Article

Diagnosis of the Intraductal Component of Invasive Breast CancerAssessment With Mammography and SonographyDoo Kyoung Kang, MD, Gyeong Sik Jeon, MD, Hyunee Yim, MD, Yong Sik Jung, MDObjective. The aim of this study was to investigate mammographic and sonographic features and their sensitivities for depiction of the intraductal component associated with invasive ductal carcinoma (IDC). Methods. During a 1-year period, 132 patients with IDC underwent surgical treatment. All patients underwent mammography and high-resolution sonography, and the findings were reported according to the American College of Radiologys Breast Imaging Reporting and Data System lexicon. Tumors were classified as pure IDC and IDC with an intraductal component by histopathologic evaluation. We compared mammographic and sonographic features between the above 2 groups and attempted to correlate them with histopathologic findings. We also investigated separate and combined sensitivities, specificities, and accuracies of both mammography and breast sonography for showing intraductal components. Finally, imaging measurements were compared with pathologic measurements. Results. One hundred four (79%) of the 132 IDCs contained an intraductal component. Patients with IDC with an intraductal component showed calcifications on mammography and showed an echogenic halo, duct dilatation, calcifications, and increased vascularity in surrounding tissue on sonography more frequently than patients with pure IDC. The sensitivities of mammography, sonography, and their combined assessment for detection of an intraductal component were 55%, 80%, and 86%, respectively. The combined assessment (r = 0.90) measured the extent of the tumor more accurately than mammography (r = 0.71) or sonography (r = 0.79) separately. Conclusions. Combined assessment with mammography and sonography offers more accurate information for the presence of an intraductal component and the extent of a tumor than each separate assessment. Key words: breast neoplasms; breast sonography; mammography; pathologic examination.

Abbreviations BI-RADS, Breast Imaging Reporting and Data System; DCIS, ductal carcinoma in situ; EIC, extensive intraductal component; IDC, invasive ductal carcinoma; MRI, magnetic resonance imaging

D

Received May 10, 2007, from the Departments of Diagnostic Radiology (D.K.K., G.S.J.), Pathology (H.Y.), and General Surgery (Y.S.J.), Ajou University, School of Medicine, Suwon, Korea. Revision requested June 12, 2007. Revised manuscript accepted for publication July 11, 2007. Address correspondence to Doo Kyoung Kang, MD, Department of Diagnostic Radiology, Ajou University, School of Medicine, San 5, Woncheondong, Yeongtong-gu, Suwon, Kyongi-do 442-749, Korea. E-mail: kdklsm@ajou.ac.kr

uctal carcinoma is the most common type of malignancy arising from the breast parenchyma. Examination of invasive ductal carcinoma (IDC) reveals an intraductal component in 50% to 80% of pathologic studies.1,2 The presence of an intraductal component is a very important risk factor for local recurrence in breast-conserving therapy because tumors with an intraductal component can leave residual islands of intraductal carcinoma.35 Actually, 26% of patients with an extensive intraductal component (EIC) had a local recurrence compared with 7% of patients without an EIC.6 However, when a microscopic clear margin was obtained after breast-conserving surgery, there was no difference in local recurrence between EIC-positive and -negative cancer.7,8 Therefore, our ultimate goal is to accurately detect intraductal components and to completely remove them for achieving clear margins.

2007 by the American Institute of Ultrasound in Medicine J Ultrasound Med 2007; 26:15871600 0278-4297/07/$3.50

Diagnosis of the Intraductal Component of Invasive Breast Cancer

The mammographic diagnosis of an intraductal component is based mainly on the presence of calcifications. Calcifications outside or adjacent to a mass or malignant calcifications without a tumor shadow are characteristic of intraductal components.911 Especially, when greater than 3 cm in extent, they are suggestive of a lesion with an EIC.9 Cancers showing calcifications on mammograms have been shown to be associated with an EIC in 22% to 63% of cases.912 However, mammography is of little value in cases without calcifications: mammographic detection of intraductal carcinomas without calcifications may be quite difficult, especially in dense breasts; therefore, approximately 23% of intraductal carcinomas are not visible on mammography.1315 On the other hand, it is easier to visualize noncalcified intraductal carcinomas than calcified intraductal carcinomas on sonography.16 Sonography can also show the intraductal component associated with invasive carcinoma. Sonographic features that characterize intraductal components of cancer are a dilated duct (or a tubular hypoechoic structure) radiating from the tumor and the presence of satellite lesions (or daughter tumors) around the main tumor.2,11,17 However, the sensitivity of sonography for detection of intraductal components varies from 21% to 89%.1012,17 The results depend mainly on the case selection method, the investigators skill, and the spatial resolution of the equipment.18 Furthermore, the effectiveness of sonography is partly lessened because of its limited capability to depict microcalcifications, although some investigators have reported that sonography depicts clustered microcalcifications in breast cancers.1921 Therefore, mammography and sonography appear to be complementary. The aims of this study, therefore, were to assess the mammographic and sonographic features of the intraductal component associated with IDC and to investigate separate and combined sensitivities of mammography and breast sonography for showing the intraductal component in patients with IDC. In addition, to our best knowledge, a study with application of the American College of Radiologys Breast Imaging Reporting and Data System (BI-RADS) ultrasound lexicon has not been reported previously.221588

Materials and MethodsStudy Population From March 2006 to February 2007, 4191 consecutive patients underwent both mammography and sonography for clarification of suspicious breast findings. Three hundred ninety-four patients were recommended for tissue confirmation of suspicious lesions (BI-RADS category 4 or 5); 373 of them actually underwent mammographically guided needle localization with excision or sonographically guided core needle biopsy, and 187 patients were confirmed as having IDC or ductal carcinoma in situ (DCIS). Finally, 175 patients were surgically treated, except 12 patients who were scheduled for neoadjuvant chemotherapy or palliative treatment. A total of 132 patients were confirmed as having IDC and were enrolled in this study, excluding the remaining 43 patients with DCIS. Our Institutional Review Board did not require its approval or informed consent for the retrospective evaluation of patients records and data. The mean age of the study population was 46 years (range, 2279 years). Thirty-three patients (32%) underwent breast-conserving surgery, and 71 patients (68%) underwent mastectomy, including modified radical mastectomy. The diagnoses of the invasive components included ductal carcinoma, not otherwise specified (n = 126); mucinous carcinoma (n = 4); and medullary carcinoma (n = 2). Mammographic and Sonographic Examinations Mammograms from all 132 patients were obtained with a Senographe DMR mammography unit (GE Healthcare, Milwaukee, WI). Using the BI-RADS mammography lexicon, 1 experienced breast radiologist (D.K.K.) prospectively interpreted the mammograms. At that time, we regarded a mass or focal asymmetry as soft tissue density and then simply classified the mammographic findings as calcifications alone, calcifications with soft tissue density, and soft tissue density alone for statistical analysis. Whole-breast sonography was performed by a radiologist (D.K.K.) with 8 years of experience in breast sonography using an Acuson Sequoia ultrasound system (Siemens Medical Solutions,J Ultrasound Med 2007; 26:15871600

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Mountain View, CA) with an 8- to 13-MHz linear array transducer. Radial scanning techniques and careful analysis of the ductal structures were used to evaluate the extent of the tumors. For evaluation of the capability of US to depict microcalcifications, breast sonography was initially performed without information on mammographic findings. Thereafter, sonography was again performed immediately with careful correlation with mammographic findings, and the findings were finally reported according to the BI-RADS ultrasound lexicon.22 Histopathologic Evaluation In the Department of Pathology, surgical specimens were serially sliced at 5-mm intervals, prepared as paraffin-embedded sections, and stained with hematoxylin-eosin. The sections stained in each case were reviewed by 1 experienced pathologist (H.Y.) without knowledge of the results of the mammographic and sonographic examinations. The specimens were evaluated according to the following histopathologic features: histologic type, Black nuclear grade, modified Bloom-Richardson histologic grade, and the presence of hormone receptors (estrogen receptor, progesterone receptor, and c-ErbB2). Tumors were classified into 2 groups, based on the absence or presence of in situ component: pure IDC with no intraductal component and IDC with an intraductal component. In the IDC with an intraductal component group, EIC referred to invasive breast cancer wherein at least 25% of the tumor was composed of an intraductal component, and the intraductal component extended beyond the invasive tumor.23 In addition to size measurement of the invasive component (T status), the maximum extent including the intraductal component around the main tumor was also measured. The overall stage of cancer was classified according to American Joint Committee on Cancer TNM staging of breast cancer.24 Data Analysis We retrospectively analyzed the data of each examination in our study population. First, we compared the mammographic and sonographic features between the 2 groups and attempted to correlate them with the histopathologic findings.J Ultrasound Med 2007; 26:15871600

Second, we investigated the separated and combined sensitivities, specificities, and accuracies of mammography and breast sonography for showing the intraductal component associated with IDC. Referring to earlier reports,9,10,12 calcifications around the mass or malignant calcifications without a mass on mammography and duct dilatation radiating from the tumor or satellite lesions around the main tumor on sonography were considered suspicious for an intraductal component of IDC (Figure 1). We also assessed the diagnostic performance, using additional sonographic features that were significantly different between pure IDC and IDC with an intraductal component. Third, we compared the imaging tumor size with the pathologic tumor size whenever it was possible to preoperatively measure them on both mammography and sonography. Statistical Analysis SPSS version 11.9 (SPSS Inc, Chicago, IL) and Microsoft Excel 2000 (Microsoft Corporation, Redmond, WA) software packages were used for the statistical analyses. Statistical comparisons of the characteristics between the subgroups of cases were performed with the Pearson 2 statistic or, when appropriate, the Fisher exact test. Separate and combined sensitivities, specificities, and accuracies for both mammography and breast sonography for showing intraductal components were calculated, and these diagnostic performances were compared among the above 3 methods by a McNemar test. We also used the Student t test and linear regression analysis for comparison of imaging and pathologic sizes. P < .05 was considered indicative of a significant difference. Correlation coefficients between 0 and 0.2 were regarded as no correlation, between 0.2 and 0.4 as a weak correlation, between 0.4 and 0.7 as a moderate correlation, and greater than 0.7 as a strong correlation.

ResultsPathologic Characteristics One hundred four (79%) of the 132 IDCs contained an intraductal component. Fifty-two tumors contained an intraductal component occupying 1% to 24% of the area of the tumor,1589

Diagnosis of the Intraductal Component of Invasive Breast Cancer

and 52 tumors contained an EIC. The remaining 28 tumors, which were pure IDCs, did not contain any intraductal component in or around the main tumor. There were no statistical differencesFigure 1. Infiltrating ductal carcinoma with an EIC in a 39-year-old woman. A, Mediolateral oblique mammogram shows a 2.5-cm irregularly shaped hyperdense mass (short arrows) with a spiculated margin in the left breast. There are clustered pleomorphic microcalcifications (long arrows) within the mass. B, Radial sonogram shows a 2.8-cm microlobular hypoechoic mass in the right breast. The mass has an echogenic halo, associated duct dilatation (long arrow), and associated satellite nodules (short arrows) around the mass. These masses were confirmed as IDC with EICs. The maximum size of the malignant process was 3.5 cm on histopathologic analysis. The extent of the malignancy was consequently underestimated on both mammography and sonography.

in patient age (P = .386), symptoms (P = .059), tumor size (T status, P = .346), regional lymph node status (P = .515), cancer stage (P = .811), nuclear grade (P = .658), and histologic grade (P = .189) between patients with pure IDC and patients with IDC and an intraductal component (Table 1). Mammographic and Sonographic Features The most common mammographic feature of pure IDC was soft tissue density alone (86%; Figure 2), followed by calcifications with soft tissue density (7%) and negative findings (7%), whereas the most common feature of IDC with an intraductal component was calcifications with soft tissue density (48%; Figure 3), followed by soft tissue density alone (42%), calcifications alone (7%), and negative findings (3%; Table 2). Invasive ductal carcinoma with an intraductal component showed calcifications on mammography more frequently (55%) than pure IDC (7%). As for the mass, IDC with an intraductal component showed a more irregular shape (Figure 4) than pure IDC (P < .001), but margin and density were not significantly different between the 2 groups (Table 3). We could not obtain statistically significant results on calcifications because only a small number of cases with pure IDC revealed calcifications on mammography. All cases could be detected by sonography. On the other hand, sonography with knowledge of mammographic findings showed calcifications in 48 (81%) of 59 cases in which calcifications were revealed on mammography, whereas initial sonography without mammographic information showed calcifications in only 34 (58%) cases. Sonographic findings that showed significant differences between pure IDC and IDC with an intraductal component included the lesion boundary (P = .014), duct dilatation (P = .003), calcifications (P < .001), and vascularity (P = .002). Pure IDC showed an abrupt interface (Figure 2) and increased vascularity in or immediately adjacent to lesions more frequently, whereas IDC with an intraductal component showed an echogenic halo (Figure 4), duct dilatation (Figure 5), calcifications (Figure 6), and increased vascularity in surrounding tissue more frequently (Figure 7 and Table 4).J Ultrasound Med 2007; 26:15871600

A

B

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Detection of Intraductal Components On mammography, we could detect intraductal component in 57 of 104 IDCs with an intraductal components. The sensitivity, specificity, and accuracy of mammography for detection of an intraductal component were 55%, 93%, and 63%, respectively (Figure 8). In cases in which duct dilatation and satellite lesions on sonography were considered suspicious for an intraductal component, we could detect intraductal components in 65 cases. On the other hand, when microcalcifications inside or outside mass and increased vascularity in surrounding tissue were included in the sonographic criteria for an intraductal component, we could detect intraductal components in 83 cases. Therefore, according to the latter sonographic criteria for detection of an intraductal component, the overall sensitivity, specificity, and accuracy were 80%, 79%, and 80%. In comTable 1. Characteristics of 132 Patients With IDCCharacteristic Pure IDC (n = 28)

bined assessment with both mammography and sonography, we were able to detect intraductal components in 89 cases, and the sensitivity, specificity, and accuracy were 86%, 79%, and 84% (Figure 8). According to the McNemar test, the sensitivity and accuracy of the combined assessment were significantly higher than those of mammography or sonography separately, whereas the specificity was not different significantly. The sensitivity and accuracy of sonography using traditional criteria of duct dilatation and satellite lesions were not significantly different compared with those of mammography (Figure 8). However, when the presence of calcifications and diffusely increased vascularity in the surrounding tissue were used as additional criteria for an intraductal component, the sensitivity and accuracy of sonography were significantly higher than those of mammography.

IDC With Intraductal Component (n = 104)

P

Mean age, y Symptom, n (%) Asymptomatic (n = 36) Palpable mass (n = 93) Nipple discharge (n = 3) Surgery, n (%) BCS (n = 45) Mastectomy (n = 87) Tumor size, n (%) T1 (n = 55) T2 (n = 69) T3 (n = 6) T4 (n = 2) Regional lymph node status, n (%) N0 (n = 71) N1 (n = 39) N2 (n = 15) N3 (n = 7) Stage, n (%) I (n = 38) II (n = 70) III (n = 24) Nuclear grade, n (%) 1 (n = 60) 2 (n = 57) 3 (n = 8) Histologic grade, n (%) 1 (n = 19) 2 (n = 48) 3 (n = 59) BCS indicates breast-conserving surgery.

47.5 3 (10.7) 24 (85.7) 1 (3.6) 12 (42.9) 16 (57.1) 13 12 2 1 16 9 1 2 (46.4) (42.9) (7.1) (3.6) (57.1) (32.1) (3.6) (7.1)

45.6 33 (31.7) 69 (66.3) 2 (1.9) 33 (31.7) 71 (68.3) 42 57 4 1 55 30 14 5 (40.4) (54.8) (3.9) (1.0) (52.9) (28.8) (13.5) (4.8)

.386 .059

.270

.346

.515

9 (32.1) 15 (53.6) 4 (14.3) 13 (46.4) 9 (32.1) 2 (7.1) 6 (21.4) 6 (21.4) 12 (42.9)

29 (27.9) 55 (52.9) 20 (19.2) 47 (45.2) 48 (46.2) 6 (5.8) 13 (12.5) 42 (40.4) 47 (45.2)

.811

.658

.189

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In 51 (49%) of 104 cases, both mammographic and sonographic findings were positive (Figure 3). In 6 (6%) of 104 cases, mammographic findings were positive, whereas sonographic findings were false-negative. In 32 (31%) of 104 cases, sonographic findings were positive, whereas mammographic findings were false-negativeFigure 2. Pure IDC in a 49-year-old woman. A, Mediolateral oblique mammogram shows a hyperdense mass (arrow) with an obscured margin in the right breast. Calcifications are not shown around the mass. The mass measured 3 cm in maximum dimension. B, Transverse sonogram shows an oval hypoechoic mass (arrow) with circumscribed margins measuring 2.6 cm. Duct dilatation or satellite lesions are not shown around the mass. The mass was confirmed as IDC without an intraductal component. Histopathologic examination of the mass indicated a high nuclear grade and a poorly differentiated histologic grade. The mass measured 2.5 cm on pathologic examination and was consequently overestimated on mammography.

(Figure 5). In 15 (14%) of 104 cases, the intraductal component was missed by both mammography and sonography (Figure 4). In the combined assessment of all 132 invasive carcinomas, we misdiagnosed 6 (21%) of 28 cases of pure IDC as IDC with an intraductal component. These falsepositive cases were revealed as clustered puncFigure 3. Infiltrating ductal carcinoma with an intraductal component in a 53-year-old woman. A, Mediolateral oblique mammogram shows a 3-cm oval hyperdense mass with microlobulated margins in the right breast. There are segmental pleomorphic microcalcifications (arrows) within and around the mass. B, Radial sonogram shows a 3.2-cm oval hypoechoic mass with microlobulated margins and calcifications (long arrow) within the mass. There is duct dilatation (short arrow) extending from the main tumor. The mass was confirmed as IDC containing an intraductal component. The malignant process measured 4 cm on histopathologic examination and was underestimated on both mammography and sonography.

A

A

B

B

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tate (n = 1) and amorphous (n = 1) calcifications around the mass on mammography and duct dilatation (n = 4) around the main tumor on sonography. However, they were all confirmed as fibrocystic changes, such as epithelial hyperplasia or adenosis. Measurement of Lesion Extent In the cases of pure IDC (n = 23), the mean size of the lesions SD was 26.4 12.2 mm (range, 1560 mm). Mammography underestimated the size in 8 cases (range, 125 mm) and overestimated it in 7 cases (range, 212 mm). Sonography underestimated the size in 10 cases (range, 110 mm) and overestimated it in 12 cases (range, 112 mm). In the cases of pure IDC, the size measured by mammography (r = 0.80; P < .01) and sonography (r = 0.91; P < .01) showed a strong correlation with pathologic size. In the cases of IDC with an intraductal component (n = 77), the mean size of the lesions was 26.6 12.3 mm (range, 570 mm). Mammography underestimated the size in 39 cases (range, 130 mm) and overestimated it in 29 cases (range, 125 mm). Sonography underestimated the size in 36 cases (range, 117 mm) and overestimated it in 39 cases (range, 119 mm; Table 5). The size measured by mammography (r = 0.69; P < .01) and sonography (r = 0.75; P < .01) showed a moderate correlation with the pathologic size. Cases containing an EIC showed the poorest correlation on both mammography (r = 0.47; P < .01) and sonography (r = 0.58; P < .01). The size measured by combined assessment of mammography and sonography showed the highest correlation in all pure IDC (r = 0.97; P < .01) and IDC with an intraductal component (r = 0.88; P < .01) compared with separate mammographic or sonographic assessment. Cases containing an EIC showed a strong correlation (r = 0.80; P < .01) between imaging and pathologic tumor sizes (Table 6).

dence of an EIC has previously been reported to be 13% to 39%. Recently, Elling et al25 retrospectively analyzed 250 resected surgical specimens of invasive breast cancer to determine the presence of intraductal components within the primary tumors and found that DCIS of varying extent was identified in addition to the invasive carcinoma in 127 (50.8%) of the 250 specimens. In our study, 104 (79%) of 132 IDCs contained an intraductal component, and 52 cases (39%) were EIC positive. The detection of an intraductal component is clinically important because an intraductal component associated with invasive cancer is one of the major reasons for a positive margin and recurrence after breast conservation surgery.4 Therefore, therapeutic management may differ depending on the presence and extent of an intraductal component. An earlier study actually suggested that computed tomographic imageguided lumpectomy diminished the positive surgical margin rate to 21% compared with 42% of cases without computed tomographic imageguided lumpectomy (P = .0055).26 The mammographic diagnosis of intraductal components is based mainly on the presence of calcifications.11 However, approximately 23% of intraductal carcinomas do not reveal calcifications on mammography.13,14 In cases without calcifications, mammography is of little value in detection of intraductal carcinomas. In our cases, 47 (45%) of 104 IDCs with an intraductal component, especially 16 (31%) of 52 cases containing an EIC, did not show calcifications on mammography. Among these 47 cases without

Table 2. Correlation of Mammographic and Histopathologic Findings in IDCFinding Pure IDC (n = 28) IDC With Intraductal Component (n = 104)

DiscussionInvasive ductal carcinoma is the most common type of breast malignancy and often has an intraductal component that is considered a noninvasive component of the tumor. An intraductal component associated with IDC has been found in 50% to 80% of cases.1,2 Particularly, the inciJ Ultrasound Med 2007; 26:15871600

Calcifications only, n (%) Calcifications with soft tissue density, n (%) Calcifications + mass Calcifications + asymmetry Soft tissue density only, n (%) Mass Asymmetry Negative, n (%) Total, n (%)

0 2 (7) 2 0 24 (86) 21 3 2 (7) 28 (100)

7 (7) 50 (48) 39 11 44 (42) 38 6 3 (3) 104 (100)

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calcifications, 32 (76%) showed calcifications on sonography. In contrast, sonography is less sensitive than mammography in showing calcifications. The low capability to visualize microcalcifications remains a major limitation of sonography for diagnosing intraductal carcinoma. In one earlier study, sonography depictedFigure 4. Infiltrating ductal carcinoma with and intraductal component in a 60-year-old woman. A, Craniocaudal mammogram shows a 1.5-cm irregular hyperdense mass (arrow) with spiculated margins. Calcifications are not shown within or around the mass. B, Transverse sonogram shows a 1.8-cm irregular hypoechoic mass (arrow) with spiculated margins. The mass is associated with an echogenic halo and posterior acoustic shadowing. Duct dilatation or satellite lesions are not shown around the mass. The malignant process was confirmed as IDC containing an intraductal component. The malignant process measured 2.2 cm on histopathologic examination and was underestimated on mammography and sonography.

A

associated breast abnormalities in only 45% of mammographically detected microcalcifications.27 On the other hand, the visibility on sonography becomes much higher for calcifications associated with malignant tumors or calcification clusters larger than 10 mm, although some isolated calcifications or small groups of calcifications may not be seen on sonography.16 Furthermore, sonography is highly dependent on the operators experience and technique.18 In this study, we could initially detect only 58% of mammographically detected calcifications on sonography without knowledge of the mammographic findings. However, when the scans were performed again with mammographic knowledge of the presence and areas of microcalcifications, we were able to detect calcifications in 81% of cases. Accordingly, with no knowledge of mammographic findings, some microcalcifications or small lesions could be missed by sonography. Dynamic contrast-enhanced breast magnetic resonance imaging (MRI) has a high degree of sensitivity for the diagnosis of invasive breast Table 3. Mammographic Findings in Pure IDC and IDC With an Intraductal ComponentIDC With Intraductal Component (n = 104)

Mammographic Lexicon

Pure IDC (n = 28)

P

B

Mass Shape Round Oval Lobular Irregular Margin Circumscribed Microlobulated Obscured Indistinct Spiculated Density High Equal Calcifications Type Punctate Amorphous Fine, pleomorphic Fine, linear Distribution Regional Clustered Segmental

3 5 6 9 1 0 3 9 10 15 8

3 3 6 65 0 9 10 26 32 48 29