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1 All authors: Instituto de Radiología y Centro de Lucha Contra el Cáncer, Pereira Rossell Hospital, B. Artigas 1550, 11600 Montevideo, Uruguay.
Received January 18, 2002;
accepted after revision March 13, 2002.
F. Leborgne, J. Mezzera, and S. Jaumandreu are supported by fellowships
from the Comisión Honoraria de Lucha Contra el Cáncer.
Abstract
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MATERIALS AND METHODS. During 1996, mammography was performed in 18,435 women of whom 544 (3.0%) had lesions assigned to Breast Imaging Reporting and Data System (BI-RADS) category 3 for nonpalpable, probably benign lesions. The lesions in the women were assessed as BI-RADS category 3 after the patients had undergone a diagnostic study that included additional imaging, sonography, and a focused physical examination. Patients with BI-RADS category 3 lesions were recommended for mammographic surveillance. A minimum of 2 years of follow-up data was available for 511 patients, our study population. We compared the findings for our study population with those of the previous study.
RESULTS. Ninety-seven percent of the follow-up mammograms showed stability or regression of the BI-RADS category 3 lesions. Fourteen patients (3%) had nonpalpable interval progression revealed on mammography and underwent biopsy. The breast cancer detection rate in category 3 lesions among the study population was 0.4% (2/511), which was 14% of the patients who had undergone biopsies because of interval progression of the lesions. The pathologic stage of the cancers in these two patients was T1b N0.
CONCLUSION. Compared with the findings from the 1987-1989 study, the frequency of BI-RADS category 3 lesions has remained stable; patient compliance for follow-up has increased; and the positive predictive value of category 3 lesions for cancer has decreased from 1.7% to 0.4% (p = 0.04).
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Since the first studies on nonpalpable, probably benign lesions were performed, several technical procedures and methodologies have been adopted in our institution, such as the implementation of stringent quality assurance requirements, BI-RADS assessment categorization, magnification images [2], on-site high-resolution real-time sonography with color Doppler capability, on-site fine needle aspiration cytology under sonographic guidance, and imaging-guided percutaneous core biopsy procedures. More recent advances such as full-field digital mammography and computer-aided diagnosis software are not currently available in our center.
Our study was undertaken to evaluate the impact in the late 1990s of technologic advances, stricter quality assurance requirements, and more experience in mammographic follow-up of BI-RADS category 3 lesions in comparison with the experience at our institution one decade earlier, especially in regard to the frequency and stage of cancers found in the surveyed population and to patient compliance.
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Mammography was performed with two units (Senograph 600T, General Electric Medical Systems, Columbia, MD; Alpha RT, Instrumentarium, Tuusula, Finland). Screen films and dedicated processors were used, and the appropriate quality assurance requirements were met. The estimated radiation dose to the average mid breast for a single mammographic view was 1.06 mGy. All women had a standard two-view bilateral study; two of the authors separately interpreted each of the mammograms (double interpretation for each study). Previous mammograms were available for review. All patients with nonpalpable, probably benign lesions underwent a diagnostic study that included magnification and spot compression views, as appropriate. MR imaging was not indicated for these lesions. Patients who reported abnormal breast masses or who had abnormal mammographic findings were also offered a diagnostic study.
After reviewing the mammograms, trained radiologists performed a physical examination of the breasts for all patients reporting a palpable abnormality in the breast and for women with abnormal findings on mammography. In our practice, a lesion is defined as nonpalpable when the findings of a focused physical examination of the area of interest performed by radiologists are negative; negative results due to insufficient clinical examination or failure by the patient to disclose a palpable abnormality were therefore excluded. This retrospective physical examination performed after reviewing the mammograms and clinical data ensures a truly clinically occult situation.
Focused sonography with 7-13—MHz linear array transducers (Dynaview II, SSD-1700; Aloka, Tokyo, Japan) was performed by a radiologist immediately after the physical examination of the breast. State-of-the-art sonography was useful in distinguishing solid from cystic small lesions and, in some instances, in characterizing solid nodules. Cysts detected on sonography were not considered nonpalpable, probably benign lesions. Because of the volume-averaging effects in small cysts or high signal content of some simple cysts, a few of these BI-RADS category 2 lesions were included in category 3. Sonographically guided fine-needle aspiration cytology, if indicated, was performed by the radiologist in the presence of the cytopathologist who assessed the adequacy of the aspirate before the patient was dismissed.
Five hundred forty-four studies (3.0%) were prospectively assigned to BI-RADS category 3. Descriptions of mammographic features for lesions in this category have been previously reported [3]. Sharply marginated masses with rounded or gently lobulated margins; multiple, rounded, clustered, or scattered microcalcifications in an area of breast parenchyma measuring a quadrant or less; and an area of localized dense breast tissue having neither definable margins nor architectural distortion visible in two projections and persisting after spot compression mammography were all considered BI-RADS category 3 lesions. Clustered amorphous microcalcifications and all palpable lesions were excluded from category 3 classification.
Patients with mammograms revealing category 3 lesions were interviewed by a radiologist and offered entry into a mammographic surveillance protocol, which consisted of a 6-month unilateral follow-up mammogram. A written report was sent to the referring physician. If at the 6-month follow-up, the lesion had not progressed and no abnormal physical findings had been detected, the patient resumed annual bilateral mammography after 6 months had elapsed. Interval progression of a lesion or a palpable abnormality prompted tissue diagnosis. Microcalcifications were followed for 4 years and noncalcified masses, for 2 years. In 466 (82%) of 544 patients, the abnormality was seen in both projections. Patients ranged in age from 29 to 90 years (median age, 53 years). The reference standard or definite diagnosis of category 3 lesions was made on the basis of stability or regression of the lesion on follow-up mammography or as the result of biopsy performed on lesions that showed mammographic interval progression or lesions in which tissue diagnosis had been performed because of the patient's or the attending physician's preference. The reference standard was based on the results of a minimum 2-year follow-up period (patients with microcalcifications had follow-up for 4 years). Patients with category 3 lesions that had regressed or disappeared before the specified follow-up period ended were not required to fulfill the entire time requirement because the lesions were considered benign.
Excluded from analysis were 30 patients who were lost to follow-up and three patients who died of causes not related to breast cancer before the minimum 2-year follow-up period had elapsed. The remaining 511 patients (93%) constitute our study population. The mean follow-up period for the 89% (454/511) of the patients who returned for follow-up mammography was 36 months. Fourteen patients refused the surveillance protocol and opted for tissue diagnosis. The remaining 43 patients who failed to complete their 2- or 4-year follow-up were interviewed over the telephone. Additional information was sought from the referring physicians, and oral information on mammographic examinations at other institutions was obtained, if warranted. The patients were also checked for entry in the National Cancer Registry for breast neoplasms for 5 years after inclusion in our study. If these actions did not reveal evidence of breast cancer, these patients were considered to have fulfilled their reference standard and were included in our study population.
The mammographic features of BI-RADS category 3 lesions are listed in Table 1. The size range of masses, clustered microcalcifications, and areas of abnormal parenchymal opacity was between 3 and 35 mm (mean size, 10 mm).
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Data were prospectively entered into a database using a statistical software package (SPSS, Chicago, IL). Univariate analysis was carried out by selecting corresponding, paired batches of data. The pairs were compared using the chi-square test with one degree of freedom and the Fisher's exact test (two-tailed) when appropriate. A finding in which p was greater than 0.05 was considered significant.
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Overall, 31 biopsy procedures were performed, all but one on nonpalpable lesions. Fourteen of the biopsies were performed because of interval progression after a mean follow-up period of 24 months (range, 6-41 months): nine by open surgery after needle localization, four by sonographically guided fine-needle aspiration cytology, and one by stereotactic percutaneous core biopsy. An additional 14 biopsies were performed because of physician or patient preference: nine by open surgery after needle localization and five by sonographically guided fine-needle aspiration cytology. Finally, three open biopsies were performed on de novo interval-detected BI-RADS category 4 or 5 lesions that were independent from the initial category 3 lesion under observation.
Table 2 lists the frequency and stage [4] of cancers found according to the reason for performance of the biopsy. Two patients with mammographic interval progression were found to have cancer after a follow-up of 11 and 17 months; both patients were alive with no evidence of recurrence at 30 and 36 months after treatment. Cancer was found in two (0.4%) of 511 patients in follow-up and in two (14%) of 14 patients who showed interval progression. Mammographic progression was a statistically significant feature for development of cancer (p = 0.0009). Findings of all 14 biopsies performed because of physician or patient preference were negative for cancer. Cancer was confirmed in all three of the de novo category 4 and 5 lesions unrelated to the previous category 3 lesion under surveillance. Two lesions were nonpalpable and one presented as a palpable mass in a patient who had discontinued her annual screening.
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Patient compliance was estimated as the percentage of patients with mammographic follow-up relative to the 544 women who had a BI-RADS category 3 lesion diagnosed in this period, not the 511 women comprising our study population as described above. Compliance with the surveillance protocol was 83%, up from 76% in the previous study (p = 0.003) [3].
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Ideally, an early breast cancer detection facility actively pursuing mammographic follow-up of patients with nonpalpable, probably benign lesions should strive to achieve the following diagnostic levels: A less than 2% incidence of false-negative results or missed cancers in BI-RADS category 3 lesions (otherwise, a large percentage of probably malignant lesions are being included in category 3); a more than 50% incidence of true-positive results for malignancy in percutaneous and needle localization biopsy procedures for BI-RADS categories 4 and 5 lesions (otherwise, a large percentage of benign lesions are being subjected to biopsy); and a less than 5% incidence of BI-RADS category 3 lesions (otherwise, a large percentage of characteristically benign lesions are being included in BI-RADS category 3). Experts do not agree on the latter two percentages, and currently, no established guidelines exist. Ideally, duplication of imaging-guided percutaneous biopsies and needle localization biopsies for BI-RADS category 5 lesions should also be avoided, except in cases in which the surgeons or patients prefer to have a percutaneous tissue diagnosis before any needle localization open biopsy procedure is performed [7].
In a given study population, an inverse relationship exists between the percentage of patients with lesions assigned to BI-RADS category 3 and the cancer yield in this category. Because the number of prevalent cancers in this population is fixed, generously increasing the denominator—that is, the nonpalpable, probably benign lesion population—will consequently decrease the cancer yield.
Table 3 shows the frequency and positive predictive value for cancer in women from this study and from the previous study [3]. In both studies, the same definition for category 3 lesions was used. Technologic advances in the imaging of breast lesions, better quality assurance requirements, and more experience have decreased the false-negative results (missed cancers or positive predictive value for cancer) in follow-up mammograms. from 1.7% to 0.4% (p = 0.04), without simultaneously increasing the requirement for follow-up mammography in patients with nonpalpable, probably benign lesions. It is possible that, as observed by D'Orsi [8], we are using a similar receiving operating characteristic curve and similar decision criteria for including patients in these protocols. It appears that improved breast imaging has resulted in lowering our positive predictive value for cancer.
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Interval growth should be measured and documented. As stressed by Erasmus et al. [9], the perception of growth depends on the initial size of the lesion. Because the eye perceives the arithmetic increase in the lesion diameter instead of in the lesion volume, smaller nodules appear to grow at a slower rate than larger ones, even if both types are doubling in volume at the same rate. A 5-mm nodule with a doubling time of 6 months will only increase its diameter by 1.25 mm. This issue is further confounded by the fact that small changes in mammographic views of the follow-up study may project different diameters of an otherwise stable, oval or lobulated circumscribed nodule. In addition, as stated by Lane et al. [10], the perception of enhanced border lesions varies greatly among observers because of the Mach band effect.
Previous studies have shown that when examined through tissue diagnosis, missed cancers in BI-RADS category 3 lesions have a similar size and nodal extension to those found in lesions in BI-RADS categories 4 and 5. It appears that a short delay in diagnosis of these false-negative lesions would have a negligible impact in prognosis [11, 12]. The proposal to eliminate the first 6-month repeated mammogram is based on the fact that most false-negative category 3 lesions surface in an average time of 1 year [13]. Sickles [14] and Rubin [15] have previously discussed the favorable (Sickles) and unfavorable (Rubin) aspects of short-term follow-up for the first screening interval after diagnosis of a category 3 lesion. Our study was designed before the indication for a 6-month follow-up was questioned. Admittedly, patients with clustered microcalcifications may well benefit from obviating the 6-month mammogram. However, we emphasize that a delay of 1 year in diagnosing the few fast-growing cancers missed in this population may have deleterious effects on survival.
Therefore, the policy at our institution has been to recommend a 6-month follow-up mammogram for women first diagnosed with a probably benign lesion and at yearly intervals thereafter. At the present level of reimbursement for a two-view unilateral mammogram at 6-month follow-up, this additional procedure would add a minute amount to the cost of screening compared with any future invasive procedure that may have to be performed. As reported by Lindfors et al. [16], the anxiety of patients after discovery of a category 3 lesion was lower than that of patients who underwent a core biopsy.
Naturally, eliminating the false-negative results (missed cancers) in follow-up mammograms is desirable, although one wonders if false-negative results can be eradicated altogether, given the overlapping mammographic features of some benign lesions and minimal breast cancer. The advantages of reducing the false-negative rates for malignancy are obvious, mainly the increased accuracy of mammographic diagnosis, reduced costs and patient anxiety, and a decreased threat of litigation in a medicolegally sensitive environment.
The important contribution of sonography in characterizing solid nodules, as well as in differentiating solid from cystic lesions, has been reported by several investigators [17]. Targeted sonography was also used successfully by Zonderland et al. [18] in The Netherlands, which significantly increased the sensitivity of mammography for cancer detection. Rubin et al. [13] have presented evidence of an impressive increase (from 21% to 68%) in the cancer yield for needle localization biopsies of nonpalpable lesions over the years with the selective use of sonographically guided fine needle aspiration cytology and other imaging-guided procedures. No randomized trials have been designed to test the effectiveness of sonography in nonpalpable, probably benign lesions, but apparently, in many facilities, its use as a targeted adjunct to mammography is established.
As a corollary to the results of this study, needle localization procedures for nonpalpable BI-RADS categories 4 and 5 lesions should reveal an increase in cancer yield [13, 19]. In 1996 at our center, 75 needle localization procedures were performed for BI-RADS categories 4 and 5 lesions in 18,435 (0.4%) patients. This incidence is similar to that reported by Rubin et al. [13]. The median size for these nonpalpable lesions in our study was 10 mm (range, 3-90 mm). Malignancy was proven in 60% (45/75) of lesions subjected to biopsy, up from 48% reported in the previous study [3]. Of these malignancies, 24% were ductal carcinoma in situ. Only 12% of the invasive carcinomas had invaded the axillary nodes. A low percentage of axillary nodes with positive findings for malignancy is one of the parameters by which a screening program should be judged [20]. Of 29 biopsies with negative findings, six proved to be radial scars and one, atypical hyperplasia.
Imaging-guided percutaneous biopsy for palpable and nonpalpable lesions in BI-RADS categories 4 and 5 is an evolving technology that has been gradually incorporated into mammography practice worldwide. Clearly, the situation in 1996 does not represent what we do or recommend in 2002. Imaging-guided percutaneous biopsy has been progressively implemented into our practice throughout the years. However, our aim is not to add core biopsy procedures to needle localization biopsies for category 5 lesions, which carry more than a 90% positive predictive value for carcinoma. Even if percutaneous procedures, including vacuum-assisted excisions, are increasingly now used, the issue of increasing costs should be kept in mind. BI-RADS category 4 microcalcifications are commonly subjected to core biopsy in our practice. Fine needle aspiration cytology has, in our hands, proved to be an accurate and cost-effective procedure for preoperative diagnosis of palpable and non-palpable category 4 lesions. Sonographically guided cytology performed with a cyto-pathologist present is our current preferred method for diagnosing nonpalpable masses. In 1996, 69 percutaneous procedures were performed on nonpalpable breast lesions, mostly BI-RADS category 4 (17 core biopsies and 52 fine-needle aspirations). Cancer was found in six lesions (9%), with a 100% sensitivity and a 95% specificity.
As shown by our study, a de novo lesion (appearing on follow-up mammograms and unrelated to the nonpalpable, probably benign lesion under surveillance) should be considered a high-risk situation. A review of the patient's previous mammograms and a tissue diagnosis should be recommended.
The limitations of our study are that 30 patients were excluded from analysis because of insufficient follow-up and that 43 additional patients lacked complete follow-up mammograms. To exclude the possibility of malignancy in this latter group, efforts included conducting telephone interviews with patients, gathering oral information concerning mammograms obtained at other institutions, and checking for entry in the National Cancer Registry for 5 years after entering our study.
In conclusion, our study has shown that, compared with the study performed in 1987-1989, the frequency of follow-up mammography for nonpalpable, probably benign lesions has remained stable, patient compliance for follow-up has increased, and the positive predictive value for cancer has decreased from 1.7% to 0.4% (p = 0.04).
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