammography, one obtains follow-up data on BI-RADS category 4 and 5 (but not category 0) assessments. There are two principal false-positive scenarios concerning mammography interpretation. First is the recommendation to perform additional imaging (recall examination), *Some mammography practices interpret screening examinations while women are still on site, so that many detected abnormalities for which recall otherwise would be recommended are worked-up immediately; in such cases, there is no need for formal screening interpretation, and only diagnostic (final) assessments are made. Some other practices do not make formal interpretations for recalled screening examinations, but rather recall each woman directly and wait until the imaging work-up is completed to render a single (final) assessment. In both such situations, although BI-RADS category 0 assessments are not formally made for screening-detected abnormalities, the screening components of these examinations nonetheless should be considered to be positive, independent of the assessments made for the diagnostic examinations.
based on screening-detected findings, for which cancer ultimately is not identified. Second is the recommendation to perform tissue diagnosis procedures, to assess unresolved abnormalities further following a complete breast imaging work-up, for which cancer is not found . Successful methods to reduce the recall rate for screening mammography (without substantially reducing the rate of detecting favorable-prognosis cancer) involve (1) obtaining previous mammograms for comparison at the time of initial image interpretation, (2) confidently and correctly identifying some summation artifacts from the two standard screening views of each breast, and ( 3 ) learning to ignore subtle mammographic findings of doubtful significance. Successful methods to reduce the rate of benign tissue diagnosis after full breast imaging work-up involve (1) confidently and correctly identifying the as yet unrecognized summation artifacts by properly tailoring the diagnostic mammography examination, and (2) substituting management by periodic mammographic surveillance in place of tissue diagnosis for probably benign findings (BI-RADS category 3 assessments). COMPARISON WITH PREVIOUS MAMMOGRAMS AT TIME OF INITIAL SCREENING INTERPRETATION
The recall rate for screening mammography is highly dependent on whether examinations are interpreted with or without comparison films from previous screening examinations. Indeed, one can expect a significant (approximately 50%) reduction in the recall rate, with no accompanying reduction in the detection of nonpalpable early stage cancers, when screening examinations are interpreted in comparison with recent previous screening mammograms.7,9,17,24,27-29,37.43,44,48 1n my own practice at the University of California at San Francisco (UCSF), based on data for 118,783 consecutive screening mammography examinations, the recall rate is 7.4% for examinations interpreted without the benefit of previous films, versus 3.2% for examinations interpreted in comparison with previous UCSF screening mammograms. One factor that helps to explain this disparity is that some lesions detected at initial screening are excised, so that fewer abnormalities are still present at subsequent screening
SUCCESSFUL METHODS TO REDUCE FALSE-POSITIVE MAMMOGRAPHY INTERPRETATIONS
to be available for recall. In addition, some other lesions detected at initial screening undergo percutaneous tissue sampling yielding benign diagnoses that are concordant with imaging findings, so that although portions of these lesions remain, they do not prompt recall on subsequent screening because they are now known to be benign. There also are two major reasons why mammographic findings that otherwise might prompt recall at current screening do not do so, simply because previous films are available for comparison. (1) The previous films include those from a recall examination already performed for the given mammographic finding, in which the recall examination itself demonstrates confidently benign features, thereby eliminating any further concern at subsequent screening. (2) The findings seen currently are just above the threshold for recall, but demonstration of stability in comparison with previous films reduces the level of concern below the threshold for recall. On the basis of these various observations, it is clear that one successful method to reduce the recall rate for screening mammography substantially is to implement policies that maximize the availability of previous mammograms at the time of image interpretation. Radiology practices should develop procedures to facilitate the reliable retrieval of their own previous films in the interval between when a woman makes a screening mammography appointment and when the films from that examination are interpreted. Primary care providers and women themselves must be more effectively educated to the advantage of deferring screening mammography examinations until they first obtain previous mammograms from different radiology facilitie~.~~ CONFIDENTLY AND CORRECTLY IDENTIFYING SUMMATION ARTIFACTS
It is not at all unusual for potentially abnormal findings to be identified at screening mammography on only one of the two standard-projection images. The great majority of these findings represent superimposition of normal structures (summation artifact); relatively few eventually are found to be malignant. Several imaging approaches have been described to distinguish summation artifacts
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from more important lesions in these cases, principally involving additional mammography using nonstandard projections, such as off-angle views, roll views, and 90-degree lateral views, and spot-compression and magnification tecKques.4, 8, 11. 12. 15. 22, 25. 31. 39, 42 Based on a recent large-scale UCSF study, there is emerging evidence that one can (1) reliably characterize many summation artifacts simply by enlightened screening mammography interpretation, thereby reducing the recall rate; and (2) characterize the remainder of summation artifacts by obtaining tailored diagnostic mammographic views at the time of recall examination, thereby averting benign biopsy or short-term interval follow-up.33 The UCSF study involved consecutive mammography screening examinations for which radiologists prospectively identified a variety of potentially abnormal findings seen only on one of the two standard screening views. The study catalogued the frequency of occurrence of examinations with one-viewonly findings, the mammographic features of the findings, whether recall for additional imaging work-up was recommended, and the final assessment after imaging was complete. For examinations with screening-detected findings undergoing tissue sampling, pathologic diagnosis was recorded, cancer being defined as invasive carcinoma or DCIS. To identify breast cancers among the remaining examinations with one-view-only findings, computer linkage of these cases was performed with the data stored in a regional tumor registry, the linkage taking place a minimum of 2 years after screening was done. There were 61,273 screening examinations reviewed in the UCSF study. One-view-only findings were identified on 2023 examinations, representing 3.3% of these cases. This amounts to 1 in approximately every 30 examinations, so that a moderately busy mammography screening practice can expect to encounter one-view-only findings on a daily basis. The great majority of these findings were noncalcified densities, with relatively small percentages of cases representing areas of possible architectural distortion and microcalcifications. Of the 2023 one-view-only findings, 1086 (53.7%) were interpreted as representing superimposition of normal structures simply on the basis of the standard two-view screening examination. Each of these cases presented as a one-view-only noncalcified density or area of architectural distortion at screening mam-
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mography. Of the remaining 937 cases, for which recall imaging was requested and performed, an additional 587 cases (also noncalcified densities or areas of architectural distortion) were found to represent superimposition of normal structures. Summation artifact accounted for 1673 (82.7%) of the 2023 one-view-only cases. These assessments indicating the presence of summation artifact indeed were highly accurate, despite the lack of confirmation by tissue diagnosis, because none of the cases were eventually found to involve breast carcinoma, either at subsequent routine mammography screening (if done), or by linkage with the regional tumor registry. As shown in the UCSF study, it is possible to recognize a large percentage of summation artifacts simply by careful analysis of the two standard-projection screening images. By eliminating recall for these 1086 UCSF cases, the total number of recalled cases during the study period decreased from 4310 to 3224, thereby decreasing the recall rate by slightly more than one third (from 6.8% to 5.1%), without overlooking any cancers. The fact that this (UCSF) approach to screening mammography interpretation is not in widespread use indicates a great opportunity for largescale reduction in recall rates. It is unknown, however, to what degree the success achieved at UCSF can be transferred to other screening mammography practices. As applies to the introduction of any new interpretive approach, one should exercise caution in implementation. A simple and safe method is to attempt the UCSF approach but still recommend recall, and then determine performance by assessing outcomes at recall examination, putting the approach into practice only after success has been demonstrated. It also is important for radiologists to develop sufficient skills to make the diagnosis of summation artifact using additional imaging after recall from screening. In the UCSF study, had all 1673 cases interpreted as summation artifact actually received a recommendation for tissue diagnosis (fine-needle aspiration biopsy, core biopsy, or surgical biopsy), the number of requested biopsies during the study period would have increased from 932 to 2605, without any increase in the 328 cancers discovered, thereby decreasing the cancer rate for positive diagnostic interpretations from 35.2% to an unacceptably low rate of 12.6%.
IGNORING SUBTLE MAMMOGRAPHIC FINDINGS OF DOUBTFUL SIGNIFICANCE Most radiologists are aware that 25% to 75% of breast cancers detected at mammography screening are visible in retrospect on at least one previous mammography examinat i ~ n ,19,~ 26, , 46 usually as subtle findings below traditional thresholds for recall imaging or biopsy. The genuine desire to identify breast cancer at its earliest detectable stage, and the fear of malpractice exposure if such subthreshold findings are ignored, causes many radiologists to request recall examinations for mammographic findings that have an exceedingly low likelihood of malignancy. One consequence of adopting this approach is an increase in false-positive interpretations. Another study was recently published from UCSF that demonstrated the radiographic and clinical outcomes for such findings, which were described as being of "doubtful" mammographic signifi~ance.~~ In this study, selected subthreshold findings were identified prospectively at routine screening, circled with wax crayon directly on the films, but the examinations were interpreted as negative or benign (BI-RADS category 1 or 2), with no recommendation for further imaging evaluation or tissue diagnosis. Circled findings displayed a variety of mammographic features, including loosely grouped calcifications, small low-opacity partially circumscribed densities, poorly defined asymmetric densities, and larger areas of asymmetric breast tissue. These findings were judged to be benign for several different reasons, including substantial variation in appearance on the two standard mammographic views; presence of similar benign-appearing findings elsewhere (especially if multiple and bilateral); and lack of suspicious associated features. The hallmark of the doubtful finding, however, was the assessment that it appeared sufficiently benign so as to permit repeat mammography in 1 year rather than further work-up. In the UCSF study on doubtful findings, 5514 consecutive screening examinations were reviewed for which a previous negative or benign screening examination was available for comparison. There were 543 wax crayon circles present on 382 of the previous examinations, marking doubtful findings for which the radiographic and clinical outcomes were then determined. The mean follow-up
SUCCESSFUL METHODS TO REDUCE FALSE-POSITIVE MAMMOGRAPHY INTERPRETATIONS
interval was 2.5 years. At subsequent mammography screening, 74% of the doubtful findings were unchanged; 21% had decreased in visibility or disappeared entirely; 4% were so slightly more prominent that the apparent changes were judged to be caused by differences in imaging technique; and 1% (six cases) had increased sufficiently to prompt recall examination. After full diagnostic imaging evaluation, three lesions underwent biopsy, with the diagnosis of only one malignancy, a low-grade cribriform DCIS that had changed only after 4 years of stability as a doubtful finding. This lesion then was completely excised and almost certainly cured by that treatment. After completion of case accrual, 1 year after the most recent subsequent screening examination, linkage of all study cases with the regional tumor registry failed to identify any other cases of breast cancer. Among 543 doubtful findings in 382 women, only one proved to be malignant, still favorable in prognosis when ultimately detected. This represented a cancer frequency of 0.2% per finding and 0.3% per woman screened, rates so low that they are essentially identical to the cancer incidence rate in an asymptomatic population. These results were interpreted as suggesting that prospective identification of mammographic findings below conventional thresholds for abnormality is not an effective method for detecting clinically occult breast cancer. The observations that virtually all doubtful mammographic findings are benign, and that subthreshold precursors of malignancy are difficult if not impossible to detect prospectively at mammography screening, indicate that recall or biopsy of such findings has little if any clinical use. To reduce false-positive screening interpretations substantially without meaningfully affecting the cancer detection rate, radiologists should learn to ignore such doubtful mammographic findings. MAMMOGRAPHIC SURVEILLANCE FOR PROBABLY BENIGN LESIONS
It is important to distinguish probably benign lesions from the doubtful findings described in the previous section of this article. Doubtful findings are so very unlikely to be malignant that they can safely be ignored. In contrast, probably benign lesions (BI-RADS category 3) usually are managed by periodic mammographic surveillance. Unlike doubtful
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findings, probably benign lesions have much less subtle mammographic features (e.g., circumscribed noncalcified mass, clustered round microcalcifications,and focal asymmetric density), prompting additional imaging to supplement that provided by the standard two-view-per-breast screening mammography examination. Ultrasonography is done for the circumscribed noncalcified mass, to establish or exclude the diagnosis of simple benign cyst, and to look for suspicious sonographic features that prompt a tissue diagnosis. Solid masses, densities, and lesions involving microcalcifications all benefit from fine-detail mammographic imaging, especially spot-compression magnification mammography, to portray the shapes and marginal characteristics of these lesions more clearly and also to serve as a baseline in case additional fine-detail images are obtained subsequently during the course of mammographic follow-up.40 The strongest evidence suggesting the use of noninterventional management for probably benign lesions comes from two longitudinal studies of prospectively identified, consecutive cases, collectively involving more than 80,000 mammography examination^.^^ In these studies from UCSF36,38 and from the Hospital Pereira Rossell in Montevideo, Uruand in other smaller and less wellcontrolled investigations, the frequency of cancer among probably benign lesions has 49 Indepenranged from 0.5% to 1.7%.1°, dent demonstration that probably benign lesions have such a low likelihood of malignancy justifies the now widespread practice of managing these lesions with periodic mammographic surveillance. The purpose of this approach is to avert the morbidity and substantial cost of tissue diagnosis (fine-needle aspiration, core, or surgical biopsy) for lesions that almost always are benign. It also has been shown that careful mammographic surveillance (1) likely identifies by interval change those few lesions that actually are malignant, and (2) does so while the tumors still have a favorable prognosis. Among the presenting mammographic features of the cancers that were detected during the course of mammography surveillance in the UCSF and Montevideo studies, 23 cancers presented as solitary circumscribed noncalcified solid masses (among 1692 such cases), indicating a positive predictive value of 1.4% for this mammographic feature.35The remaining types of probably benign lesions
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each had a positive predictive value of less than 1%.The positive predictive value for all probably benign lesions combined was 0.7%. The findings of the UCSF and Montevideo studies indicated that mammographic surveillance of probably benign lesions correctly identifies almost all of those lesions that are malignant, likely while the tumors remain curable.35Indeed, 31 of the 33 cancers in these studies underwent biopsy because mammography showed interval progression, before the development of palpable findings. In addition, prognostic factors were very favorable for the 33 malignancies. Four of the cancers were DCIS, and all but two of the invasive cancers were T1 lesions (2 cm or less in greatest dimension). Only 12% (4 of 33) of the cancers had axillary lymph node metastasis. All of the 24 UCSF cancer patients have been free of recurrent tumor after a median followup period of more than 7 years; only one of the nine patients in the Montevideo series has shown evidence of recurrence (distant metastasis from a TlNO cancer) after an average follow-up of 23 months. These various indicators of good prognosis are similar in fact to those found in large-scale screening programs using modern m a m m ~ g r a p h y .47, ~ ~48, There does not appear to be a clinically significant delay in diagnosis of cancer because of periodic mammographic follow-up of those few probably benign lesions that actually are malignant. Results of the UCSF and Montevideo studies also show that the use of a less aggressive management approach for probably benign lesions (i.e., periodic mammographic surveillance) should produce an increase in the biopsy yield of cancer from the current United States average of 20% to 30% up to approximately 40%, without a substantial reduction in the detection of small cancers. During the periods of case accrual in the UCSF and Montevideo studies, the biopsy yield of cancer for nonpalpable lesions read as suspicious for malignancy indeed was 38% and 47%’ respectively. These results were obtained during the same periods in which only 0.5% and 1.7% of probably benign interpretations eventually proved to represent malignant lesions. An as yet unresolved issue concerning probably benign lesions is whether to use patient age and lesion size (for circumscribed noncalcified masses) as additional criteria in choosing between the management alternatives of mammographic follow-up and immediate tissue diagnosis. The UCSF study has
provided what so far is the only objective evidence on the validity of using age and size threshold^.^^ These data indicated trends showing a slightly increased likelihood of malignancy among older women and for larger masses, but the differences among age and size subgroups were very small and did not approach statistical significance. More important, neither age nor size criteria permitted identification of masses that have so high a probability of malignancy as to justify immediate biopsy. Even the most likely malignant subgroup, involving women age 50 and older, contained 60 benign masses for each cancer. Results also showed that neither age nor size criteria defined subgroups that selectively permit diagnosis while more cancers remain curable: (1) the vast majority of cancers were stage 0 or stage 1 tumors, despite diagnosis 6 months to 3 years after initial detection, regardless of age or size; (2) the few stage 2 cancers did not show a predilection for earlier identification on the basis of either age or size; and (3) none of the women with cancer in the entire study showed evidence of local, regional, or systemic tumor recurrence. Overall results of this study suggest that probably benign masses should be managed with periodic mammographic surveillance regardless of patient age or lesion size. This conclusion would be strengthened by publication of similar results from at least one more prospectively derived, consecutive case series. By providing such strong evidence, more radiologists would likely abandon the use of age and size criteria to guide management decisions; by subjecting all (rather than just some) circumscribed noncalcified masses to periodic follow-up, the number of recommended biopsies for truly benign lesions would decrease substantially, without a meaningful decrease in the number of favorable-prognosis cancers, thereby reducing the false-positive rate for diagnostic mammography. The other controversial issue concerning probably benign lesions involves the specific details of the follow-up protocol used for periodic mammographic surveillance. There is considerable diversity of opinion among radiologists about the proper timing, frequency, and duration of follow-up for probably benign lesions, probably because of the lack of consensus in published reports.20,36* 38, 47 The features common to most suggested protocols are (1) repeat mammography of the ipsilateral
SUCCESSFUL METHODS TO REDUCE FALSE-POSITIVE MAMMOGRAPHY INTERPRETATIONS
breast at 4 to 6 months, (2) bilateral mammography 6 months later, and (3) one to three more annual bilateral mammography examinations. The UCSF experience, recently updated to involve 36 cancers diagnosed during a 3-year surveillance period of 7484 probably benign lesions, has provided the only published data on the relative efficacy of the specific component examinations of follow-up.34 Twenty-four (67%) of the 36 cancers were found at 1-year or 2-year follow-up, examinations that would have been performed anyway for routine screening, given the current (annual) screening guidelines in the United States.', 16, 23 There is general agreement that both 1-year and 2-year follow-up examinations are efficacious. Debate has concentrated on the value of the single short-interval follow-up examination (done at 6 months in the UCSF study), at which only 6 (17%) of 36 cancers were identified. The principal argument against 6month follow-up is that the resultant added cost and anxiety affecting all women with probably benign lesions does not justify the benefit of earlier diagnosis of relatively few cancers.3oThe principal argument in favor of retaining the 6-month follow-up examination is to achieve earlier diagnosis of the most rapidly growing, aggressive cancers among probably benign lesions, while they are demonstrated to still have good prognosis. This latter argument is based on several points: (1) four (80%) of the five stage 2 cancers in the updated UCSF series were found before 1year follow-up examination; (2) none of these cancers has yet recurred locally, regionally, or systemically (mean follow-up, 9.3 years); (3) although the detection rate of probably benign cancers at 6-month follow-up is only 0.1%, this rate is not much smaller than what is considered acceptable for incidence screening mammography, and probably benign cancers grow more rapidly than those usually detected at screening; and (4) there is considerable indirect evidence that the added anxiety imparted by the request for 6-month follow-up, although slight, has the benefit of increasing patient compliance with recommendations for the generally accepted 1-year and 2-year follow-up examination^.^^ SUMMARY
Several approaches to mammographic interpretation and breast imaging management
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have been developed that substantially reduce the frequency of false-positive cases, involving both recall examinations and biopsies, without meaningfully reducing the detection of nonpalpable favorable-prognosis cancers. By applying these approaches successfully, on a nationwide scale, radiologists should be able to demonstrate convincingly that the benefits of mammography far outweigh the risks of false-positive interpretations. The challenge we face is to learn to use the approaches effectively, thereby achieving widespread use. References 1. American Medical Association Council on Scientific Affairs: Mammographic screening for asymptomatic women. CSA Report 16(A-99):15, 1999 2. Anderson I, Janzon L: Reduced breast cancer mortality in women under age 50: Updated results from the Malmo mammographic screening program. Monogr Natl Cancer Inst 22:63, 1997 3. Beam CA, Layde PM, Sullivan DC: Variability in the interpretation of screening mammograms by US radiologists: Findings from a national sample. Arch Intern Med 156:209, 1996 4. Berkowitz JE, Gatewood OMB, Gaylor BW Equivocal mammographic findings: Evaluation with spot compression. Radiology 171:369, 1989 5. Bird RE, Wallace TW, Yankaskas BC: Analysis of cancers missed at screening mammography.. Radiology 184:613, 1992 6. Bjurstam N, Bjorneld L, Duffy SW, et al: The Gothenburg breast screening trial: First results on mortality, incidence, and mode of detection for women ages 3 9 4 9 years at randomization. Cancer 80:2091, 1997 7. Blanks RG, Wallis MG, Moss SM: A comparison of cancer detection rates achieved by breast cancer screening programmes by number of readers, for one and two view mammography: Results from the UK National Health Service breast screening programme. J Med Screen 5:195, 1998 8. Brenner RJ: Asymmetries of the breast: Extended use of the rolled projection. Appl Radiol 215, 1998 9. Callaway MP, Boggis CRM, Astley SA, et al: The influence of previous films on screening mammographic interpretation and detection of breast carcinoma. Clin Radiol 52:527, 1997 10. de Waal JC: Periodic mammographic follow-up of probably benign lesions-[letter]. Radiology 181:608, 1991 11. Eklund G W Tailoring the mammographic examination. In Kapans DB, Mendelson EB, (eds). RSNA Categorical Course in Breast Imaging. Oak Brook, IL, Radiological Society of North America, 1995, p 117 12. Eklund GW, Cardenosa C: The art of mammographic positioning. Radiol Clin North Am 30:21, 1992 13. Elmore JG, Barton MB, Moceri VM, et al: Ten-year risk of false positive screening mammograms and clinical breast examinations. N Engl J Med 338:1089, 1998 14. Elmore JG, Wells CK, Lee CH, et al: Variability in radiologist's interpretations of mammograms. N Engl IMed 331:1493. 1994
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15. Feig SA: Importance of mammographic views to diagnostic accuracy. AJR Am J Roentgenol 151:40, 1988 16. Feig SA, DOrsi CJ, Hendrick RE, et al: American College of Radiology guidelines for breast cancer screening. AJR Am J Roentgenol 171:29, 1998 17. Frankel SD, Sickles EA, Curpen BN, et al: Initial versus subsequent screening mammography: Comparison of findings and their prognostic significance. AIR Am J Roentgenol 164:1107, 1995 18. Hall FM, Storella JM, Silverstone DZ, et al: Nonpalpable breast lesions: Recommendations for biopsy based on suspicion of carcinoma at mammography. Radiology 167:353, 1988 19. Harvey JA, Fajardo LL, Innis CA: Previous mammograms in patients with impalpable breast carcinoma: Retrospective vs blinded interpretation. AJR Am J Roentgenol 161:1167, 1993 20. Helvie MA, Pennes DR, Rebner M, et al: Mammographic follow-up of low suspicion lesions: Compliance rate and diagnostic yield. Radiology 178:155, 1991 21. Hendrick RE, Smith RA, Rutledge JH 111, et al: Benefit of screening mammography in women aged 40-49: A new meta-analysis of randomized controlled trials. Monogr Natl Cancer Inst 22:87, 1997 22. Kopans DB: Breast Imaging, ed 2. Philadelphia, Lippincott-Raven, 1998 23. Leitch AM, Dodd GD, Costanza M, et al: American Cancer Society guidelines for the early detection of breast cancer: Update 1997. CA Cancer J Clin 47150, 1997 24. Libstug AR, Moravan V, Aitken SE: Results from the Ontario breast screening program, 1990-1995. J Med Screen 5:73, 1998 25. Logan WW, Janus J: Use of special mammographic views to maximize radiographic information. Radiol Clin North Am 25:953, 1987 26. Martin JE, Moskowitz M, Milbrath J R Breast cancer missed by mammography. AJR Am J Roentgenol 132:737, 1979 27. May DS, Lee NC, Nadel MR, et al: The national breast and cervical cancer early detection program: Report on the first 4 years of mammography provided to medically underserved women. AJR Am J Roentgenol 170:97, 1998 28. Pamilo M, Anttinen I, Soiva M, et al: Mammography screening: Reasons for recall and the influence of experience on recall in the Finnish system. Clin Radiol 41:384, 1990 29. Robinson JI, Crane CEB, King JM, et al: The South Australian breast x-ray service: Results from a statewide mammographic screening programme. Br J Cancer 73:837, 1996 30. Rubin E: Six-month follow-up: an alternative view [editorial]. Radiology 213:15, 1999 31. Sickles EA: Combining spot compression and other special views to maximize mammographic information [letter]. Radiology 173:571, 1989 32. Sickles EA: False positive rate of screening mammography [letter]. N Engl J Med 339:561, 1998 33. Sickles EA: Findings at mammographic screening on
only one standard projection: Outcomes analysis. Radiology 208:471, 1998 34. Sickles EA: Probably benign breast lesions: when should follow-up be recommended and what is the optimal follow-up protocol [editorial]? Radiology 213:11, 1999 35. Sickles EA: Management of probably benign breast lesions. Radiol Clin North Am 33:1123, 1995 36. Sickles EA: Nonpalpable, circumscribed, noncalcified solid breast masses: Likelihood of malignancy based on lesion size and age of patient. Radiology 192:439, 1994 37. Sickles EA, Ominsky SH, Sollitto RA, et al: Medical audit of a rapid-throughput mammography screening practice: Methodology and results of 27,114 examinations. Radiology 175:323, 1990 38. Sickles EA: Periodic mammographic follow-up of probably benign lesions: Results in 3,184 consecutive cases. Radiology 179:463, 1991 39. Sickles EA: Practical solutions to common mammographic problems: Tailoring the examination. AJR Am J Roentgenol 151:31, 1988 40. Sickles EA: Probably benign breast nodules: Followup of all cases requires initial full problem-solving imaging [editorial]. Radiology 194:305, 1995 41. Sickles EA: Quality assurance: How to audit your own mammography practice. Radiol Clin North Am 30265, 1992 42. Sickles EA: Triangulating the location of a lesion by using the oblique view. In Sickles EA, Destouet JM, Eklund GW, et a1 (eds): Breast Disease (Second Series): Test and Syllabus. Reston, VA, American College of Radiology, 1993, p 2 43. Tabir L, Fagerberg G, Duffy SW, et al: Update of the Swedish two-county program of mammographic screening for breast cancer. Radiol Clin North Am 30:187, 1992 44. Tabir L, Gad A, Holmberg L, et al: Significant reduction in advanced breast cancer: Results of the first seven years of mammography screening in Kopparberg, Sweden. Diagn I p a g Clin Med 54:158, 1985 45. Thurfjell EL, Lindgren J A Population-based mammography screening in Swedish clinical practice: Prevalence and incidence screening in Uppsala County. Radiology 193:351, 1994 46. Van Dijck JAAM, Verbeek ALM, Hendriks JHCL, et al: The current detectability of breast cancer in a mammographic screening program. Cancer 72:1933, 1993 47. Varas X, Leborgne F, Leborgne JH: Nonpalpable probably benign lesions: Role of follow-up mammography. Radiology 184:409, 1992 48. Warren Burhenne LJ, Burhenne HJ, Kan L: Qualityoriented mass mammography screening. Radiology 194:185, 1995 49. Wolfe JN, Buck KA, Salane M, et al: Xeroradiography of the breast: Overview of 21,057 consecutive cases. Radiology 165:305, 1987 50. Wolverton DE, Sickles E A Clinical outcome of doubtful mammographic findings. AJR Am J Roentgenol 1671041, 1996 Address reprint requests to
Edward A. Sickles, MD 2330 Post Street Room 180 San Francisco, CA 94115