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Original Research |
1 Both authors: Department of Radiology, University of California, San Francisco Medical Center, Box 1667, San Francisco, CA 94143-1667.
Received March 21, 2006;
accepted after revision July 31, 2006.
Presented at the 2006 annual meeting of the American Roentgen Ray Society,
Vancouver, BC, Canada.
Abstract
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MATERIALS AND METHODS. This study was performed in a retrospective cohort manner. We searched for all cases of developing asymmetry consecutively entered in our mammography database from April 1985 to April 2005. We examined radiology records to determine whether sonography and MRI were used as adjunctive diagnostic tools and examined pathology records to determine tissue diagnosis.
RESULTS. Developing asymmetry was present in 292 (0.16%) of 180,801 consecutive screening examinations and 32 (0.11%) of 27,330 consecutive diagnostic examinations. After exclusion for absent data, the study consisted of 281 screening and 30 diagnostic cases. In the 281 cases of screening-detected developing asymmetry, biopsy was recommended and was performed in 84 (29.9%) of the cases. Thirty-six cases of cancer were identified, resulting in a positive predictive value of 12.8%, obtained by division of the number of cases of cancers by the number of examinations with abnormal mammographic findings (PPV1), and a PPV2 of 42.9%, obtained by division of the number of cases of cancer by the number of mammographic examinations in which findings led to a recommendation for biopsy. Biopsy was recommended and performed in 26 (86.7%) of the 30 cases of diagnostic mammography. Eight cases of cancer were identified, resulting in a PPV1 of 26.7% and a PPV2 of 30.8%. Of the 44 cancers detected at screening and diagnostic mammography, 21 had available sonographic data. Five (23.8%) of these 21 cases of cancer had no correlate at sonographic examination. MRI was performed in only two cases, both with benign diagnoses.
CONCLUSION. Developing asymmetry is an uncommon finding. When this sign is identified on screening and diagnostic mammography, the likelihood of malignancy is sufficiently high to justify recall and biopsy. Normal sonographic findings do not exclude malignancy in the case of developing asymmetry.
Keywords: breast • breast cancer • mammography • screening • sonography
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Part of the reason that the clinical importance of the developing density sign is not well known is that there is no widely accepted definition of the finding. None of the four editions of BI-RADS describes this sign [6-9]. The earlier editions differentiate mass, focal asymmetric density, and asymmetric breast tissue. In the fourth edition, the terms focal asymmetric density and asymmetric breast tissue are replaced with focal asymmetry and global asymmetry [9]. Therefore the mammographic finding previously known as developing density is more appropriately termed developing asymmetry, neoasymmetry, and enlarging asymmetry. We use the term developing asymmetry.
Despite the lack of a widely accepted definition of developing asymmetry, a workable definition may be readily established among the several radiologists who work in a given mammography practice. Having a definition facilitates single-institution studies on the clinical importance of developing asymmetry. However, because the frequency of breast cancer among cases of developing asymmetry has been estimated as being low [2], a large number of such cases must be studied to produce statistically meaningful results. Furthermore, because developing asymmetry itself is an uncommon finding, it has been difficult for investigators to collect a sufficient number of cases from a single institution.
Sonography often is useful for evaluation of mammographic findings [10]. It aids in the diagnosis of cysts, benign solid masses such as fibroadenoma, and cancer [11]. When developing asymmetry is identified on mammography, sonography targeted to the finding can be performed. Identification of a sonographic correlate then guides management. It is not known, however, whether lack of a sonographic correlate can be used to exclude malignancy and thus eliminate the need for biopsy of developing asymmetry [12]. Similarly, the role of MRI as an adjunctive imaging technique in the evaluation of developing asymmetry is undetermined. MRI is known to be sensitive for invasive carcinoma [13, 14], so perhaps the absence of an MRI correlate can be used to exclude malignancy and thus obviate biopsy of developing asymmetry.
The goal of this study was to use our large-scale clinical experience with mammography to determine the frequency, imaging outcome, and pathologic significance of developing asymmetry. We also investigated the roles of sonography and MRI in the evaluation of such imaging findings and whether demographic factors contribute to prediction of malignancy in cases of developing asymmetry.
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Mammographic interpretations were prospectively entered into a computer database for clinical use and for internal quality assurance [15]. In particular, at interpretation the principal abnormal mammographic finding, if any, for each mammographic examination was recorded by the radiologist. From 1985 to 1998, data were collected for screening mammographic examinations performed in a mobile van operated by our institution. In addition, beginning in 1996, data also were collected for both screening and diagnostic mammographic examinations performed at all fixed locations within our institution [16].
The subjects in this study were women who underwent screening or diagnostic mammography at our institution whose mammograms were interpreted as having the finding of developing asymmetry. We identified this study cohort by searching our database for all cases prospectively coded with the finding developing asymmetry. Until November 2003, we coded using the term developing density. After publication of the fourth edition of BI-RADS, we used developing asymmetry, because the BI-RADS terminology for asymmetry changed in the fourth edition [9]. We also extracted from the database the following demographic information: patient age, menopause status, and family and personal history of breast cancer. We examined radiology records to obtain information about the use of sonography and MRI as adjunctive diagnostic tools and pathology records to determine tissue diagnosis.
Samples for pathologic diagnosis were obtained through fine-needle aspiration biopsy, core biopsy, or surgical excision. Cancer was defined as invasive carcinoma or ductal carcinoma in situ (DCIS). Our database contained information on whether the biopsy result was benign or malignant along with the histologic findings for all malignant cases, whether or not biopsy was performed at our institution. For biopsies performed at our institution, we obtained information on the histologic features of benign diagnoses by retrospectively reviewing pathology records. Histologic data were not available for benign findings of biopsies performed at outside institutions.
For cases in which biopsy was not performed, we ascertained that the finding was benign through long-term (at least 2 years) mammographic follow-up. We also performed computer linkage between our database and our regional Surveillance, Epidemiology and End Results (SEER) tumor registry. Such linkage and use of the computer-based outcome tracking system at our institution (also used in this study) aided in identification of more than 95% of breast cancer cases in our catchment area [17]. Thus linkage was important for ensuring the absence of malignancy in our study, because some of the patients who did not undergo biopsy underwent limited mammographic follow-up.
All mammograms were screen-film. All mammography units, technologists, radiologists, and our several mammography facilities had been accredited by the American College of Radiology Mammography Accreditation Program since its inception in 1987 [18]. The characteristics of the interpreting radiologists have been previously reported [16].
Screening examinations involved craniocaudal and mediolateral oblique mammograms of each breast in women nominally free of symptoms. These examinations were performed with no radiologist on site and were batch-interpreted at a later time. All patients in whom developing asymmetry was identified on screening mammography were recalled for additional imaging assessment. Recall imaging included additional mammography (usually spot-compression magnification views) and occasionally sonography (if indicated after additional mammographic assessment was completed).
Cases of developing asymmetry also were identified initially on diagnostic mammography. Some of these examinations were performed for evaluation of breast problems, such as palpable abnormality, nipple discharge, or focal breast pain. Other diagnostic examinations were performed for short-term follow-up of a probably benign mammographic finding, for short-term follow-up after benign and concordant imaging-guided percutaneous breast biopsy, and for follow-up of patients with breast cancer treated with breast conservation within 5 years of surgery. On diagnostic mammography, craniocaudal and mediolateral oblique views were interpreted by an on-site radiologist, who obtained additional mammographic views, sonograms, and MR images as needed for complete evaluation.
All sonographic examinations were performed by a radiologist using a high-resolution linear array (7-12 MHz) transducer on one of two machines (Acuson 128 XP, Acuson, or Advanced Technology Laboratories 3500, Philips Medical Systems). The sonographic examinations were aimed at the area corresponding to the developing asymmetry, and transverse and longitudinal images were obtained.
MRI was performed with a high-resolution 3D gradient-recalled echo sequence with fat saturation on a 1.5-T magnet (Signa, GE Healthcare). Images were obtained in the sagittal plane with a three-time-point protocol previously described [19]. Gadopentetate dimeglumine (Magnevist, Schering) was administered at a dose of 0.1 mmol/kg of patient body weight.
All data were entered into and analyzed with an Excel spreadsheet
(Microsoft). Positive predictive value (PPV) was defined as described in
BI-RADS [9]. Specifically,
PPV1 was calculated by division of the number of cases of cancer by
the number of mammographic examinations with findings interpreted as abnormal.
PPV2 was calculated by division of the number of cases of cancer by
the number of mammographic examinations with findings that led to
recommendation for biopsy. Statistical analysis was performed with SAS version
9.2 (SAS Institute). Statistical significance was determined with Student's
t test and 95% CI. Statistical significance was considered p
0.05, and correlation was reported with relative risk (RR).
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Of the 292 cases of developing asymmetry identified on screening mammography, 11 were excluded from the study because the patient did not return for additional imaging (n = 4) and because the patient did not undergo the biopsy recommended after additional imaging (n = 7). Of the 32 cases of developing asymmetry identified on diagnostic mammography, two were excluded from the study because the patient did not undergo the biopsy recommended after additional imaging and because of lack of mammographic follow-up. Therefore, the final study cohort consisted of 281 screening mammography patients and 30 diagnostic mammography patients. The mean and median ages of the screening patients were 59 and 58 years, respectively (range, 30-90 years). The mean and median ages of the diagnostic patients were 57 and 56 years (range, 39-81 years).
The outcome in the 281 screening-detected cases of developing asymmetry are presented in Table 1. Diagnostic mammographic views were obtained in all 281 cases and revealed summation artifacts (Fig. 1A, 1B, 1C, 1D, 1E, 1F) rather than true lesions in 161 (57.3%) of the cases. In all but 11 (6.8%) of these 161 cases of summation artifacts, spot-compression magnification views alone (without sonography) were used to exclude the presence of a true lesion. Sonography showed cysts in another 24 (8.5%) of the 281 cases. Biopsy was recommended and performed in 84 (29.9%) of the 281 cases. The pathologic results are in Table 1. Thirty-six cases of cancer were identified, resulting in a PPV for abnormal screening interpretation (PPV1) of 12.8% and a PPV for biopsy recommendation (PPV2) of 42.9%.
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The outcome in the 30 cases of developing asymmetry identified on diagnostic mammography is presented in Table 2. Biopsy was recommended and performed in 26 (86.7%) of the cases; the pathologic results are provided in Table 2. Eight cancers were identified, resulting in a PPV1 (abnormal diagnostic interpretation) of 26.7% and a PPV2 of 30.8%. Four (13.3%) of the 30 patients who underwent diagnostic mammography did not undergo biopsy. In one of these four cases, the recommendation for biopsy was based on mammographic findings alone (without sonography) and on the fact that the lesion was palpable. Biopsy was not performed, but there was no evidence of cancer after 4.5 years of mammographic follow-up. In the second case in which sonography was not performed, mastitis was suspected, and there was no evidence of cancer after 3 years of follow-up. Sonography was performed in two cases, revealing a benign simple cyst in one case and a vague hypoechoic focus in the second. The latter case was further evaluated with MRI.
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MRI was performed in two of the 30 diagnostic cases. In one of these cases, sonography showed a vague hypoechoic focus, no MRI correlate was found, and the patient underwent follow-up for 1.5 years without evidence of breast cancer. In the second case, sonography showed a vague hypoechoic focus, MRI showed regional enhancement with plateau kinetics, and biopsy showed PASH (Fig. 2A, 2B, 2C, 2D).
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Among the 22 cases of diagnostic mammography of benign lesions, nine (40.9%) of the lesions were palpable, and 13 (59.1%) were nonpalpable. Three (37.5%) of the eight malignant lesions were palpable, and five (62.5%) were nonpalpable. Therefore, palpability did not correlate with malignancy (RR, 1.5; 95% CI, 0.4-5.0).
Age did appear to correlate with malignancy. Among the cohort of 44 patients with cancer, the mean and median ages were 69 (SD, 11.3) and 70 years (range, 42-90 years). In contrast, the mean and median ages of patients with benign diagnoses were 58 (SD, 12.0) and 57 years (range, 30-80 years). This difference was statistically significant (p < 0.0001).
We also examined whether menopause status, family history of breast cancer, and personal history of breast cancer correlated with the presence of malignancy. The results are presented in Table 3. There was no correlation between family history and malignancy in the developing asymmetry (RR, 0.7; 95% CI, 0.3-1.4). Being postmenopausal was associated with increased risk of cancer in the developing asymmetry (RR, 3.3; 95% CI, 1.3-8.0), as was having a personal history of breast cancer (RR, 3.4; 95% CI, 1.9-6.3). We found no correlation between year of detection and frequency of developing asymmetry on either screening or diagnostic mammography.
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One of the reasons for the dearth of information about developing asymmetry is that the sign occurs very infrequently. Kopans et al. [20] reported that asymmetric breast tissue occurs in 221 (2.7%) of 8,048 mammograms, and Sickles [21] reported that focal asymmetry is found in 448 (1.3%) of 34,282 mammograms. Developing asymmetry differs from asymmetric breast tissue and focal asymmetry in that interval change is present in developing asymmetry, and to our knowledge there are no published data on the frequency of developing asymmetry. One [22] of the two published reports of developing asymmetry was limited to patients who had undergone biopsy. The second [5] did not give a denominator for calculation of frequency. In contrast, in our study of consecutive screening and diagnostic mammograms, the finding of developing asymmetry on screening and diagnostic mammography was rare (0.16% and 0.11%, respectively).
For developing asymmetry, the PPV1 on diagnostic mammography is higher than the PPV1 at screening. This phenomenon is not unique for developing asymmetry; it applies to all abnormal mammographic findings [23]. Many definitely benign findings (e.g., summation artifacts) are considered abnormal on screening mammography, thereby diminishing the PPV1 calculation by contributing only to the denominator, whereas on diagnostic mammography these findings are not included in the denominator because they are not considered abnormal after full diagnostic imaging evaluation.
The finding of developing asymmetry on mammography should be evaluated with additional imaging to identify possible cancer. The initial evaluation usually involves diagnostic mammographic views, including 90° lateral, shallow oblique, and rolled views and spot-compression (with or without magnification) views [12]. These views are important in differentiating true findings from summation artifacts. At our institution, and for this study, spot-compression magnification mammographic views, usually in shallow oblique projection, were the diagnostic mammographic views of choice [24] (Figs. 1E, 2C, and 3C). Spot-compression magnification views alone were used to identify nearly all cases of summation artifact characterized as developing asymmetry on screening mammography. On subsequent mammographic follow-up, analysis with our institutional computer-based outcome tracking system, and computer linkage with the SEER tumor registry of these cases, no cancer was identified. Therefore, spot-compression magnification mammography was reliable for excluding cancer in the case of screen-detected developing asymmetry (representing summation artifact) without additional sonography or biopsy. This finding is clinically important because a sizable percentage of cases of developing asymmetry on screening mammography are found to represent summation artifacts on diagnostic imaging.
Sonography is an invaluable adjunctive tool in breast imaging. In cases of developing asymmetry proved to represent true findings, sonography is helpful when a correlate (either definitely benign or suspicious for malignancy) is identified [12]. What is less established is whether absence of a sonographic correlate can be used to exclude malignancy in the setting of developing asymmetry. In a study of 16 cases of focal asymmetry and 20 of developing asymmetry, Shetty and Watson [22] found that two (28.6%) of seven malignant lesions had no sonographic correlate. One of these two tumors was nonpalpable developing asymmetry with interval enlargement from the previous study. The second tumor was palpable focal asymmetry identified on baseline mammography.
In this study, five (23.8%) of 21 malignant tumors had no sonographic correlate. In other words, the absence of a sonographic correlate does not exclude malignancy in the setting of developing asymmetry. All five malignant tumors were nonpalpable and detected at screening. This 23.8% frequency is sufficiently high to justify biopsy despite the absence of a sonographic correlate for developing asymmetry. The frequency clearly is far too high to support alternative management with imaging surveillance because the likelihood of malignancy for probably benign (BI-RADS 3) lesions should be less than 2% [9, 21, 25]. On the basis of our findings and the recommendations of others [12, 22], we advocate biopsy in true cases of developing asymmetry, even if there is no correlate on sonography.
MRI is known to be highly sensitive in the detection of malignancy [13, 14], but there is no established role for MRI in the evaluation of breast asymmetry [12]. Lee et al. [13] examined the use of MRI in the evaluation of 86 "problematic mammograms," and in 45% of the cases the finding was asymmetry seen in only one mammographic projection. No malignant tumor was seen in the 60 cases for which there was no MRI correlate. Developing asymmetry differs from one-view-only asymmetry in that developing asymmetry is seen in at least two projections and has undergone interval change. We attempted to determine the utility of MRI in assessment of developing asymmetry but drew no conclusion because MRI was performed in only two (0.64%) of 311 cases. In one of these two cases, PASH was seen as an area of regional enhancement (Fig. 2D).
Cancer manifesting as developing asymmetry can be of any histologic type, including DCIS (Tables 1 and 2). Although the most common screening mammographic sign of DCIS is calcification, DCIS also can manifest as a noncalcified lesion. This finding typically would be a primarily circumscribed mass, but it also can be developing asymmetry. In a study of 190 cases of DCIS, Ikeda and Andersson [26] found that developing asymmetry was the mammographic finding in four (2.1%) of the cases. In our study of developing asymmetry, three (6.8%) of the 44 cases of cancer were DCIS (Tables 1 and 2). Although DCIS infrequently appears as developing asymmetry, it is nevertheless important to recognize that DCIS can manifest in this way, particularly because DCIS is regarded as an almost always curable disease.
Invasive lobular carcinoma is known to manifest as subtle findings, including asymmetry, on mammography more frequently than does invasive ductal carcinoma [27, 28]. Most cases of breast cancer are of the ductal histologic type; lobular carcinoma accounts for approximately 10% of cases of cancer [29]. It is thought that invasive lobular carcinoma results in subtle mammographic findings because the cancer cells grow into adjacent tissues in a single-file pattern rather than by forming a cohesive mass of tumor cells [27]. In a study of one-view-only mammographic findings (e.g., asymmetry), Sickles [28] found that 33% of the cases of cancer found were invasive lobular carcinoma. This frequency is much higher than the reported 10% frequency of lobular carcinoma. In our series of cases of developing asymmetry, 15.9% of the cases of cancer were invasive lobular carcinoma (Tables 1 and 2), a frequency also somewhat higher than 10%. Therefore one should consider the possibility of invasive lobular carcinoma if developing asymmetry is found, just as one would for one-view-only asymmetry.
Palpability has been known to increase the probability of malignancy in breast asymmetry [12, 20]. In our study of developing asymmetry, palpability did not correlate with malignancy. In other words, being nonpalpable did not negate or decrease the chance of malignancy. Therefore all cases of developing asymmetry, not only palpable lesions, necessitate biopsy. Similarly, the absence of a family history of breast cancer should not be used to obviate biopsy in the presence of developing asymmetry. Finally, even though statistically significant correlations were found when the determination of whether a case of developing asymmetry was malignant was compared with menopause status or personal history of breast cancer, a substantial number of cases of cancer would still be missed if biopsy was not always performed. Therefore we also recommend that biopsy be performed whenever developing asymmetry is found, regardless of menopause status or personal history of breast cancer.
Patient age correlated with the presence of malignancy associated with developing asymmetry in a statistically significant manner. Developing asymmetry in older women was more likely to be malignant than developing asymmetry in younger women. These results are consistent with the widely reported general observation that the incidence of breast cancer increases with advancing age [30].
If developing asymmetry is identified on screening mammography, it is important to recall the patient for diagnostic imaging before recommending biopsy. In this series, 57.3% of screening-detected cases of asymmetry were found to be summation artifacts on diagnostic imaging, and 8.5% were found to be benign cysts (Table 1). These lesions do not necessitate biopsy or even short-interval follow-up imaging.
PASH is a benign proliferative stromal lesion made up of myofibroblasts. The condition usually is found in premenopausal women or postmenopausal women taking hormone replacement therapy [5, 31]. Although the typical mammographic appearance of PASH is a circumscribed or partially circumscribed noncalcified mass [32, 33], the lesion can also appear as developing asymmetry [5]. In a study of 21 cases of nonpalpable developing asymmetry, Piccoli et al. [5] found no cases of cancer, and PASH was identified in all 13 cases retrospectively reviewed by a pathologist. PASH was prospectively identified as a specific diagnosis in only two (15.4%) of these 13 cases. PASH was not described in any of the 20 cases of developing asymmetry or 16 cases of focal asymmetry reported by Shetty and Watson [22]. This finding probably occurred because PASH is not always recognized as a specific entity at pathologic examination and because not all pathologists are making this diagnosis.
We found PASH prospectively in seven (13.5%) of 52 biopsies with benign results (Tables 1 and 2) and agree with Piccoli et al. [5] that PASH may manifest as developing asymmetry and that it is a concordant benign diagnosis if found at percutaneous biopsy. Our findings about PASH differ from those of Piccoli et al. in that two (28.6%) of our seven patients with a PASH diagnosis were postmenopausal (one was taking hormone replacement therapy and the other was not), whereas all 21 patients in the study by Piccoli et al. were premenopausal. PASH in postmenopausal women not taking hormone replacement therapy also has been reported [34].
There were several limitations to our study. First, the data on sonography use and on the histologic features of the benign lesions were incomplete. A similar limitation was the lack of data on hormone replacement therapy because we did not have sufficient information on this subject to report or to draw conclusions. This study of consecutively registered subjects spanned more than 20 years, so we did not analyze data that were not prospectively collected or recorded. It was necessary to collect data over a long time period to have a sufficient number of cases for statistical power, given the infrequent occurrence of developing asymmetry. Another limitation was that we did not have at least 2 years of follow-up data for all cases in which imaging findings were interpreted as negative (i.e., summation artifact) or benign and biopsy was not performed. To remedy this limitation, we linked our cohort to the SEER tumor registry and found no missed cases of cancer among the cases in which findings were interpreted as negative or benign. Last, MRI was performed in only two cases, so no meaningful conclusion can be drawn about the role of MRI in the evaluation of developing asymmetry.
We set out to investigate the incidence and significance of developing asymmetry on mammography in a large-scale study because this sign is an infrequent but known indicator of malignancy. We conclude that all patients with developing asymmetry detected at screening need recall and that all findings that still represent developing asymmetry after full diagnostic imaging evaluation necessitate biopsy. Negative findings on sonographic examination do not preclude malignancy. Future studies should be performed to examine the role of MRI in excluding malignancy and obviating biopsy in the setting of developing asymmetry.
Acknowledgments
We thank Philip W. Chu for his immense contribution to statistical analysis
and Yelena Borodina for her invaluable assistance in manuscript
preparation.
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