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FALSE-NEGATIVE MAMMOGRAMS
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FALSE-NEGATIVE MAMMOGRAMS Medical, Legal, and Risk Management Implications R. James Brenner, MD, JD
The opportunity to detect preclinical breast cancer by mammographic evaluation and to facilitate biopsy for a sign or symptom of possible breast cancer by a variety of breast imaging techniques is founded on the evidence-based conclusion that early diagnosis and treatment are likely to improve both disease-free and overall survival in a significant percentage of cases.33,34 The impetus to provide an imaging basis for early intervention has prompted criticism, with commentators suggesting an unnecessarily high rate of recall of patients for additional studies and biopsy.23,31 Radiologists are confronted with a difficult situation, balancing the need for early tissue diagnosis of potential breast cancer with the overuse of resources for lesions that do not represent malignancy and may not require biopsy. The contrasting notions regarding possible lesions seen in only one standard mammographic screening view exemplify the dilemma. In one prospective study, the likelihood of malignancy associated with these circumstances was shown to be very small, whereas a retrospective review of missed breast cancers in a different study indicated that this phenomenon was statistically significant in accounting for features of lesions for which there was a delay in diagnosis of breast cancer.26,41
Attempts to reconcile these two studies and others reported in the literature are virtually impossible based on published reports. Only trends, clinical observations, and a few examples are afforded in any given report; a sufficient number of published imaging examples are not feasible for such purposes. Any critical analysis depends on case-specific circumstances. For example, a truly spiculated density seen on one view only is unlikely to represent a benign condition, whereas a summation artifact that gives the false impression of a mass with irregular margins is unlikely to represent malignancy. Both situations may be categorized for purposes of a study design as a potential abnormality seen in one view only, but proper management and final imaging impressions of each are fundamentally different. Errors in detection and diagnosis are not peculiar to mammography. They may occur in virtually any radiologic examination, and errors in interpretation in other organ systems, such as the colon, have also been carefully studied.6,40 Perhaps one distinguishing feature regarding missed lesions in breast imaging generally, and mammography in particular, is derivative of the large numbers of breast examinations that are conducted each year. Such volumes invite larger numbers of
From the Eisenberg Keefer Breast Center, John Wayne Cancer Institute, Saint Johns Health Center, and the Department of Radiology, University of California Los Angeles School of Medicine, Los Angeles, California
RADIOLOGIC CLINICS OF NORTH AMERICA VOLUME 38 NUMBER 4 * JULY 2000
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absolute errors even if the percentage of errors is commensurate with other types of radiologic evaluation. Most mammography is performed on asymptomatic women, where the clinical index of suspicion may be low and the potential benefit high. According to the Physicians Insurers Association of America (PIAA), delay in diagnosis of breast cancer is the most common reason for which physicians are sued for malpract i ~ e . 3In ~ part because most of the women bringing litigation against physicians for delay in diagnosis of breast cancer have undergone mammography, the most commonly named defendant in such lawsuits is the radiologist. The elements of a lawsuit have previously been described.12 Most medical malpractice lawsuits are tried under the civil law of negligence, which defines a departure from conduct that is expected of a reasonable and prudent radiologist under similar circumstances. Legal negligence is defined by four elements: (1) duty, (2) breach, (3) causation, and (4) damages. If the radiologist fails, under a given set of circumstances, to provide reasonable images, render a reasonable interpretation, and effectively communicate that interpretation, then a case for negligence may be found. Where legal damages, such as worsening prognosis or added treatment requirements can be shown, a so-called cause ofaction may be established and a lawsuit filed. The problems derivative of excess use of resources for additional studies and biopsies are not trivial, but they are uncommonly associated with lawsuits.1° The so-called missed or delayed diagnosis of breast cancer is the incident that provokes litigation. Whether such error occurs secondary to the lack of detection because of poor technical reasons or observer error, an unreasonable diagnostic evaluation or impression, or problems in communication, the rendering of a diagnosis that improperly fails to indicate a sufficient suspicion for malignancy is considered a false-negative mammogram. This article addresses those aspects about false-negative mammograms that have been studied, and focuses on correctable causes for such error. TYPES OF ERROR As already suggested, abnormalities seen on one view may represent benign or malignant conditions, absent further evaluation.
This issue highlights the interplay among the types of errors that may lead to a false mammogram. First, a lesion may be left undetected on the mammographic study. Second, if detected, the lesion may be insufficiently evaluated, causing an unreasonable interpretation. Finally, if either of these events should occur, or even if the lesion is reasonably interpreted but not made known in a sufficient manner to the intended party, the radiologist may have provided insufficient communication." Most mammographic errors are analyzed by retrospective analysis of patients who have developed interval breast cancers, usually based on clinical presentation.% In the 1970s and early 1 9 8 0 ~ where ~ conventional filmscreen and xeromammographic techniques were used without additional supplementary imaging (e.g., altered projections, microfocal spot compression magnification, ultrasound), errors were attributed to most of the same causes that remain problematic. Reporting of such errors varies in methodology, making it difficult to reconcile different results without reviewing individual cases, even for more recently reported series. If technical errors are omitted from analysis, a problem that accounts for 6% to 17% of problems, then as a first approximation falsenegative mammograms may be secondary to one of three factors that each constitute about a third of reviewed cases: (1) no mammographic features of malignancy, (2) subthreshold features of malignancy, and (3) observer error.5,17, 19, 28, 29, 36 The issues defined by these studies may be compared with data obtained in a review of 100 screening mammogram cases and 99 diagnostic mammogram cases that were subject to litigation and analyzed for types of errors.15,38 In the PIAA-American College of Radiology (ACR) study of screening mammography claims for negligence, 13% of the cases involved issues in image quality. An error in diagnosis, presumably including nondetection and incorrect assessment of detected abnormalities, occurred in 64% of cases. It was noted that half of these errors occurred because additional views were not recommended for more definitive evaluation. For diagnostic studies, image quality was an issue in 16% of cases, affecting outcome 92% of the time. Although these were diagnostic cases presumably involving women with signs or symptoms of breast cancer, additional films were not obtained in nearly
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75% of cases. Additional films are not always required, but this high percentage of cases may indicate either an insufficient lack of concern for a focal abnormality or a failure of detection. One problem in any analysis of false-negative mammograms by category or reason is the interrelationship of all factors. Poor mammographic technique makes detection of an abnormality more difficult and compromises diagnostic evaluation. This was demonstrated in the previously described PIAA-ACR study where outcome was directly affected by image quality in a large percentage of cases. Beyond technique issues, consider the problems concerning certain anatomic areas that may be more difficult to image routinely than others. For example, breast tissue associated with the inferior mammary fold or axillary tail region may only be demonstrated routinely on the mediolateral oblique (MLO) projection, and often is not seen on craniocaudal projection unless specially tailored modifications of this latter view are obtained. If such areas are not adequately included in the MLO view, there is no opportunity to intercept a lesion that, with further evaluation, might be more properly evaluated. Imaging all of the breast tissue is a goal that is not always achieved, but imaging as much tissue as is reasonably possible is an issue that is fundamental to understanding the concept of standard of care. The ability to characterize an abnormality adequately is often dependent on obtaining the proper image. An apparently well-circumscribed mass may show irregular or indistinct margins when subject to high detail microfocal spot compression imaging with magnification. Morphology of clustered microcalcifications may be better assessed with similar techniques. Obtaining such views, however, is no assurance of image adequacy. Spot compression may be performed in an area that either does not sufficiently image the lesion in question or may displace the lesion from view. Magnification views may require prolonged mammographic exposure, which introduces the possibility of image blur, causing the morphology of individual calcific particles to be radiographically evaluated in a suboptimal manner. Rolled projections that displace a mass into an area of dense tissue instead of fat may give the erroneous impression of a summation artifact.8 It is the coupling of additional imaging together with deliberate evaluation of those images that
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lessens the risk of an erroneous and even unreasonable diagnostic impression leading to a false-negative mammogram. The issue of detection has been raised and studied in many areas of radiology but cannot be easily resolved.44* 45 Problems of improper reading conditions (e.g., extraneous light, noise, and other distractions) may be remedied but such solutions are often compromised by the conditions of clinical practice. Suboptimal but otherwise satisfactory imaging may provide a basis for detection, but make successful efforts more difficult. The phenomenon of "satisfaction of search" whereby the identification of one abnormality interferes with the search for another (and even more significant abnormality) applies to many fields of imaging, including mammography. The availability of prior films may facilitate the detection of an otherwise benignappearing abnormality as being suspicious by virtue of chronologic change. Measures to help resolve detection errors have been addressed. For example, reviewing a sufficient number of studies each year likely has a positive impact on reader performan~e.~O The feasibility of double reading of screening mammograms has been studied with one study showing as high as a 15% increased detection rate without compromise of positive predictive values at biopsy.46This rate has not been achieved by others and critical analysis of the value of double reading seems in part dependent on the nature of the paired readers (kappa values); namely, certain pairs show a sufficiently increased detection rate (sensitivity) without sufficient compromise of specificity, whereas others do not (Taplin SH, et al, unpublished data).4,16, 20,21 This issue is complicated by the different clinical circumstances surrounding screening mammography. First, if double reading is efficient in the evaluation of other organ systems, then applying such efforts to mammography may create a standard that must subsequently be addressed by other modalities. The analysis extends to computer-assisted detection and diagnosis. Beyond imaging modalities, the efficacy of more than one breast physical examination or physical examination of other organ systems may be evaluated in the same context. The potential legal liability of applying one standard to breast evaluation and a different one to other organ systems (both physical examination and imaging) may be problematic. Second,
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the problem of cost-efficacy is unavoidable where resources are limited to care for a large population of patients. Although courts are unlikely to relieve physicians from their basic duty to care for a patient without regards to cost, if the efficacy of double reading cannot be shown to be universally applicable, then as a standard of care issue its role is more difficult to justify.16 Given a limited public health-oriented reimbursement schedule afforded most screening mammography examinations, the additional cost for double reading under one set of circumstances has been calculated as 10% of the professional fee?, 47 On the other hand, there are studies in which there are simply no features on the mammographic images that indicate malignancy, and double reading is unlikely to impact outcome. This issue requires further comment. The ability to diagnose breast cancer by ultrasound, for example, when a palpable abnormality is present, has been experienced by most imaging centers. Although physical evaluation of a clinically suspicious mass is indicated regardless of the mammographic result, sometimes palpable areas are not sufficiently specific to permit blinded percutaneous intervention; in such cases ultrasound may provide a basis for raising a high index of suspicion and even provide image guidance for biopsy. In such cases, so-called false-negative mammograms are converted in essence to true-positive breast imaging studies. This rationale relates to what should be called subthreshold mammographic findings. The availability of a pertinent clinical history has shown impact on the accuracy of mammographic diagnosis.24Moreover, the positive predictive value for malignancy of otherwise subthreshold mammographic features may increase when a known palpable abnormality is associated with the same anatomic area.37 Both the need for additional studies and the identification of mammographic abnormalities that might otherwise be subthreshold-absent a relevant palpable finding-are dependent on obtaining a proper clinical history. This essential element in assigning patients to a diagnostic or screening schedule may be used to intercept shortcomings in interpretation. Unfortunately, such histories may also be misleading if not analyzed correctly. The patient who presents to a breast center for the first time indicating that she has had a lump for many years and that it is unchanged, may dissuade the facility from performing a diagnostic study with whatever
ancillary imaging is required. Two inherent problems exist under these circumstances. First, the lump that she may have felt (absent corroborative clinical breast examination) in the past may or may not be the same one she is feeling at the present time. The possibility of a cyst that has spontaneously regressed in the past being in a similar location to an emerging malignancy that has never been evaluated by imaging represents a definable situation where misdiagnosis or delayed diagnosis may be a ~ o i d a b l e , 'although ~ this phenomenon may even occur after reasonable diagnostic evaluation. Second, the lump that she feels may in fact be a slowly growing cancer. Although one may perhaps reasonably elect not to perform additional imaging each time a woman presents with the same palpable area following satisfactory work-up and evaluation initially, the lack of any additional evaluation in the past should prompt consideration for ancillary imaging. Each situation is case specific because the term of art, dominant mass, which is used as a benchmark for diagnostic imaging, is not sufficiently specific to all women or breast care providers. Some clinicians, for example, do not or cannot distinguish nonspecific nodularity from a distinct mass. Areas of palpable concern may vary from one examiner to another and assessment of clinical history, like images, must be based on specific circumstances. Misdiagnosis is a multifactoral and complicated subject, and also needs to be assessed on a case-by-case basis. Interventions, such as educational initiatives and attention to quality control efforts, have been shown to impact reader performance p ~ s i t i v e l yUltimate .~~ success in diagnostic evaluation requires a range of experience and knowledge, which escapes specific recommendations. Decision aids have been proposed,22but perhaps the most useful guidance can be established by understanding the rationale of proper reporting. The ACR has published the breast imaging reporting and data system (BI-RADS) lexicon, which offers a glossary of descriptive terms to help characterize different mammographic lesions.' Whether or not the actual terms are accepted into one's practice, the rationale of such descriptors is essential to understanding and establishing a successful approach to diagnosis. Indeed, the simple nondeliberative use of the lexicon does not ensure successful practice.32Rather, deliberate and deductive reasoning inherent in a proper description of an observed mammographic abnormality
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likely intercepts errors based on conclusionary impressions that have not been subject to the analytic process. For example, the interval development of a mass in a postmenopausal woman that is not a lymph node or cyst is likely to be considered suspicious for malignancy. If a new density is seen on only one screening view distinct enough likely to represent a true mass and that mass already shows irregular margins, then the differential diagnosis does not reasonably include cyst or lymph node. Unless this density is shown to be representing a summation artifact, the index of suspicion for malignancy is relatively high. Accurate description of the lesion and its appearance is likely to lead to a reasonable conclusion. Electing simply to subject this area to imaging surveillance is not only unreasonable, but falls into the category of observer error, included in the global term false-negative mam-
mogram. PREVENTABLE CAUSES OF FALSENEGATIVE MAMMOGRAMS Based largely on the previous discussion and a series of cases reviewed by this author regarding litigation involving mammography and the delay in diagnosis of breast cancer, the following is a summary of recurrent themes that identify preventable reasons for legal exposure. The list is not exhaustive, and this discussion does not attempt to reconcile misdiagnosis based on the improper application of imaging features discussed in other publications. The risk management implications of different circumstances attendant to the practice of breast imaging are stressed. Comparison With Old Films Attempts to retrieve old films and compare them with current examinations is a universal issue for radiology and a particular one for mammography, where women often visit different facilities; where original films are often released for review by other health care professionals (as provided by Mammography Quality Standards Act requirements); and where limited reimbursement is a disincentive to expend additional resources when women are invited to bring prior studies and fail to do so. Some facilities request old films on an as needed basis, others do not do so
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at all, and finally others request old films routinely. The last approach is preferred, if only because the identification of a neodensity, one cause for delay in diagnosis identified in prior report^,^, 17, 19, 28, 29, 36 is not possible without prior films. On the other hand, studies have been done to document the inability of efforts successfully to obtain old films unif ~ r m l yReasonable .~ attempts or requests for old films should satisfy any legal threshold and reasonable medical practice standard. Beyond such thresholds, however, otherwise benign-appearing mammographic features may rise to a level of higher suspicion when old films are available (Fig. 1). In addition, because many breast cancers grow slowly, comparison should be performed with studies older than the most recent one to detect changes that might otherwise be too subtle to recognize from year to year (Fig. 2). It is the practice of this author routinely to compare studies separated by approximately 3 years difference, with additional studies reviewed from earlier (e.g., for asymmetries) or later (e.g., for interval scarring) examinations as needed. Attention to Technical Detail and Additional Imaging The failure to obtain additional films was a common issue in litigation claims previously described in the PIAA-ACR study.20,21 Frequently, spot compression magnification films demonstrate features of a mass, such as margins, or morphology of calcific particles that support either a benign or suspicious impression that might not have otherwise been entertained or recognized with confidence (Fig. 3). This observation does not obligate the radiologist to obtain additional views in all cases; rather reasonable judgement based on knowledge and experience must be exercised. Concordance of Mammographic and Sonographic Features The measured sonographic size of a mass may differ slightly from the mammographic size, but significant differences cannot be reconciled readily by a change in imaging modalities. This principle is important because the majority of breast cysts are not mammographically visible, an issue that is not relevant to screening for cancer because nonde-
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Figure 1. Interval development of invasive lobular carcinoma. A, Craniocaudal view of left breast shows otherwise nonspecific parenchymal pattern without mass or architectural distortion (arrows). B, Compared with same view from previous study, this area represents neodensity, which cannot be attributed to exogenous hormonal therapy, inflammation, or trauma. Under such circumstances, the interval change is sufficient to prompt biopsy.
tection of mammographically occult simple cysts is inconsequential. Rather, the presence of a cyst (or lymph node) is important as a benign explanation for a palpable lump or mammographically demonstrated mass. If the sizes as measured mammographically and sonographically do not reasonably approximate each other, then it is more likely that the cyst identified on the ultrasound examination is mammographically occult and does not account for the mammographic mass being evaluated. This issue becomes particularly important for new or enlarging mammographic masses. If a small cyst is seen that does not account for the size of the observed mammographic mass, then this origin of the mammographic mass has not been reconciled and further evaluation is usually indicated (Fig. 4).
numbers of mammographic cases reviewed, especially for clinically occult disease, cause this issue to be more relevant in the field of breast imaging. Sometimes two lesions abut one another and care needs be taken to avoid dismissing a benign lesion when a malignant lesion is located anatomically adjacent to the benign one (Fig. 5). This same problem may arise when the radiologist is following a lesion considered probably benign or benign but, during surveillance, a second lesion emerges that has different characteristics that are more likely malignant. A related issue occurs not infrequently when a patient is referred for evaluation of a particular clinical problem, but the only significant mammographic abnormality is unrelated to that problem. Such pitfalls emphasize the importance of reviewing all breast tissue during each study as a screening exercise, regardless of the purpose of the individual examination.
Satisfaction of Search
The analytic conclusion following the evaluation of a specific mammographic finding may distract the observer from noticing other significant areas of concern. Although this is a universal phenomenon in radiology, often referred to as satisfaction of search, the large
Difficult Anatomic Locations
The axillary tail and inferior mammary fold regions of the breast may often be seen only on MLO projection during routine mammography (Fig. 6). This issue is important because
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Figure 2. Slowly growing invasive ductal carcinoma. A, Mediolateral view of mass suggests irregular margins, but the appearance of the mass does not appear appeciably different than prior year. B, Compared with the same view from several years prior, there is unequivocal change, increasing both the detectability of the change and suspicion for malignancy.
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Figure 3. Infiltrating ductal carcinoma. A, Mass seen on conventional craniocaudal view seems nonspiculated with many smooth margins and some questionable indistinct margins (arrow). 13, Spot compression magnification view demonstrates both indistinct and irregular margins suspicious for malignancy (arrows).
Figure 4. Interval enlargement (current examination on right compared with mirror image from prior study on left side of each figure) of a 2.5-cm mass in the upper outer quadrant, as seen on cannot be accounted for by craniocaudal (arrow) and mediolateral oblique (arrowhead) (A and 4, initial sonographic image, demonstrating a small 8-mm cyst that is probably mammographically occult (C). Re-evaluation by ultrasound identified a 2.5-cm solid mass, correctly accounting for the enlarging mammographic mass (0). (Courtesy of R. James Brenner, MD, Los Angeles, CA.)
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Figure 4. See legend on opposite page
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Figure 5. Satisfaction of search. Palpable lesion in the upper outer quadrant on craniocaudal and mediolateral oblique projection shows a 6-cm mass with well-circumscribed margins and both fatty and soft tissue components, characteristic of a fibrolipoma (hamartoma), likely explaining the physical findings (note metallic film marker). Adjacent to this benign mass is a small, 4-mm spiculated mass representing infiltrating ductal carcinoma (arrowheads).
many lesions are identifiable on two projections, affording the radiologist the increased ability to detect them even if they are overlooked on one of these views. Lesions in the axillary region may also be more difficult to detect because of the overlying pectoralis muscle causing decreased contrast in the region of the abnormality. Awareness of these limitations on routine mammography may assist the radiologist in paying attention to these anatomic locations. In other words, you can’t call what you can’t see.
Misapplication of Diagnostic Evaluation Once the decision to evaluate an abnormality further has been made, one cause of falsenegative mammograms has been satisfied. There is nothing automatic about diagnostic evaluations, however, which is one reason that the ACR Standards on Diagnostic Evalua t i ~ nrecommends ~~ on-site evaluation by a radiologist. For example, the obtaining of spot compression magnification films usually requires a longer radiographic exposure. Mi-
crocalcifications may be either blurred or virtually obliterated from view by the effect of motion. Placement of a spot compression device requires skill and evaluation. The device may actually displace the area of concern in a manner that compromises diagnosis (Fig. 7). In other words, don’t make good calls on bad films.
Elevating Subthreshold Mammographic Findings to Threshold With Addition of Clinical History Historic data regarding the false-negative rates of mammography were based on radiographic imaging alone. The ability to suggest a malignant diagnosis based on the demonstration of a sonographically defined solid mass with irregular margins in a patient where no features of malignancy are present on the mammogram, but clinical findings are specified to one particular focus prompting ultrasound evaluation, has been documented repeatedly in this author’s experience. Because most cases falling into this category do
Figure 6. Interval cancers (arrows) developing at inferior mammary fold and axillary tail of breast. Lesions are developing at the inferior mammary fold (A) (arrow) in an area that is not imaged on prior mammographic study (4 (craniocaudal and mediolateral oblique). Spiculated mass (not consistent with lymph node) in axillary tail (C) (arrow) may be visible only on initial screening mediolateral oblique projection, because routine craniocaudal views often may not include such areas in view, unless modifications of the view are obtained, which should be completed before final assessment. (Courtesy of R. James Brenner, MD, Los Angeles, CA.)
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Figure 6. See legend on opposite page
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Figure 7. A, Misapplication of diagnostic evaluation. Lesion seen in the upper outer quadrant of breast (arrows) on exaggerated craniocaudal and mediolateral oblique projections is evaluated using spot compression magnification technique. 6,this view, the mass has been superimposed on dense axillary tail breast tissue, compromising evaluation of its margins by fat-soft tissue interfaces (arrow). Such a view is not diagnostic and must be repeated.
not show features of cancer, controversy exists as to the efficacy of this approach. The approach may be criticized as unnecessary if the lesion will undergo biopsy on a clinical basis alone, regardless of the sonographic findings. The approach is supported by the increased directive toward biopsy provided by imaging results, especially when clinical examination is equivocal or when the palpable area is not clearly delineated. In one sense, the false-negative mammogram is salvaged by sonography for such cases. Beyond this controversy, otherwise subthreshold mammographic features may be more easily detected and more likely to prompt further imaging and successful evaluation when associated with an area of clinical palpable concern (Fig. 8). Invalid Assumptions
Relevant and appropriate patient history is an important component, not only for helping to evaluate mammographic findings properly, but also for purposes of scheduling screening and diagnostic patients, especially when screening examinations are not performed with on-site evaluation. Obtaining a history of a palpable mass and identifying its location and likely etiology are often not as simple as they appear. Vague histories, suboptimal
breast physical examinations, and frankly incorrect information complicate an optimal approach. Each circumstance must be handled on a case-by-case basis because some examiners fail to detect palpable lumps and others have difficulty distinguishing normal tissue from dominant lumps so that almost all patients are referred for evaluation of one or more lumps. If a patient indicates a clearly definable mass that has not previously been evaluated, then evaluation should not necessarily be deterred by a long history of having such lump. The threshold used by this author is the index finger test, namely, if the patient or breast health provider can place the tip of the index finger on a specific location, then there is more likely to be a dominant mass that need be evaluated (Fig. 9). Once no lesion or a benign lesion is established in such a location, less aggressive approaches may be appropriate, but only after sufficient evaluation. As always, clinical evaluation plays a major role in management determinations, with the imaging information available. DISCUSSION
One of the difficulties in assessing falsenegative mammograms is identifying lesions that should be reasonably recognized as possible signs of malignancy. The legal corollary
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Figure 8. Subthreshold mammographic findings elevated to suspicious because of pertinent clinical findings. Multiple areas of asymmetry between the right and left breast are noted on craniocaudalviews. A, A more focal area of asymmetry, possibly associated with architectural distortion, is detected more easily (arrow) because of the metallic film marker placed in this area. B, Same views with metallic marker masked by bilateral symmetric black tape to obviate bias and expose the relative difficulty of identifying the 11-mm infiltrating ductal carcinoma associated with a palpable lump.
to this process, and the test of negligent conduct, is forseeability, namely, is it reasonably foreseeable that a focus on the mammogram represents malignancy and requires additional evaluation and possible recommendation for biopsy. Conversely, one may ask if it is reasonably foreseeable that the abnormality of concern represents a normal variation of tissue appearance, or a benign lesion. Although an adverse outcome usually trig-
gers the filling of a lawsuit, it is the conduct of the physician that is of issue to the court in deciding negligence. That conduct is directly related to the issue of forseeability. Consider the issue of asymmetric densities in the breast, a common mammographic observation. Depending on their appearance as defined by different commentators, an otherwise bland-appearing area has a low likelihood of representing early malignancy.
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Figure 9. A, Invalid assumption regarding a palpable mass. Mediolateral oblique view of right (left)and left (righf) breast in 1993 show subtle signs of malignancy as a focus of increased density with architectural distortion (arrow). Subsequent studies showed increasing prominance of this area, always accompanied by a history of a mass that had been present for many years. B, Similar mediolateral oblique views 3 years later with same history shows 5-cm mass (arrow) with architectural distortion, prompting excision and diagnosis of infiltrating carcinoma.
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The likelihood is not zero, however, and if a cancer should arise in such an area of asymmetry, the court decides whether or not it should have undergone biopsy sooner rather than later.13,42 Likewise, such features need be distinguished for purposes of declaring a normal interpretation as a false-negative. The same rationale holds true for masses, architectural distortions, and calcifications. Indeed, often clusters of suspicious microcalcifications may emerge against a background of otherwise benign (even as proved histologically following surgery) calcifications and such distinguishing features enter into the analysis of whether an area was foreseeable suspicious in a legal sense, or truly a missed lesion from an audit perspective of determining false-negative statistics. The studies mentioned at the beginning of this article were conducted retrospectively. In an elegantly constructed experiment, Harvey et alZ7attempted as close to a prospective analysis as has been published. Under the guise of a cross-monitor quality assurance program with patient name and date of study identification blinded to the second reader, prior cases of missed cancer were interpersed among normal cases and subject to reinterpretation. These investigators not only demonstrated a statistically significant difference between blinded prospective and retrospective identification of abnormalities, which in fact represented breast cancer, but also that such differences were particularly relevant to the issue of asymmetric density. Perhaps the term false-negative mammogram in cases where the lesion is demonstrable on the film and is either not detected or inadequately evaluated is a misnomer. Patients whose breast cancers are detected subsequently either by clinical examination (the classic definition of interval cancer) or even by subsequent mammography (an alternative definition of interval cancer), however, are unlikely to discriminate among the different reasons for delayed diagnosis.%As far as they are concerned the mammographic study did not immediately lead to the diagnosis of breast cancer. Older reviews of interval cancers as outlined in this article identify reasons for false mammograms. Many of these reasons may be mitigated, both by conditions that were applicable in the past (nondetection, technical deficiency) and emerging technologies and applications (e.g., microfocal spot compression magnification views, ultrasound). In-
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deed, current investigation into the efficacy of newer technologies, such as MR imaging, may in selected circumstances further decrease the incidence of false-negative mammograms without necessarily increasing the morbidity associated with decreasing specificity? Variability in interpretation has been studied and is of interest to the imaging community to the extent of defining those parameters of observation and interpretation that characterize clinical practice.25Where lesions should be identified and are not, such variability is unlikely to reconcile to the patient’s satisfaction. Instead, the end result regardless of the reason often is seen as a worsened prognosis that may have been avoided. The validity of this contention depends on the particular case but whatever the outcome of such analysis, the study is considered as a false-negative mammogram. SUMMARY
From a strictly biologic perspective, delay in diagnosis of breast cancer is axiomatic. The number of cell divisions that must occur before detection is possible by either clinical or mammographic methods means that a finite time has occurred in which the outcome for any given case may have already been determined. That early detection and diagnosis of breast cancer lead to improved survival may be intuitive, but clinical trials have been necessary to validate the concept. Delay in diagnosis is unavoidable but the period of delay may be lessened in many cases, prompting earlier intervention and impacting outcomes. Mammography is an important vehicle for such earlier intervention and the issue of the false-negative mammogram is of concern to the radiology community, the lay community, and the courts. Mammographic interpretation has not yet approached a sufficiently standardized benchmark. Detection and diagnosis are dependent on a series of factors that need to be integrated to achieve the dual goals of timely intervention for bonafide purposes and reduction of unnecessary procedures and interventions. Some of the reasons for delay in diagnosis are unavoidable, beginning with the absence of clinical or imaging features of malignancy and extending to limitations of sufficiently specific features to prompt intervention. On the other hand, other reasons
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are avoidable and attention to many of these causes should lessen the incidence of such delay. Regardless of the reason, those women who feel that their breast cancer should have been diagnosed at an earlier time may consider subjecting their mammographic studies to independent reviews. At such a point, the precise reasons for delay may be better analyzed, all in an attempt to provide an adequate reconciliation of what has come to be known as the false-negative mammogram.
References 1. American College of Radiology: ACR Standard for the Performance of Diagnostic Mammography (Effective 1/ 1/ 99). Reston, VA, American College of Radiology, 1998 2. American College of Radiology: Breast Imaging Reporting and Data System (BIRADS), ed 3. Reston, VA, American College of Radiology, 1998 3. Bassett LW, Shayestehfar B, Hirbawi I: Obtaining previous mammograms for comparison: Usefulness and cost. AJR Am J Roentgenol 163:1083-1086, 1994 4. Beam CA, Sullivan DC, Layde PM: Effect of human variability on independent double reading in screening mammography. Acad Radiol 3:891-897, 1996 5. Bird RE, Wallace TW, Yankaskas BC: Analysis of cancers missed at screening mammography. Radiology 184613417, 1992 6. Brady AP, Stevenson GW, Stevenson E: Colorectal cancer overlooked at barium enema examination and colonoscopy: A continuing perceptual problem. Radiology 192~373-378,1994 7. Brenner RJ: An analysis of the role of breast MRI with respect to other imaging and interventional modalities. Magn Reson Imaging Clin 2:705-725, 1994 8. Brenner RJ: Asymmetries of the breast: Extended use of the rolled projection. Applied Radiology 2:15-24, 1998 9. Brenner RJ: Cost-effectiveness issues and breast imaging. Presented at the third Postgraduate Course Syllabus, Society of Breast Imaging, San Diego, April 1997 10. Brenner RJ: Medical legal aspects of mammography. AJR Am J Roentgenol 153:53-56, 1989 11. Brenner RJ: Medical legal aspects of mammography: Variable standards of care relating to differing types of practice. AJR Am J Roentgenol 156:719-723, 1991 12. Brenner RJ: Medical legal aspects of breast imaging. Radiol Clin North Am 32:277-286, 1992 13. Brenner RJ: Surveillance mammography versus biopsy for probably benign breast lesions. In Thrall J (ed): Current Practice in Radiology. St. Louis, BC Decker, Mosby-Yearbook, 1993, pp 403406 14. Brenner RJ, Bein M, Sarti DA, et al: Spontaneous regression of interval benign cysts of the breast. Radiology 193:365-368, 1994 15. Brenner RJ, Lucey LL, Smith JJ, et al: Radiology and medical malpractice claims: A report on the practice standards claims survey of the Physician Insurers Association of America and the American College of Radiology. AJR Am J Roentgenol 171:19-22, 1998 16. Brown J, Bryan S, Warren R Mammography screen-
ing: An incremental cost-effectiveness analysis of double versus single reading of mammograms. BMJ 312~809-812,1996 17. Burhenne HJ, Burhenne LW, Goldberg F, et al: Interval breast cancers in the screening mammography program of British Columbia: Analysis and classification. AJR Am J Roentgenol 162:1067-1071, 1994 18. Burrell HC, Sibbering DM, Wilson ARM, et al: Screening interval breast cancers: Mammographic features and prognostic factors. Radiology 199:811817, 1996 19. Cahill CJ, Boulter PS, Gibbs NM, et al: Features of mammographically negative breast tumours. Br J Surg 68:882-884, 1981 20. Ciatto S, Del Turco MR, Morrone D, et al: Independent double reading of screening mammograms. J Med Screen 2:99-101,1995 21. Ciccone G, Vineis P, Frigerio A, et al: Inter-observer and intra-observer variability of mammogram interpretation: A field study. Eur J Cancer 28A:10541058, 1992 22. DOrsi CJ, Getty DJ, Swets JA, et al: Reading and decision aids for improved accuracy and standardization of mammographic diagnosis. Radiology 184:619-622, 1992 23. Elmore JG, Barton MB, Moceri VM, et al: Ten-year risk of false positive screening mammograms and clinical breast examinations. N Engl J Med 338:10891096, 1998 24. Elmore JG, Wells CK, Howard DH, et al: The impact of clinical history on mammographic interpretations. JAMA 27749-52, 1997 25. Elmore JG, Wells CK, Lee CH, et al: Variability in radiologists’ interpretations of mammograms. N Engl J Med 331:1493-1499, 1994 26. Goergen SK, Evans J, Cohen GPB, et al: Characteristics of breast carcinomas missed by screening radiologists. Radiology 204131-135, 1997 27. Harvey JA, Fajardo LL, Innis C A Previous mammograms in patients with impalpable breast carcinoma: Retrospective vs blinded interpretation. AJR Am J Roentgenol 161:1167-1172, 1993 28. Ikeda DM, Anderson I, Wattsgard C, et al: Interval carcinomas in the Malmo mammographic screening trial: Radiographic appearance and prognostic considerations. AJR Am J Roentgenol 159:287-294, 1992 29. Kalisher L: Factors influencing false negative rates in xeromammography. Radiology 133:297-301, 1979 30. Kan L, Olivotto IA, Burhenne LJW, et al: Standardized abnormal cell and cancer detection ratios to assess reading volume and reader performance in a breast screening program. Radiology, in press 31. Kerlikowske K, Grady D, Barclay J, et al: Likelihood ratios for modem screening mammography: Risk of breast cancer based on age and mammographic interpretation. JAMA 276:39-43, 1996 32. Kerlidowske KK, Grady D, Barclay J, et al: Variability and accuracy in mammographic interpretation using the American College of Radiology Breast Imaging Reporting and Data System. J Natl Cancer Inst 90:1801-1809, 1998 33. 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 47150153, 1997 34. Linver MN, Osuch J, Brenner RJ, et al: The mammographic audit: A primer for MQSA. AJR Am J Roentgenol 165:19-25, 1995 35. Linver MN, Paster SB, Rosenberg RD, et al: Improve-
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36. 37. 38. 39.
40.
ment in mammography interpretation skills in a community radiology practice after dedicated teaching courses: 2-year medical audit of 38,633 cases. Radiology 184:39-43, 1992 Martin JE, Moskowitz M, Milbrath J R Breast cancer missed by mammography. AJR Am J Roentgen01 132737-739, 1979 Moskowitz M: The predictive value of certain mammographic signs in screening for breast cancer. Cancer 51:1007-1011, 1983 Physicians Insurers Association of America: Breast Cancer Study. Rockville, MD, Physicians Insurers Association of America, 1995 Physician Insurers Association of America, American College of Radiology: Practice Standards Claims Survey. Rockville, MD, Physician Insurers Association of America, 1997 Redrew D, Franken EA, Berbaum KS, et al: Error in radiology: Classification and lessons in 182 cases presented at a problem case conference. Radiology 183:145-150, 1992
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41. Sickles E A Findings at mammographic screening on only one standard projection: Outcomes analysis. Radiology 208:471-475, 1998 42. Sickles EA: Periodic follow-up of probably benign lesions: Results in 3184 consecutive cases. Radiology 179:463-469, 1991 43. Smart CR, Byme C, Smith RA, et al: Twenty-year follow-up of the breast cancers diagnosed during the Breast Cancer Detection Demonstration Project. CA Cancer J Clin 47:134-149, 1997 44. Swets JA: Measuring the accuracy of diagnostic systems. Science 240:1285-1293, 1988 45. Swets JA, Getty DJ, Pickett RM, et al: Enhancing and evaluating diagnostic accuracy. Med Decis Making 11~9-18,1991 46. Thurfjell EL, Lernevall KA, Taube AAS Benefit of independent double reading in a population-based mammography screening program. Radiology 191241-244, 1994 47. Wickline 'u State of California, 183 Cal App 1064, 118 Cal Rptr 661 (1986)
Address Reprint Requests to: R. James Brenner, MD, JD Eisenberg Keefer Breast Center Saint Johns Health Center 1328 22nd Street Santa Monica, CA 90404 e-mail: [email protected]
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FALSE-NEGATIVE MAMMOGRAMS Medical, Legal, and Risk Management Implications R. James Brenner, MD, JD
The opportunity to detect preclinical breast cancer by mammographic evaluation and to facilitate biopsy for a sign or symptom of possible breast cancer by a variety of breast imaging techniques is founded on the evidence-based conclusion that early diagnosis and treatment are likely to improve both disease-free and overall survival in a significant percentage of cases.33,34 The impetus to provide an imaging basis for early intervention has prompted criticism, with commentators suggesting an unnecessarily high rate of recall of patients for additional studies and biopsy.23,31 Radiologists are confronted with a difficult situation, balancing the need for early tissue diagnosis of potential breast cancer with the overuse of resources for lesions that do not represent malignancy and may not require biopsy. The contrasting notions regarding possible lesions seen in only one standard mammographic screening view exemplify the dilemma. In one prospective study, the likelihood of malignancy associated with these circumstances was shown to be very small, whereas a retrospective review of missed breast cancers in a different study indicated that this phenomenon was statistically significant in accounting for features of lesions for which there was a delay in diagnosis of breast cancer.26,41
Attempts to reconcile these two studies and others reported in the literature are virtually impossible based on published reports. Only trends, clinical observations, and a few examples are afforded in any given report; a sufficient number of published imaging examples are not feasible for such purposes. Any critical analysis depends on case-specific circumstances. For example, a truly spiculated density seen on one view only is unlikely to represent a benign condition, whereas a summation artifact that gives the false impression of a mass with irregular margins is unlikely to represent malignancy. Both situations may be categorized for purposes of a study design as a potential abnormality seen in one view only, but proper management and final imaging impressions of each are fundamentally different. Errors in detection and diagnosis are not peculiar to mammography. They may occur in virtually any radiologic examination, and errors in interpretation in other organ systems, such as the colon, have also been carefully studied.6,40 Perhaps one distinguishing feature regarding missed lesions in breast imaging generally, and mammography in particular, is derivative of the large numbers of breast examinations that are conducted each year. Such volumes invite larger numbers of
From the Eisenberg Keefer Breast Center, John Wayne Cancer Institute, Saint Johns Health Center, and the Department of Radiology, University of California Los Angeles School of Medicine, Los Angeles, California
RADIOLOGIC CLINICS OF NORTH AMERICA VOLUME 38 NUMBER 4 * JULY 2000
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absolute errors even if the percentage of errors is commensurate with other types of radiologic evaluation. Most mammography is performed on asymptomatic women, where the clinical index of suspicion may be low and the potential benefit high. According to the Physicians Insurers Association of America (PIAA), delay in diagnosis of breast cancer is the most common reason for which physicians are sued for malpract i ~ e . 3In ~ part because most of the women bringing litigation against physicians for delay in diagnosis of breast cancer have undergone mammography, the most commonly named defendant in such lawsuits is the radiologist. The elements of a lawsuit have previously been described.12 Most medical malpractice lawsuits are tried under the civil law of negligence, which defines a departure from conduct that is expected of a reasonable and prudent radiologist under similar circumstances. Legal negligence is defined by four elements: (1) duty, (2) breach, (3) causation, and (4) damages. If the radiologist fails, under a given set of circumstances, to provide reasonable images, render a reasonable interpretation, and effectively communicate that interpretation, then a case for negligence may be found. Where legal damages, such as worsening prognosis or added treatment requirements can be shown, a so-called cause ofaction may be established and a lawsuit filed. The problems derivative of excess use of resources for additional studies and biopsies are not trivial, but they are uncommonly associated with lawsuits.1° The so-called missed or delayed diagnosis of breast cancer is the incident that provokes litigation. Whether such error occurs secondary to the lack of detection because of poor technical reasons or observer error, an unreasonable diagnostic evaluation or impression, or problems in communication, the rendering of a diagnosis that improperly fails to indicate a sufficient suspicion for malignancy is considered a false-negative mammogram. This article addresses those aspects about false-negative mammograms that have been studied, and focuses on correctable causes for such error. TYPES OF ERROR As already suggested, abnormalities seen on one view may represent benign or malignant conditions, absent further evaluation.
This issue highlights the interplay among the types of errors that may lead to a false mammogram. First, a lesion may be left undetected on the mammographic study. Second, if detected, the lesion may be insufficiently evaluated, causing an unreasonable interpretation. Finally, if either of these events should occur, or even if the lesion is reasonably interpreted but not made known in a sufficient manner to the intended party, the radiologist may have provided insufficient communication." Most mammographic errors are analyzed by retrospective analysis of patients who have developed interval breast cancers, usually based on clinical presentation.% In the 1970s and early 1 9 8 0 ~ where ~ conventional filmscreen and xeromammographic techniques were used without additional supplementary imaging (e.g., altered projections, microfocal spot compression magnification, ultrasound), errors were attributed to most of the same causes that remain problematic. Reporting of such errors varies in methodology, making it difficult to reconcile different results without reviewing individual cases, even for more recently reported series. If technical errors are omitted from analysis, a problem that accounts for 6% to 17% of problems, then as a first approximation falsenegative mammograms may be secondary to one of three factors that each constitute about a third of reviewed cases: (1) no mammographic features of malignancy, (2) subthreshold features of malignancy, and (3) observer error.5,17, 19, 28, 29, 36 The issues defined by these studies may be compared with data obtained in a review of 100 screening mammogram cases and 99 diagnostic mammogram cases that were subject to litigation and analyzed for types of errors.15,38 In the PIAA-American College of Radiology (ACR) study of screening mammography claims for negligence, 13% of the cases involved issues in image quality. An error in diagnosis, presumably including nondetection and incorrect assessment of detected abnormalities, occurred in 64% of cases. It was noted that half of these errors occurred because additional views were not recommended for more definitive evaluation. For diagnostic studies, image quality was an issue in 16% of cases, affecting outcome 92% of the time. Although these were diagnostic cases presumably involving women with signs or symptoms of breast cancer, additional films were not obtained in nearly
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75% of cases. Additional films are not always required, but this high percentage of cases may indicate either an insufficient lack of concern for a focal abnormality or a failure of detection. One problem in any analysis of false-negative mammograms by category or reason is the interrelationship of all factors. Poor mammographic technique makes detection of an abnormality more difficult and compromises diagnostic evaluation. This was demonstrated in the previously described PIAA-ACR study where outcome was directly affected by image quality in a large percentage of cases. Beyond technique issues, consider the problems concerning certain anatomic areas that may be more difficult to image routinely than others. For example, breast tissue associated with the inferior mammary fold or axillary tail region may only be demonstrated routinely on the mediolateral oblique (MLO) projection, and often is not seen on craniocaudal projection unless specially tailored modifications of this latter view are obtained. If such areas are not adequately included in the MLO view, there is no opportunity to intercept a lesion that, with further evaluation, might be more properly evaluated. Imaging all of the breast tissue is a goal that is not always achieved, but imaging as much tissue as is reasonably possible is an issue that is fundamental to understanding the concept of standard of care. The ability to characterize an abnormality adequately is often dependent on obtaining the proper image. An apparently well-circumscribed mass may show irregular or indistinct margins when subject to high detail microfocal spot compression imaging with magnification. Morphology of clustered microcalcifications may be better assessed with similar techniques. Obtaining such views, however, is no assurance of image adequacy. Spot compression may be performed in an area that either does not sufficiently image the lesion in question or may displace the lesion from view. Magnification views may require prolonged mammographic exposure, which introduces the possibility of image blur, causing the morphology of individual calcific particles to be radiographically evaluated in a suboptimal manner. Rolled projections that displace a mass into an area of dense tissue instead of fat may give the erroneous impression of a summation artifact.8 It is the coupling of additional imaging together with deliberate evaluation of those images that
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lessens the risk of an erroneous and even unreasonable diagnostic impression leading to a false-negative mammogram. The issue of detection has been raised and studied in many areas of radiology but cannot be easily resolved.44* 45 Problems of improper reading conditions (e.g., extraneous light, noise, and other distractions) may be remedied but such solutions are often compromised by the conditions of clinical practice. Suboptimal but otherwise satisfactory imaging may provide a basis for detection, but make successful efforts more difficult. The phenomenon of "satisfaction of search" whereby the identification of one abnormality interferes with the search for another (and even more significant abnormality) applies to many fields of imaging, including mammography. The availability of prior films may facilitate the detection of an otherwise benignappearing abnormality as being suspicious by virtue of chronologic change. Measures to help resolve detection errors have been addressed. For example, reviewing a sufficient number of studies each year likely has a positive impact on reader performan~e.~O The feasibility of double reading of screening mammograms has been studied with one study showing as high as a 15% increased detection rate without compromise of positive predictive values at biopsy.46This rate has not been achieved by others and critical analysis of the value of double reading seems in part dependent on the nature of the paired readers (kappa values); namely, certain pairs show a sufficiently increased detection rate (sensitivity) without sufficient compromise of specificity, whereas others do not (Taplin SH, et al, unpublished data).4,16, 20,21 This issue is complicated by the different clinical circumstances surrounding screening mammography. First, if double reading is efficient in the evaluation of other organ systems, then applying such efforts to mammography may create a standard that must subsequently be addressed by other modalities. The analysis extends to computer-assisted detection and diagnosis. Beyond imaging modalities, the efficacy of more than one breast physical examination or physical examination of other organ systems may be evaluated in the same context. The potential legal liability of applying one standard to breast evaluation and a different one to other organ systems (both physical examination and imaging) may be problematic. Second,
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the problem of cost-efficacy is unavoidable where resources are limited to care for a large population of patients. Although courts are unlikely to relieve physicians from their basic duty to care for a patient without regards to cost, if the efficacy of double reading cannot be shown to be universally applicable, then as a standard of care issue its role is more difficult to justify.16 Given a limited public health-oriented reimbursement schedule afforded most screening mammography examinations, the additional cost for double reading under one set of circumstances has been calculated as 10% of the professional fee?, 47 On the other hand, there are studies in which there are simply no features on the mammographic images that indicate malignancy, and double reading is unlikely to impact outcome. This issue requires further comment. The ability to diagnose breast cancer by ultrasound, for example, when a palpable abnormality is present, has been experienced by most imaging centers. Although physical evaluation of a clinically suspicious mass is indicated regardless of the mammographic result, sometimes palpable areas are not sufficiently specific to permit blinded percutaneous intervention; in such cases ultrasound may provide a basis for raising a high index of suspicion and even provide image guidance for biopsy. In such cases, so-called false-negative mammograms are converted in essence to true-positive breast imaging studies. This rationale relates to what should be called subthreshold mammographic findings. The availability of a pertinent clinical history has shown impact on the accuracy of mammographic diagnosis.24Moreover, the positive predictive value for malignancy of otherwise subthreshold mammographic features may increase when a known palpable abnormality is associated with the same anatomic area.37 Both the need for additional studies and the identification of mammographic abnormalities that might otherwise be subthreshold-absent a relevant palpable finding-are dependent on obtaining a proper clinical history. This essential element in assigning patients to a diagnostic or screening schedule may be used to intercept shortcomings in interpretation. Unfortunately, such histories may also be misleading if not analyzed correctly. The patient who presents to a breast center for the first time indicating that she has had a lump for many years and that it is unchanged, may dissuade the facility from performing a diagnostic study with whatever
ancillary imaging is required. Two inherent problems exist under these circumstances. First, the lump that she may have felt (absent corroborative clinical breast examination) in the past may or may not be the same one she is feeling at the present time. The possibility of a cyst that has spontaneously regressed in the past being in a similar location to an emerging malignancy that has never been evaluated by imaging represents a definable situation where misdiagnosis or delayed diagnosis may be a ~ o i d a b l e , 'although ~ this phenomenon may even occur after reasonable diagnostic evaluation. Second, the lump that she feels may in fact be a slowly growing cancer. Although one may perhaps reasonably elect not to perform additional imaging each time a woman presents with the same palpable area following satisfactory work-up and evaluation initially, the lack of any additional evaluation in the past should prompt consideration for ancillary imaging. Each situation is case specific because the term of art, dominant mass, which is used as a benchmark for diagnostic imaging, is not sufficiently specific to all women or breast care providers. Some clinicians, for example, do not or cannot distinguish nonspecific nodularity from a distinct mass. Areas of palpable concern may vary from one examiner to another and assessment of clinical history, like images, must be based on specific circumstances. Misdiagnosis is a multifactoral and complicated subject, and also needs to be assessed on a case-by-case basis. Interventions, such as educational initiatives and attention to quality control efforts, have been shown to impact reader performance p ~ s i t i v e l yUltimate .~~ success in diagnostic evaluation requires a range of experience and knowledge, which escapes specific recommendations. Decision aids have been proposed,22but perhaps the most useful guidance can be established by understanding the rationale of proper reporting. The ACR has published the breast imaging reporting and data system (BI-RADS) lexicon, which offers a glossary of descriptive terms to help characterize different mammographic lesions.' Whether or not the actual terms are accepted into one's practice, the rationale of such descriptors is essential to understanding and establishing a successful approach to diagnosis. Indeed, the simple nondeliberative use of the lexicon does not ensure successful practice.32Rather, deliberate and deductive reasoning inherent in a proper description of an observed mammographic abnormality
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likely intercepts errors based on conclusionary impressions that have not been subject to the analytic process. For example, the interval development of a mass in a postmenopausal woman that is not a lymph node or cyst is likely to be considered suspicious for malignancy. If a new density is seen on only one screening view distinct enough likely to represent a true mass and that mass already shows irregular margins, then the differential diagnosis does not reasonably include cyst or lymph node. Unless this density is shown to be representing a summation artifact, the index of suspicion for malignancy is relatively high. Accurate description of the lesion and its appearance is likely to lead to a reasonable conclusion. Electing simply to subject this area to imaging surveillance is not only unreasonable, but falls into the category of observer error, included in the global term false-negative mam-
mogram. PREVENTABLE CAUSES OF FALSENEGATIVE MAMMOGRAMS Based largely on the previous discussion and a series of cases reviewed by this author regarding litigation involving mammography and the delay in diagnosis of breast cancer, the following is a summary of recurrent themes that identify preventable reasons for legal exposure. The list is not exhaustive, and this discussion does not attempt to reconcile misdiagnosis based on the improper application of imaging features discussed in other publications. The risk management implications of different circumstances attendant to the practice of breast imaging are stressed. Comparison With Old Films Attempts to retrieve old films and compare them with current examinations is a universal issue for radiology and a particular one for mammography, where women often visit different facilities; where original films are often released for review by other health care professionals (as provided by Mammography Quality Standards Act requirements); and where limited reimbursement is a disincentive to expend additional resources when women are invited to bring prior studies and fail to do so. Some facilities request old films on an as needed basis, others do not do so
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at all, and finally others request old films routinely. The last approach is preferred, if only because the identification of a neodensity, one cause for delay in diagnosis identified in prior report^,^, 17, 19, 28, 29, 36 is not possible without prior films. On the other hand, studies have been done to document the inability of efforts successfully to obtain old films unif ~ r m l yReasonable .~ attempts or requests for old films should satisfy any legal threshold and reasonable medical practice standard. Beyond such thresholds, however, otherwise benign-appearing mammographic features may rise to a level of higher suspicion when old films are available (Fig. 1). In addition, because many breast cancers grow slowly, comparison should be performed with studies older than the most recent one to detect changes that might otherwise be too subtle to recognize from year to year (Fig. 2). It is the practice of this author routinely to compare studies separated by approximately 3 years difference, with additional studies reviewed from earlier (e.g., for asymmetries) or later (e.g., for interval scarring) examinations as needed. Attention to Technical Detail and Additional Imaging The failure to obtain additional films was a common issue in litigation claims previously described in the PIAA-ACR study.20,21 Frequently, spot compression magnification films demonstrate features of a mass, such as margins, or morphology of calcific particles that support either a benign or suspicious impression that might not have otherwise been entertained or recognized with confidence (Fig. 3). This observation does not obligate the radiologist to obtain additional views in all cases; rather reasonable judgement based on knowledge and experience must be exercised. Concordance of Mammographic and Sonographic Features The measured sonographic size of a mass may differ slightly from the mammographic size, but significant differences cannot be reconciled readily by a change in imaging modalities. This principle is important because the majority of breast cysts are not mammographically visible, an issue that is not relevant to screening for cancer because nonde-
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Figure 1. Interval development of invasive lobular carcinoma. A, Craniocaudal view of left breast shows otherwise nonspecific parenchymal pattern without mass or architectural distortion (arrows). B, Compared with same view from previous study, this area represents neodensity, which cannot be attributed to exogenous hormonal therapy, inflammation, or trauma. Under such circumstances, the interval change is sufficient to prompt biopsy.
tection of mammographically occult simple cysts is inconsequential. Rather, the presence of a cyst (or lymph node) is important as a benign explanation for a palpable lump or mammographically demonstrated mass. If the sizes as measured mammographically and sonographically do not reasonably approximate each other, then it is more likely that the cyst identified on the ultrasound examination is mammographically occult and does not account for the mammographic mass being evaluated. This issue becomes particularly important for new or enlarging mammographic masses. If a small cyst is seen that does not account for the size of the observed mammographic mass, then this origin of the mammographic mass has not been reconciled and further evaluation is usually indicated (Fig. 4).
numbers of mammographic cases reviewed, especially for clinically occult disease, cause this issue to be more relevant in the field of breast imaging. Sometimes two lesions abut one another and care needs be taken to avoid dismissing a benign lesion when a malignant lesion is located anatomically adjacent to the benign one (Fig. 5). This same problem may arise when the radiologist is following a lesion considered probably benign or benign but, during surveillance, a second lesion emerges that has different characteristics that are more likely malignant. A related issue occurs not infrequently when a patient is referred for evaluation of a particular clinical problem, but the only significant mammographic abnormality is unrelated to that problem. Such pitfalls emphasize the importance of reviewing all breast tissue during each study as a screening exercise, regardless of the purpose of the individual examination.
Satisfaction of Search
The analytic conclusion following the evaluation of a specific mammographic finding may distract the observer from noticing other significant areas of concern. Although this is a universal phenomenon in radiology, often referred to as satisfaction of search, the large
Difficult Anatomic Locations
The axillary tail and inferior mammary fold regions of the breast may often be seen only on MLO projection during routine mammography (Fig. 6). This issue is important because
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Figure 2. Slowly growing invasive ductal carcinoma. A, Mediolateral view of mass suggests irregular margins, but the appearance of the mass does not appear appeciably different than prior year. B, Compared with the same view from several years prior, there is unequivocal change, increasing both the detectability of the change and suspicion for malignancy.
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Figure 3. Infiltrating ductal carcinoma. A, Mass seen on conventional craniocaudal view seems nonspiculated with many smooth margins and some questionable indistinct margins (arrow). 13, Spot compression magnification view demonstrates both indistinct and irregular margins suspicious for malignancy (arrows).
Figure 4. Interval enlargement (current examination on right compared with mirror image from prior study on left side of each figure) of a 2.5-cm mass in the upper outer quadrant, as seen on cannot be accounted for by craniocaudal (arrow) and mediolateral oblique (arrowhead) (A and 4, initial sonographic image, demonstrating a small 8-mm cyst that is probably mammographically occult (C). Re-evaluation by ultrasound identified a 2.5-cm solid mass, correctly accounting for the enlarging mammographic mass (0). (Courtesy of R. James Brenner, MD, Los Angeles, CA.)
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Figure 4. See legend on opposite page
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Figure 5. Satisfaction of search. Palpable lesion in the upper outer quadrant on craniocaudal and mediolateral oblique projection shows a 6-cm mass with well-circumscribed margins and both fatty and soft tissue components, characteristic of a fibrolipoma (hamartoma), likely explaining the physical findings (note metallic film marker). Adjacent to this benign mass is a small, 4-mm spiculated mass representing infiltrating ductal carcinoma (arrowheads).
many lesions are identifiable on two projections, affording the radiologist the increased ability to detect them even if they are overlooked on one of these views. Lesions in the axillary region may also be more difficult to detect because of the overlying pectoralis muscle causing decreased contrast in the region of the abnormality. Awareness of these limitations on routine mammography may assist the radiologist in paying attention to these anatomic locations. In other words, you can’t call what you can’t see.
Misapplication of Diagnostic Evaluation Once the decision to evaluate an abnormality further has been made, one cause of falsenegative mammograms has been satisfied. There is nothing automatic about diagnostic evaluations, however, which is one reason that the ACR Standards on Diagnostic Evalua t i ~ nrecommends ~~ on-site evaluation by a radiologist. For example, the obtaining of spot compression magnification films usually requires a longer radiographic exposure. Mi-
crocalcifications may be either blurred or virtually obliterated from view by the effect of motion. Placement of a spot compression device requires skill and evaluation. The device may actually displace the area of concern in a manner that compromises diagnosis (Fig. 7). In other words, don’t make good calls on bad films.
Elevating Subthreshold Mammographic Findings to Threshold With Addition of Clinical History Historic data regarding the false-negative rates of mammography were based on radiographic imaging alone. The ability to suggest a malignant diagnosis based on the demonstration of a sonographically defined solid mass with irregular margins in a patient where no features of malignancy are present on the mammogram, but clinical findings are specified to one particular focus prompting ultrasound evaluation, has been documented repeatedly in this author’s experience. Because most cases falling into this category do
Figure 6. Interval cancers (arrows) developing at inferior mammary fold and axillary tail of breast. Lesions are developing at the inferior mammary fold (A) (arrow) in an area that is not imaged on prior mammographic study (4 (craniocaudal and mediolateral oblique). Spiculated mass (not consistent with lymph node) in axillary tail (C) (arrow) may be visible only on initial screening mediolateral oblique projection, because routine craniocaudal views often may not include such areas in view, unless modifications of the view are obtained, which should be completed before final assessment. (Courtesy of R. James Brenner, MD, Los Angeles, CA.)
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Figure 6. See legend on opposite page
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Figure 7. A, Misapplication of diagnostic evaluation. Lesion seen in the upper outer quadrant of breast (arrows) on exaggerated craniocaudal and mediolateral oblique projections is evaluated using spot compression magnification technique. 6,this view, the mass has been superimposed on dense axillary tail breast tissue, compromising evaluation of its margins by fat-soft tissue interfaces (arrow). Such a view is not diagnostic and must be repeated.
not show features of cancer, controversy exists as to the efficacy of this approach. The approach may be criticized as unnecessary if the lesion will undergo biopsy on a clinical basis alone, regardless of the sonographic findings. The approach is supported by the increased directive toward biopsy provided by imaging results, especially when clinical examination is equivocal or when the palpable area is not clearly delineated. In one sense, the false-negative mammogram is salvaged by sonography for such cases. Beyond this controversy, otherwise subthreshold mammographic features may be more easily detected and more likely to prompt further imaging and successful evaluation when associated with an area of clinical palpable concern (Fig. 8). Invalid Assumptions
Relevant and appropriate patient history is an important component, not only for helping to evaluate mammographic findings properly, but also for purposes of scheduling screening and diagnostic patients, especially when screening examinations are not performed with on-site evaluation. Obtaining a history of a palpable mass and identifying its location and likely etiology are often not as simple as they appear. Vague histories, suboptimal
breast physical examinations, and frankly incorrect information complicate an optimal approach. Each circumstance must be handled on a case-by-case basis because some examiners fail to detect palpable lumps and others have difficulty distinguishing normal tissue from dominant lumps so that almost all patients are referred for evaluation of one or more lumps. If a patient indicates a clearly definable mass that has not previously been evaluated, then evaluation should not necessarily be deterred by a long history of having such lump. The threshold used by this author is the index finger test, namely, if the patient or breast health provider can place the tip of the index finger on a specific location, then there is more likely to be a dominant mass that need be evaluated (Fig. 9). Once no lesion or a benign lesion is established in such a location, less aggressive approaches may be appropriate, but only after sufficient evaluation. As always, clinical evaluation plays a major role in management determinations, with the imaging information available. DISCUSSION
One of the difficulties in assessing falsenegative mammograms is identifying lesions that should be reasonably recognized as possible signs of malignancy. The legal corollary
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Figure 8. Subthreshold mammographic findings elevated to suspicious because of pertinent clinical findings. Multiple areas of asymmetry between the right and left breast are noted on craniocaudalviews. A, A more focal area of asymmetry, possibly associated with architectural distortion, is detected more easily (arrow) because of the metallic film marker placed in this area. B, Same views with metallic marker masked by bilateral symmetric black tape to obviate bias and expose the relative difficulty of identifying the 11-mm infiltrating ductal carcinoma associated with a palpable lump.
to this process, and the test of negligent conduct, is forseeability, namely, is it reasonably foreseeable that a focus on the mammogram represents malignancy and requires additional evaluation and possible recommendation for biopsy. Conversely, one may ask if it is reasonably foreseeable that the abnormality of concern represents a normal variation of tissue appearance, or a benign lesion. Although an adverse outcome usually trig-
gers the filling of a lawsuit, it is the conduct of the physician that is of issue to the court in deciding negligence. That conduct is directly related to the issue of forseeability. Consider the issue of asymmetric densities in the breast, a common mammographic observation. Depending on their appearance as defined by different commentators, an otherwise bland-appearing area has a low likelihood of representing early malignancy.
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Figure 9. A, Invalid assumption regarding a palpable mass. Mediolateral oblique view of right (left)and left (righf) breast in 1993 show subtle signs of malignancy as a focus of increased density with architectural distortion (arrow). Subsequent studies showed increasing prominance of this area, always accompanied by a history of a mass that had been present for many years. B, Similar mediolateral oblique views 3 years later with same history shows 5-cm mass (arrow) with architectural distortion, prompting excision and diagnosis of infiltrating carcinoma.
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The likelihood is not zero, however, and if a cancer should arise in such an area of asymmetry, the court decides whether or not it should have undergone biopsy sooner rather than later.13,42 Likewise, such features need be distinguished for purposes of declaring a normal interpretation as a false-negative. The same rationale holds true for masses, architectural distortions, and calcifications. Indeed, often clusters of suspicious microcalcifications may emerge against a background of otherwise benign (even as proved histologically following surgery) calcifications and such distinguishing features enter into the analysis of whether an area was foreseeable suspicious in a legal sense, or truly a missed lesion from an audit perspective of determining false-negative statistics. The studies mentioned at the beginning of this article were conducted retrospectively. In an elegantly constructed experiment, Harvey et alZ7attempted as close to a prospective analysis as has been published. Under the guise of a cross-monitor quality assurance program with patient name and date of study identification blinded to the second reader, prior cases of missed cancer were interpersed among normal cases and subject to reinterpretation. These investigators not only demonstrated a statistically significant difference between blinded prospective and retrospective identification of abnormalities, which in fact represented breast cancer, but also that such differences were particularly relevant to the issue of asymmetric density. Perhaps the term false-negative mammogram in cases where the lesion is demonstrable on the film and is either not detected or inadequately evaluated is a misnomer. Patients whose breast cancers are detected subsequently either by clinical examination (the classic definition of interval cancer) or even by subsequent mammography (an alternative definition of interval cancer), however, are unlikely to discriminate among the different reasons for delayed diagnosis.%As far as they are concerned the mammographic study did not immediately lead to the diagnosis of breast cancer. Older reviews of interval cancers as outlined in this article identify reasons for false mammograms. Many of these reasons may be mitigated, both by conditions that were applicable in the past (nondetection, technical deficiency) and emerging technologies and applications (e.g., microfocal spot compression magnification views, ultrasound). In-
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deed, current investigation into the efficacy of newer technologies, such as MR imaging, may in selected circumstances further decrease the incidence of false-negative mammograms without necessarily increasing the morbidity associated with decreasing specificity? Variability in interpretation has been studied and is of interest to the imaging community to the extent of defining those parameters of observation and interpretation that characterize clinical practice.25Where lesions should be identified and are not, such variability is unlikely to reconcile to the patient’s satisfaction. Instead, the end result regardless of the reason often is seen as a worsened prognosis that may have been avoided. The validity of this contention depends on the particular case but whatever the outcome of such analysis, the study is considered as a false-negative mammogram. SUMMARY
From a strictly biologic perspective, delay in diagnosis of breast cancer is axiomatic. The number of cell divisions that must occur before detection is possible by either clinical or mammographic methods means that a finite time has occurred in which the outcome for any given case may have already been determined. That early detection and diagnosis of breast cancer lead to improved survival may be intuitive, but clinical trials have been necessary to validate the concept. Delay in diagnosis is unavoidable but the period of delay may be lessened in many cases, prompting earlier intervention and impacting outcomes. Mammography is an important vehicle for such earlier intervention and the issue of the false-negative mammogram is of concern to the radiology community, the lay community, and the courts. Mammographic interpretation has not yet approached a sufficiently standardized benchmark. Detection and diagnosis are dependent on a series of factors that need to be integrated to achieve the dual goals of timely intervention for bonafide purposes and reduction of unnecessary procedures and interventions. Some of the reasons for delay in diagnosis are unavoidable, beginning with the absence of clinical or imaging features of malignancy and extending to limitations of sufficiently specific features to prompt intervention. On the other hand, other reasons
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are avoidable and attention to many of these causes should lessen the incidence of such delay. Regardless of the reason, those women who feel that their breast cancer should have been diagnosed at an earlier time may consider subjecting their mammographic studies to independent reviews. At such a point, the precise reasons for delay may be better analyzed, all in an attempt to provide an adequate reconciliation of what has come to be known as the false-negative mammogram.
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Address Reprint Requests to: R. James Brenner, MD, JD Eisenberg Keefer Breast Center Saint Johns Health Center 1328 22nd Street Santa Monica, CA 90404 e-mail: [email protected]