High Detection Rate of Breast Ductal Carcinoma In Situ Calcifications on Mammographically Directed High-Resolution Sonography

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1 Article High Detection Rate of Breast Ductal Carcinoma In Situ Calcifications on Mammographically Directed High-Resolution Sonography Beverly E. Hashimoto, MD, Dawna J. Kramer, MD, Vincent J. Picozzi, MD Objective. To assess the high-frequency sonographic characteristics of ductal carcinoma in situ of the breast. Methods. In a retrospective review, we identified 18 patients with biopsy-proven pure ductal carcinoma in situ who had received mammographic and high-frequency sonographic examinations at transducer frequencies of 10 to 13 MHz. Results. All 18 patients had mammographically identified calcifications. Four (22%) of the 18 had either asymmetric focal mammographically identified densities or masses with the calcifications. These calcifications were identified sonographically in 17 (94%) of the 18 patients. In 9 (50%) of 18 patients, the calcifications were associated with sonographically detected malignant masses, and in 3 (17%) of 18 patients the calcifications were within focally dilated ducts. Lesions that had masses or dilated ducts visible on sonography represented 9 (82%) of 11 of the grade 3 neoplasms and only 2 (28%) of 7 of the grade 1 and 2 tumors. This difference was statistically significant (P <.039). Conclusions. Our study showed that ductal carcinoma in situ may appear on sonography as calcifications, masses, or focally dilated ducts. Those lesions that were associated with masses or dilated ducts on sonography were more likely high-grade histologic specimens. Key words: breast neoplasms; breast neoplasms, ultrasonography; breast neoplasms, calcification; breast neoplasms, diagnosis. Abbreviations DCIS, ductal carcinoma in situ Received June 1, 2000, from the Departments of Radiology (B.E.H., D.J.K.) and Medicine (V.J.P.), Virginia Mason Medical Center, Seattle, Washington. Revision requested August 2, Revised manuscript accepted for publication January 2, Address correspondence and reprint requests to Beverly E Hashimoto, MD, Department of Radiology, C5-XR, Virginia Mason Medical Center, 1100 Ninth Ave, Seattle, WA Sonography generally has not been considered a diagnostic modality for ductal carcinoma in situ (DCIS), because it is less sensitive for the identification of calcifications. 1 3 However, newer sonographic equipment offers higher-frequency transducers, which have allowed breast imagers to identify the structural anatomy of the breast in much greater detail than in the past. An in vitro study reported that researchers using high-frequency sonographic equipment were able to identify neoplastic microcalcifications within biopsy or mastectomy specimens with sensitivity of 95% and specificity of 88% when using mammography as the standard of reference. 4 We retrospectively reviewed cases of histologically pure DCIS to identify the sonographic characteristics of this neoplasm and to correlate these findings with mammographic and histologic features by the American Institute of Ultrasound in Medicine J Ultrasound Med 20: , /01/$3.50

2 Sonographic Detection of Breast Ductal Carcinoma In Situ Calcifications Materials and Methods From our institutional tumor registry and pathology department database, we identified all cases of DCIS recorded in our institution from January 1997 to December Pathologic and radiologic reports were reviewed to include only those cases in which the pathologic specimen showed pure DCIS and in which the patients had received both mammographic and sonographic examinations for the neoplasm. Patients were excluded if pathologic (lumpectomy or mastectomy) specimens contained any invasive carcinoma (including microinvasion) in addition to DCIS. Seventeen of the 18 patients had pathologic reports from lumpectomy or mastectomy specimens. One elderly patient refused surgery, so her inclusion is based on a percutaneous core biopsy. Fifteen of the sonographic examinations were done as part of an experimental sonographic protocol in which high-frequency sonography was performed before all stereotaxic core biopsies. This protocol was reviewed and approved by our Institutional Review Board, and all patients who were in this experimental protocol were informed about the protocol and signed consent forms before the sonographic examinations. We used commercially available ultrasonography equipment (Sequoia; Acuson Corporation, Mountain View, CA). All patients were studied with a high-frequency linear transducer (8 15 MHz). In 15 of 18 patients, the DCIS lesions were sonographically examined and documented with a lower-frequency transducer (8 5 MHz) at a center frequency of 7.5 MHz as well as the optimized higher frequency. The available sonographic center frequency range for these 15 examinations was 5 to 13 MHz. Sonographic examinations were performed by using a highcontrast gray scale technique including a low dynamic range (55% of the equipment s maximum level), a high-contrast delta setting, and a medium-contrast postprocessing program. The mammograms were performed on commercially available dedicated mammography units (M300 and M3000; Siemens Medical Systems, Inc, Iselin, NJ) with dedicated cassettes and screens (Min R-2000; Eastman Kodak Company, Rochester, NY). Screening mediolateral oblique and craniocaudal views were performed with a 0.3-mm focal spot, and magnification views were performed with a 0.1-mm focal spot. Cases were analyzed for pathologic classification, mammographic findings, and sonographic features. The pathologic classification was determined by the pathologic report of the largest final breast specimen containing the neoplasm. The pathologic classification is based on the prognostic index described by Silverstein and coworkers. 5 The system is a combination of the nuclear grade and the presence or absence of comedo-type necrosis. Grade 1 consists of tumors without a high nuclear grade and without necrosis. Grade 2 comprises neoplasms without a high nuclear grade but with necrosis. Grade 3 consists of high-nuclear-grade lesions with or without necrosis. 5 The mammograms were reviewed by a single radiologist who was aware of the final diagnosis but not aware of the pathologic size or histologic grade of the DCIS. The mammographic findings were classified according to the American College of Radiology Breast Imaging, Reporting, and Data System categories. 6 The sonograms were reviewed by another radiologist who was aware of the final diagnosis but not aware of the pathologic size or histologic grade of the DCIS. This radiologist was also responsible for determining that the sonographic findings corresponded to the mammographically identified abnormality. The sonographic findings were classified according to sonographic categories described by Stavros and coworkers. 7 Sonographically, calcifications appeared as hyperechoic foci; therefore, breast parenchymal lines or artifactual speckle would simulate calcifications in 1 view. Because the presence of calcifications was impossible to identify on still images, sonographic identification of calcifications was determined by the report of the radiologist who originally performed the real-time examination. The real-time method used to differentiate calcifications from artifactual speckle or parenchymal lines was based on real-time evaluation of the hyperechoic foci from many transducer positions. Calcifications were hyperechoic foci that had reproducible positions and configurations in multiple planes and transducer positions. Parenchymal lines were linear when the transducer was rotated. Speckle was not reproducible in position and configuration when imaged in multiple planes and transducer positions. Because identification of calcifications was a sonographic challenge, multiple frequencies 502 J Ultrasound Med 20: , 2001

3 Hashimoto et al were always used to image them. The protocol for imaging calcifications used in this group of patients was as follows. We initially examined the breast with the highest frequency that would penetrate the entire thickness of the breast. Once the calcifications were identified, the optimal frequency (see Results ) for imaging the calcifications was defined as the frequency at which the calcifications were identified as the smallest individual hyperechoic dots. The frequency was too low if the calcifications could not be identified, if the calcifications were identified as a hazy area of hyperechogenicity, or if multiple tiny calcifications were combined into larger, poorly defined hyperechoic densities. The frequency was too high if the calcifications were farther from the transducer than the frequency was able to penetrate. Although we always followed this protocol, we documented the appearance of the calcifications over a range of frequencies ( MHz) in 15 of 18 patients. In 3 patients, we only documented the calcifications when using the optimum frequency. Statistical comparison of sonographic features of grade 3 versus non-grade 3 breast neoplasms was performed by using the Fisher exact test applied to a 2 2 table. Comparison of the mean difference between the DCIS tumor size measured sonographically and the size measured mammographically was performed by using the Wilcoxon signed rank test for a nonnormally distributed sample population. 8 Results Eighteen women had 18 malignancies that met the above criteria. Fourteen (78%) of the 18 patients had only mammographically detected calcifications. Four (22%) of 18 had calcifications associated with mammographically detected focal asymmetric densities or masses. In 1 of these 4 patients, the DCIS was a palpable mass. The characteristics of the calcifications are listed in Table 1. The sonographic examinations were targeted to the mammographically detected abnormalities. Calcifications were sonographically identified in 17 (94%) of 18 neoplasms. In 1 case, we could not identify any sonographic findings of DCIS. Sonographically, the calcifications appeared as highly echogenic punctate foci, which generally did not have shadows. The configuration of each individual calcification Table 1. Mammographic Characteristics of DCIS Calcifications Appearance Fine linear/branching 7 Amorphous/indistinct 3 Pleomorphic/heterogeneous 5 Punctate 1 Combination linear and amorphous 1 Combination pleomorphic and amorphous 1 Total 18 Distribution Clustered/grouped 13 Linear 2 Segmental 2 Regional 1 Total 18 could not be determined. Occasionally, calcifications would have shadows, but generally they did not show reduced posterior acoustic transmission. Sometimes calcifications would exhibit a short ring-down artifact (Fig. 1). The appearance of the tissue around the calcifications was grouped into 3 categories: (1) normal breast tissue, (2) focally dilated ducts, and (3) abnormal mass. Three (16%) of the 18 cases of calcifications were within focally dilated ducts. Five (28%) of 18 were surrounded by normal tissue, and 9 (44%) of 18 were within a sonographic mass. The sonographic designation of focally dilated ducts was hypoechoic, well-defined, tubular structures, which were within the sonographically visualized glandular or lobular region of the breast (Fig. 2). If the tubular structure was subareolar, it appeared to connect to the nipple. If the structure was farther away from the nipple, it appeared as an isolated tubular branching structure. The tubular structures generally appeared to be filled with hypoechoic material and calcifications. Increased acoustic transmission was not identified in any of the cases. Sonographic analysis of the 9 masses showed the following characteristics. The mean sonographic mass size was 15.8 mm. All masses had indistinct margins. Shapes were irregular in 7 and oval in 2. The masses had the following echogenicity (relative to fat): 7 hypoechoic and 2 heterogeneous. Seven masses had shadows (2 had edge shadowing, 1 had a shadow distal to the mass, and 4 had shadows obscuring the masses). Six masses were associated with sonographic architectural distortion, and 5 were associated with spiculation. Six of the masses n J Ultrasound Med 20: ,

4 Sonographic Detection of Breast Ductal Carcinoma In Situ Calcifications A B Figure 1. A, Right craniocaudal mammogram showing a needle localization wire next to the cluster of amorphous calcifications (circle). B, Right antiradial breast sonogram showing that the calcifications identified in A correspond to a group of punctate hyperechoic calcifications (arrows). No other associated abnormality is present. Histologic examination showed high-grade DCIS with necrosis. were taller than wide. If the sonographic characteristics of these masses were matched to the risk of malignancy identified in previous sonographic studies, all of these sonographically detected masses would be classified as category 4 or 5 according to the American College of Radiology Breast Imaging, Reporting, and Data System (Fig. 3). 7,9,10 A comparison of the mammographic and sonographic DCIS findings is shown in Table 2. Of the 14 patients who had mammographic calcifications alone, 6 (40%) had sonographically detected solid masses and calcifications. Four (29%) had only sonographically detected calcifications, and 3 (30%) had sonographically detected focally dilated ducts. However, of the 4 DCIS lesions that exhibited mammographic calcifications and focal asymmetric density or mass, 3 (75%) appeared on sonography as masses containing calcifications. The 1 lesion that appeared on sonography as only calcifications was a grade 2 DCIS lesion. (The other 3 cases were grade 3 lesions.) Therefore, in this small series, mammographically detected calcifications associated with masses or focal asymmetric densities are more likely to appear on sonography as masses with calcifications compared with mammographically detected calcifications without associated density. The optimal imaging frequency of all 18 DCIS lesions was recorded. During the time of review, the range of linear transducer center frequencies available was 5 to 13 MHz. In 8 cases, the optimal frequency was 10 MHz. In 5 malignancies, the optimal frequency was 11.5 MHz. In 3 lesions, the optimal frequency was 13 MHz, and in 1 lesion, the optimal frequency was 8 MHz. In 15 of the 18 patients, the DCIS lesions were documented with both a 7.5-MHz transducer and the highest optimal imaging frequency. With the use of the 7.5-MHz frequency alone, 7 of 9 masses, 1 of 2 abnormal ducts, and 1 of 4 isolated calcifications were visible. This limited study supported the results of previous studies that showed that lower-frequency sonographic examinations may identify soft tissue breast masses but do not show calcifications well. 2,9 Furthermore, when we used the 7.5-MHz transducer, we found that the asso- 504 J Ultrasound Med 20: , 2001

5 Hashimoto et al B A Figure 2. A, Left mediolateral oblique high-magnification mammogram showing a cluster of pleomorphic calcifications in the upper breast (circle). A lumpectomy specimen showed low-grade DCIS without necrosis. B, Left radial breast sonogram of the area of the calcifications in A showing the presence of abnormally dilated ducts (arrows) in a longitudinal orientation. C, Left antiradial breast sonogram showing the clustered calcifications (small arrows) within the dilated ducts (large arrows) in a crosssectional orientation. ciated calcifications within the masses and the abnormal ducts were difficult or impossible to identify unless we confirmed their presence with a higher-frequency examination. The 18 neoplasms had the following DCIS histologic grades: 11 (61%), grade 3; 5 (28%), grade 2; and 2 (11%), grade 1. Sonographic calcifications associated with a mass or focally dilated ducts represented 9 (82%) of 11 grade 3 and only 2 (28%) of 7 grade 2 and 1 neoplasms. This difference is statistically significant (P <.039). The pathologic sizes of the DCIS lesions were available for 15 of the 18 patients. In 1 patient the size was not determined, because the lesion was extremely small and the foci were on discontinuous slices. One patient had only a percutaneous biopsy, because she was elderly and refused surgery. One patient had surgical excision at a distant hospital, and the pathologic size could not be obtained. The C mean pathologic size of the DCIS lesions was 20.5 mm; the mean mammographic size was 21.4 mm; and the mean sonographic size was 16.8 mm. The sonographic measurement differed from the pathologic measurement by 8.3 mm on average. Mammographic measurement of the DCIS lesion differed from the pathologic measurement by 13.8 mm. This difference was not statistically significant as determined by the Wilcoxon signed rank test (P =.25). J Ultrasound Med 20: ,

6 Sonographic Detection of Breast Ductal Carcinoma In Situ Calcifications B A Figure 3. A, Left craniocaudal high-magnification mammogram showing 2 abnormalities. Deep to the nipple is a large, poorly defined, spiculated density (square). In the inner breast is a cluster of amorphous calcifications (circle). The calcifications were not associated with either a mammographically detected mass or focal asymmetric density. The density associated with the calcifications on this view overlap on this view alone. A mastectomy specimen showed that the central spiculated density corresponded to low-grade infiltrating ductal carcinoma. The calcifications corresponded to a separate focus of high-grade DCIS without necrosis. B, Left radial breast sonogram showing that the mammographically detected spiculated mass (identified by the square in A) corresponds to an irregular hypoechoic mass (large arrows) with severe shadowing. Echogenic spiculations (small arrows) surround the hypoechoic mass. C, Left antiradial breast sonogram showing that the mammographically detected cluster of calcifications (identified by the circle in A) corresponds to a triangular hypoechoic, spiculated mass (large arrows). Multiple calcifications (small arrows) are within the mass. C 506 J Ultrasound Med 20: , 2001

7 Hashimoto et al Discussion Table 2. Comparison of Mammographic and Sonographic Characteristics of DCIS Lesions Ultrasonographic Clustered Distribution Finding Linear Segmental Regional Mammographic calcifications alone (n = 14) Calcifications alone Duct and calcifications 2 1 Mass and calcifications No findings 1 Mammographic calcifications and focal asymmetric density (n = 4) Calcifications alone 1 Mass 3 Sonography generally has not been used for identifying DCIS. In the past, several research studies have shown that sonography is insensitive for identifying microcalcifications. 1,2,10 12 However, since these studies have been performed, there have been important improvements in sonographic equipment. Most major manufacturers now offer sonographic equipment with frequencies of 10 MHz or higher. In this study we found that almost all of the DCIS lesions required at least 10 MHz to optimally identify the sonographic calcifications, masses, or abnormal ducts. Other researchers who have published results of successful visualization of microcalcifications also confirm the necessity of higher frequencies. 4,13 Previous sonographic studies reporting a mixture of breast malignancies have described masses visible on sonography only as mammographic calcifications. Most of these malignancies are invasive ductal carcinoma, DCIS, or a combination of the two. 2,13 We are aware of only 1 previous case report that sonographically described a focally dilated duct representing a breast malignancy. In the previously reported case, the focally dilated duct was found to correspond to invasive ductal carcinoma. No mammographically detected abnormalities were present in that case. 14 The sonographic appearance of focally enlarged ducts is probably due to the tubular mass formed by DCIS. In addition to the appearance of masses and dilated ducts, previous sonographic descriptions of DCIS have also noted a diffuse reduction in echogenicity of the parenchyma surrounding the calcifications. Rickard 13 suggested that this hypoechogenicity may be due to edema. Finally, DCIS has also been found to appear sonographically as an intracystic mass. 15 In addition to mammography and sonography, magnetic resonance has also been used to identify DCIS. However, similar to sonography, studies have reported a wide range of sensitivities from 40% to 100%. Researchers postulate that the lack of magnetic resonance sensitivity is due to a variety of reasons, including tumor size, variable histologic characteristics, and angiogenesis. 16,17 Although this study supports the work of other researchers who have published descriptions of improved sonographic identification of breast calcifications, 18 this report is limited by the small number of cases and the retrospective nature of the study. Furthermore, because sonographic imaging of calcifications is experimental, we did not use sonography to guide biopsy of calcifications in these patients. Future investigation including sonographic guidance of biopsy of calcifications will be necessary to prove the true accuracy of the sonographic identification of DCIS calcifications. However, the promising results in this clinical series appear to support the previous work of British investigators who found that sonography may be reliably used to identify and localize mammographically detected calcifications. 19 Although our findings are preliminary, sonographic examination of abnormal calcifications is potentially an important area of research. Sonographic guidance of calcifications may improve guidance of percutaneous biopsies, particularly when a large area of the breast is encompassed by calcifications. A biopsy of a sonographically detected mass or a focal ductal dilatation within the area of calcifications may produce a higher probability of histologic malignancy than a random biopsy of the calcifications. Sonography may also be used to locate abnormalities characteristic of DCIS that are only visible on 1 mammographic view. Finally, in a few patients, sonographically guided biopsy or needle localization of calcifications may be preferred or necessary if the patients are unable to tolerate the prone or standing positions needed for mammographically guided procedures. J Ultrasound Med 20: ,

8 Sonographic Detection of Breast Ductal Carcinoma In Situ Calcifications Conclusion Using high-frequency sonography, we found that mammographically detected DCIS calcifications were frequently (72%) associated with other sonographic abnormalities such as dilated ducts or masses. Furthermore, high-grade DCIS was much more likely to show these additional abnormalities than non high-grade DCIS (P <.039). Because the number of patients in our study was small, further investigation is needed to explore whether these sonographic findings may add to the mammographic prediction of breast malignancy or improve assessment of the neoplasm. References 1. Bassett LW, Kimme-Smith C. Breast sonography. AJR Am J Roentgenol 1991; 156: Lambie RW, Hodgden D, Herman EM, et al. Sonomammographic manifestations of mammographically detectable breast microcalcifications. J Ultrasound Med 1983; 2: Fornage BD, Coan JD, David CL. Ultrasound-guided needle biopsy of the breast and other interventional procedures. Radiol Clin North Am 1993; 30: Yang WT, Suen M, Ahuja A, et al. In vivo demonstration of microcalcification in breast cancer using high resolution ultrasound. Br J Radiol 1997; 70: Silverstein MJ, Lagios MD, Craig PH, et al. A prognostic index for ductal carcinoma in situ of the breast. Cancer 1996; 77: D Orsi CJ, Bassett LW, Feig SA, et al. Breast Imaging Reporting and Data System (BI-RADS). Reston, VA: American College of Radiology; Potterton AJ, Peakman DJ, Young JR. Ultrasound demonstration of small breast cancers detected by mammographic screening. Clin Radiol 1994; 49: Weber WN, Sickles EA, Callen PW, et al. Nonpalpable breast lesion localization: limited efficacy of sonography. Radiology 1985; 155: Jackson VP. The current role of ultrasonography in breast imaging. Radiol Clin North Am 1995; 33: Rickard MT. Ultrasound of malignant breast microcalcifications: role in evaluation and guided procedures. Australas Radiol 1996; 40: Yang WT, King W, Metreweli C. Clinically and mammographically occult invasive ductal carcinoma diagnosed by ultrasound: the focally dilated duct. Australas Radiol 1997; 41: Tohno D, Cosgrove DO, Sloane J (eds). Malignant disease primary carcinomas. In: Ultrasound Diagnosis of Breast Diseases. New York, NY: Churchill Livingstone; 1994: Gilles R, Zafrani B, Guinebretiere JM, et al. Ductal carcinoma in situ: MR imaging-histopathologic correlation. Radiology 1995; 196: Orel SG, Mendonca MH, Reynolds C, et al. MR imaging of ductal carcinoma in situ. Radiology 1997; 202: Gufler H, Buitrago-Tellez CH, Madjar H, Allmann KH, Uhl M, Rohr-Reyes A. Ultrasound demonstration of mammographically detected microcalcifications. Acta Radiol 2000; 41: Cleverley JR, Jackson AR, Bateman AC. Pre-operative localization of breast microcalcifications using highfrequency ultrasound. Clin Radiol 1997; 52: Stavros AT, Thickman D, Rapp CL, et al. Solid breast nodules: use of sonography to distinguish between benign and malignant lesions. Radiology 1995; 196: Daniel WW. Biostatistics: A Foundation for Analysis in the Health Sciences. New York, NY: John Wiley & Sons; Cox BA, Kelly KM, Ko P, et al. Ultrasound characteristics of breast carcinoma. Am Surg 1998; 64: , 508 J Ultrasound Med 20: , 2001