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Multicentric and Multifocal Cancer: Whole-Breast US in Preoperative Evaluation¹

¹ From the Department of Radiology (W.A.B., P.L.G.) and the Greenebaum Cancer Center (W.A.B.), University of Maryland, 22 S Greene St, Baltimore, MD 21201. From the 1998 RSNA scientific assembly. Received April 9, 1999; revision requested May 11; revision received June 10; accepted July 12. Address reprint requests to W.A.B. (e-mail: waberg@umaryland.edu).

	Abstract

TOP Abstract Introduction MATERIALS AND METHODS RESULTS DISCUSSION References

 
PURPOSE: To evaluate preoperative whole-breast ultrasonography (US) in the management of breast cancer.

MATERIALS AND METHODS: The ipsilateral breast in 40 patients with known breast cancer or in whom there was high suspicion of breast cancer was evaluated with whole-breast US. Biopsy was performed on all discrete solid lesions.

RESULTS: US depicted 45 (94%) of 48 invasive tumor foci and seven (44%) of 16 foci of ductal carcinoma in situ (DCIS). Mammography depicted 39 (81%) of 48 invasive tumor foci and 14 (88%) of 16 foci of DCIS. The nine (14%) of 64 malignant foci seen only at US included three infiltrating ductal carcinomas, two mixed infiltrating and intraductal carcinomas, two infiltrating lobular carcinomas, and two foci of DCIS. Two (18%) of 11 foci of infiltrating lobular carcinoma were missed at both US and mammography. Of 20 patients mammographically suspected of having unifocal disease, three (15%) required wider excision on the basis of US findings. Two additional foci were depicted only at US in one of 16 patients mammographically suspected of having multicentric or multifocal disease. Of four patients with mammographically occult disease, US correctly depicted the diffuse (n = 2) or unifocal (n = 2) extent of the cancer.

CONCLUSION: Whole-breast US complements mammography in the preoperative evaluation of patients with breast cancer, particularly when breast conservation is contemplated.

Index terms: Breast, MR, 00.1214 • Breast neoplasms, 00.327, 00.81, 00.813 • Breast neoplasms, diagnosis, 00.327, 00.81, 00.813 • Breast radiography, comparative studies, 00.11, 00.1214, 00.1298 • Breast, US, 00.1298, 00.12985, 00.12989

	Introduction

TOP Abstract Introduction MATERIALS AND METHODS RESULTS DISCUSSION References

 
In six prospective randomized trials, mastectomy was compared with breast conservation and radiation in the treatment of stage I and II breast cancers, and no significant difference was found in the overall or disease-free survival of patients at follow-up of up to 18 years (reviewed in reference 1). Overall, the rate of local recurrence ranges from 3% to 19% after breast conservation and from 4% to 14% after mastectomy (1). Among the factors that probably account for local-regional treatment failure are margin status, tumor size, histologic grade, and presence of multifocal (within the same ductal system and/or quadrant or within 5 cm of the primary lesion) or multicentric (in different quadrants or beyond 5 cm from the primary lesion) tumor. The importance of multifocal and/or multicentric tumor in the selection of surgical approaches has long been debated (2,3), and further study of this issue is warranted.

Of patients clinically and mammographically suspected of having unifocal breast cancer, 30%–63% will have additional malignant foci in the ipsilateral breast at detailed serial sectioning of the mastectomy specimen (3,4). Multicentricity of foci and multiplicity of histologic types may portend a worse prognosis when the clinical and pathologic stage is otherwise similar (5). In a study of 282 mastectomy specimens that contained invasive cancers, Holland et al (4) found 56 (20%) to have additional unsuspected tumor foci within 2 cm of the index cancer. In another 121 (43%) specimens, additional cancer was found more than 2 cm away from the index cancer. Of the cancers beyond 2 cm, 75 (27%) were in situ and 46 (16%) were invasive.

Preoperative identification of the extent of disease facilitates appropriate surgical planning. Harms et al (6) used three-dimensional magnetic resonance (MR) imaging to examine 57 women with abnormalities that were suspicious for cancer. Of 42 malignant lesions, 13 (31%) were missed at mammography, whereas 100% were depicted by MR imaging (6). Similar results were obtained by Orel et al (7) in their study involving 176 patients with biopsy-proved or presumed breast cancer who underwent breast MR imaging. All 57 invasive cancers were depicted on MR images, as were nine (60%) of 15 in situ cancers (7). In 22 (34%) of 64 patients, MR imaging depicted additional foci that were not visible mammographically, and the MR imaging results altered disease management in seven (11%) of these patients (7).

The cost and difficulty of performing biopsy on lesions depicted only at MR imaging have limited the clinical effectiveness of this modality. In their study of post–MR imaging, second-look ultrasonography (US) for the detection of mammographically occult lesions, Panizza et al (8) found all 11 of the lesions that were depicted at MR imaging, including five cancers. We reasoned that initial whole-breast US may similarly depict tumor that is mammographically occult and sought to prospectively evaluate the role of US in the examination of patients with known breast cancer or in whom there was high suspicion of breast cancer.

	MATERIALS AND METHODS

TOP Abstract Introduction MATERIALS AND METHODS RESULTS DISCUSSION References

 
During a 1-year period, November 1997 to November 1998, 66 women (mean age, 55 years; median age, 55 years; age range, 31–79 years) had a diagnosis of breast cancer at our facility. Of these women, 40 (mean age, 55 years; median age, 55 years; age range, 31–79 years) who had known breast cancer or were highly suspected of having breast cancer mammographically—that is, they had Breast Imaging Reporting and Data System (BI-RADS) category 5 lesions (9)—underwent whole-breast US of the ipsilateral breast before surgery. The 26 women who did not undergo whole-breast US included nine patients with ductal carcinoma in situ (DCIS) (six because they were prospectively rated as having BI-RADS category 4, suspicious, lesions and three who were not willing to undergo US) and 17 patients with infiltrating tumor (14 because of the unavailability of one of the study radiologists, two because of patient refusal, and one because of low suspicion).

Before undergoing US, each patient underwent a diagnostic mammographic examination, which included appropriate additional views for the depiction of any suspicious abnormality. Magnification views of the index lesion were obtained in 37 (92%) of 40 patients. The mammograms were reviewed by one of the two Mammography Quality Standards Act–qualified interpreting physicians (W.A.B. or P.L.G.). Initially, a clinical breast examination over the clinically or mammographically suspicious area was performed by the study radiologist (W.A.B. or P.L.G.). The goals of the study were explained to the patients, and written informed consent was obtained. US was then performed by the same radiologist who had reviewed the mammograms and performed the clinical breast examination. Both radiologists had at least 5 years experience in breast US.

We used a 10-MHz linear-array transducer (Acoustic Imaging, Phoenix, Ariz). US was targeted first to the index lesion and then to the surrounding breast tissue in the same quadrant. The remainder of the ipsilateral breast was then insonated in clockwise radial and antiradial orientations around the nipple. The examination did not include imaging of the axilla. The entire examination took approximately 15 minutes (range, 10–45 minutes). After obtaining appropriate patient consent, biopsy was performed on all discrete solid lesions. A 14-gauge automated biopsy gun (Monopty; Bard Urological, Covington, Ga) was used to sample the mass with direct US visualization. An average of 4.7 passes were made (range, 1.0–7.0). All malignant lesions detected at core-needle biopsy and lesions with atypical ductal or lobular hyperplasia were excised. The following diagnoses of discrete benign lesions were made and considered to be concordant with the imaging findings: two fibroadenomas, two focal fibrosis, one sclerosing adenosis, one fat necrosis, one fibrocystic change, and one complex cyst (which resolved after one core-needle biopsy specimen was obtained).

We prospectively recorded all the mammographic findings together with the results of the clinical breast examinations and documented the surgical management planned on the basis of the clinical and mammographic results. All the US findings were recorded together with the results of biopsy on all solid lesions, and the change in the planned management (if any) was noted. Radiography of lumpectomy specimens was performed with the specimen in a Grid View carrier (Computerized Imaging Reference Systems, Norfolk, Va). The area (or areas) of interest was marked for the pathologist, and the radiograph of the specimen was sent with the specimen for pathologic analysis. US of the specimens also was performed on lesions that were detected only at US, and again the area of interest was marked for the pathologist. After mastectomy, serial 10-mm slices were evaluated by the pathologist, and sections were prepared from any grossly suspicious areas. In addition, a random section from each quadrant and a section from behind the nipple were prepared. The surgical procedure, histopathologic findings, pathologic size of the infiltrating tumors, and lymph node status (when available) were recorded. All cases were reviewed at a multidisciplinary conference, which included a comparison of the imaging and histopathologic findings.

	RESULTS

TOP Abstract Introduction MATERIALS AND METHODS RESULTS DISCUSSION References

 
Of the 40 patients with cancer, 22 (55%) presented with a palpable mass, and one presented with a bloody nipple discharge. Mastectomy was performed in 19 (48%) patients, and breast conservation therapy was performed in 21 (52%); axillary lymph node metastases were identified in nine (27%) of 33 patients who underwent lymph node dissection. Three (8%) patients underwent reexcision—one underwent lumpectomy, and the other two underwent mastectomy—because the cancer extended to the margins of resection. Of the 40 patients, four (10%) had stage 0 (DCIS) cancer; 21 (52%), stage I; 13 (32%), stage II; one (2%), stage III; and one (2%), stage IV. Twenty-two (55%) patients had unifocal disease, nine (22%) had multifocal disease, and nine (22%) had multicentric disease, with a total of 64 malignant foci detected. The average tumor size was 18 mm (median size, 12 mm; size range, 3–90 mm). At histopathologic analysis, there were 24 mixed infiltrating ductal carcinoma and DCIS foci, 16 DCIS foci, 10 infiltrating ductal carcinomas, 11 infiltrating lobular carcinomas, and three mixed infiltrating ductal and lobular carcinomas. Two foci of lobular carcinoma in situ were incidentally identified. Initially, 61 (95%) of the 64 tumor foci, including two foci of infiltrating lobular carcinoma that were missed at both mammography and US, were identified at histopathologic analysis. Three mastectomy specimens had to be resectioned to identify one subtle focus of DCIS that manifested mammographically as microcalcifications and two infiltrating ductal carcinomas (one 8 mm and one 10 mm) that were seen only at US and confirmed at core-needle biopsy.

Of the 64 cancers detected, 24 (38%) appeared as mammographic masses and four (6%) appeared as masses with calcifications (Table 1). Of these 28 masses, 27 (96%) were visible at US, and two were better seen at US. Twelve (19%) of the cancers appeared as an asymmetric density. Nine (75%) of these were palpable and seen only on one mammographic view, and 11 (92%) of them were better seen ultrasonographically (Fig 1).

View larger version (142K): [in this window] [in a new window] [Download PPT slide]   Figure 1a. Multifocal infiltrating and intraductal carcinoma in a 56-year-old woman is best seen at US. (a) Spot magnification mammogram of a palpable mass (marked by the round radiopaque marker) in the left breast shows tubular areas of increased density. (b) Radial sonogram of the lower inner quadrant (8 o'clock position) of the same breast shows multiple rounded and tubular masses (arrows), oriented radially toward the nipple, that are suspicious for carcinoma. (c) Radial sonogram of the inner region of the left breast (9 o'clock position) demonstrates a spiculated mass centrally (calipers) and several adjacent tubular masses. Core-needle biopsy (not shown) that was performed blindly in the surgeon's office yielded cancerization of the lobules. Preoperative US was performed (by drawing on the skin with permanent ink) to mark the area suspected of being involved by tumor. At US of the specimen, the spiculated mass was marked for the pathologist and proved to be infiltrating ductal carcinoma with adjacent multifocal DCIS. Clear margins were achieved. For purposes of the study, three lesions were recorded as being seen at both mammography and US, although all of the lesions were more conspicuous ultrasonographically.

View larger version (130K): [in this window] [in a new window] [Download PPT slide]   Figure 1b. Multifocal infiltrating and intraductal carcinoma in a 56-year-old woman is best seen at US. (a) Spot magnification mammogram of a palpable mass (marked by the round radiopaque marker) in the left breast shows tubular areas of increased density. (b) Radial sonogram of the lower inner quadrant (8 o'clock position) of the same breast shows multiple rounded and tubular masses (arrows), oriented radially toward the nipple, that are suspicious for carcinoma. (c) Radial sonogram of the inner region of the left breast (9 o'clock position) demonstrates a spiculated mass centrally (calipers) and several adjacent tubular masses. Core-needle biopsy (not shown) that was performed blindly in the surgeon's office yielded cancerization of the lobules. Preoperative US was performed (by drawing on the skin with permanent ink) to mark the area suspected of being involved by tumor. At US of the specimen, the spiculated mass was marked for the pathologist and proved to be infiltrating ductal carcinoma with adjacent multifocal DCIS. Clear margins were achieved. For purposes of the study, three lesions were recorded as being seen at both mammography and US, although all of the lesions were more conspicuous ultrasonographically.

View larger version (193K): [in this window] [in a new window] [Download PPT slide]   Figure 1c. Multifocal infiltrating and intraductal carcinoma in a 56-year-old woman is best seen at US. (a) Spot magnification mammogram of a palpable mass (marked by the round radiopaque marker) in the left breast shows tubular areas of increased density. (b) Radial sonogram of the lower inner quadrant (8 o'clock position) of the same breast shows multiple rounded and tubular masses (arrows), oriented radially toward the nipple, that are suspicious for carcinoma. (c) Radial sonogram of the inner region of the left breast (9 o'clock position) demonstrates a spiculated mass centrally (calipers) and several adjacent tubular masses. Core-needle biopsy (not shown) that was performed blindly in the surgeon's office yielded cancerization of the lobules. Preoperative US was performed (by drawing on the skin with permanent ink) to mark the area suspected of being involved by tumor. At US of the specimen, the spiculated mass was marked for the pathologist and proved to be infiltrating ductal carcinoma with adjacent multifocal DCIS. Clear margins were achieved. For purposes of the study, three lesions were recorded as being seen at both mammography and US, although all of the lesions were more conspicuous ultrasonographically.

There were 11 (17%) mammographically occult cancers, including three infiltrating ductal carcinomas, two foci of DCIS, two mixed infiltrating ductal carcinoma and DCIS, and four infiltrating lobular carcinomas (Table 2). Of these cancers, nine (82%) (in nine patients) were identified only at US. Two foci of infiltrating lobular carcinoma were detected only at mastectomy in one patient, who had two other foci identified mammographically and ultrasonographically. The mean size of the invasive tumors seen only at US was 27 mm (median size, 11 mm; size range, 4–90 mm). One of these nine patients had minimally dense breast tissue mammographically, six had heterogeneously dense tissue, and two had extremely dense tissue. Histopathologically, the majority (eight [89%] of nine) of the additional tumor foci that were seen only at US were the same type and grade as the index lesion.

View larger version (153K): [in this window] [in a new window] [Download PPT slide]   Figure 2a. Multifocal tubular carcinoma with DCIS in a 43-year-old woman with a second focus that was seen only at US. (a) Bilateral mediolateral oblique mammograms show a spiculated mass (arrow) in the upper outer quadrant of the right breast. (b) On the spot magnification view of the right breast, the palpable spiculated mass (marked by the round radiopaque marker) is again seen with an adjacent circumscribed and partially obscured mass, which proved to be a cyst. Fine, amorphous calcifications (arrow) also are evident and were sampled stereotactically, and a clip was placed at the biopsy site. Fibrocystic changes were identified histopathologically. (c) Compound transverse sonogram obtained immediately before surgery of the known malignant palpable mass in the right breast shows two adjacent spiculated hypoechoic masses (calipers) with posterior acoustic shadowing. On the basis of the US results, both masses were needle localized and wider excision was performed. (d) On the magnification radiograph of the specimen, the second mass, which was localized with US guidance, is not evident mammographically, although the wire was through the lesion on the sonogram of the specimen and at histopathologic analysis. Both masses proved to be infiltrating ductal carcinoma with tubular differentiation and associated DCIS. Clear margins were achieved at reexcision lumpectomy.

View larger version (148K): [in this window] [in a new window] [Download PPT slide]   Figure 2b. Multifocal tubular carcinoma with DCIS in a 43-year-old woman with a second focus that was seen only at US. (a) Bilateral mediolateral oblique mammograms show a spiculated mass (arrow) in the upper outer quadrant of the right breast. (b) On the spot magnification view of the right breast, the palpable spiculated mass (marked by the round radiopaque marker) is again seen with an adjacent circumscribed and partially obscured mass, which proved to be a cyst. Fine, amorphous calcifications (arrow) also are evident and were sampled stereotactically, and a clip was placed at the biopsy site. Fibrocystic changes were identified histopathologically. (c) Compound transverse sonogram obtained immediately before surgery of the known malignant palpable mass in the right breast shows two adjacent spiculated hypoechoic masses (calipers) with posterior acoustic shadowing. On the basis of the US results, both masses were needle localized and wider excision was performed. (d) On the magnification radiograph of the specimen, the second mass, which was localized with US guidance, is not evident mammographically, although the wire was through the lesion on the sonogram of the specimen and at histopathologic analysis. Both masses proved to be infiltrating ductal carcinoma with tubular differentiation and associated DCIS. Clear margins were achieved at reexcision lumpectomy.

View larger version (140K): [in this window] [in a new window] [Download PPT slide]   Figure 2c. Multifocal tubular carcinoma with DCIS in a 43-year-old woman with a second focus that was seen only at US. (a) Bilateral mediolateral oblique mammograms show a spiculated mass (arrow) in the upper outer quadrant of the right breast. (b) On the spot magnification view of the right breast, the palpable spiculated mass (marked by the round radiopaque marker) is again seen with an adjacent circumscribed and partially obscured mass, which proved to be a cyst. Fine, amorphous calcifications (arrow) also are evident and were sampled stereotactically, and a clip was placed at the biopsy site. Fibrocystic changes were identified histopathologically. (c) Compound transverse sonogram obtained immediately before surgery of the known malignant palpable mass in the right breast shows two adjacent spiculated hypoechoic masses (calipers) with posterior acoustic shadowing. On the basis of the US results, both masses were needle localized and wider excision was performed. (d) On the magnification radiograph of the specimen, the second mass, which was localized with US guidance, is not evident mammographically, although the wire was through the lesion on the sonogram of the specimen and at histopathologic analysis. Both masses proved to be infiltrating ductal carcinoma with tubular differentiation and associated DCIS. Clear margins were achieved at reexcision lumpectomy.

View larger version (112K): [in this window] [in a new window] [Download PPT slide]   Figure 2d. Multifocal tubular carcinoma with DCIS in a 43-year-old woman with a second focus that was seen only at US. (a) Bilateral mediolateral oblique mammograms show a spiculated mass (arrow) in the upper outer quadrant of the right breast. (b) On the spot magnification view of the right breast, the palpable spiculated mass (marked by the round radiopaque marker) is again seen with an adjacent circumscribed and partially obscured mass, which proved to be a cyst. Fine, amorphous calcifications (arrow) also are evident and were sampled stereotactically, and a clip was placed at the biopsy site. Fibrocystic changes were identified histopathologically. (c) Compound transverse sonogram obtained immediately before surgery of the known malignant palpable mass in the right breast shows two adjacent spiculated hypoechoic masses (calipers) with posterior acoustic shadowing. On the basis of the US results, both masses were needle localized and wider excision was performed. (d) On the magnification radiograph of the specimen, the second mass, which was localized with US guidance, is not evident mammographically, although the wire was through the lesion on the sonogram of the specimen and at histopathologic analysis. Both masses proved to be infiltrating ductal carcinoma with tubular differentiation and associated DCIS. Clear margins were achieved at reexcision lumpectomy.

In four patients, the mammogram was negative. Three of these patients presented with palpable masses, and one had a bloody nipple discharge. In all four patients, cancer was depicted ultrasonographically, and US-guided biopsy was performed and enabled the planning of appropriate surgical management (mastectomy in two patients and lumpectomy in two patients). Contrast material–enhanced breast MR imaging was performed in two of these patients and more clearly depicted the extent of disease than did either mammography or US (Fig 3).

View larger version (88K): [in this window] [in a new window] [Download PPT slide]   Figure 3a. Diffuse infiltrating and intraductal carcinoma in a 61-year-old woman. (a) Craniocaudal and (b) mediolateral oblique mammograms of the upper outer quadrant of the right breast show dense tissue with diffuse calcifications (arrows in b), many of which layer consistent with milk of calcium. Mammographically, there had been no change for 7 years, but the patient had developed a 6-cm palpable mass in this region. (c) Antiradial sonogram (4-MHz curved-array transducer) of the palpable mass (marked by calipers) shows diffusely heterogeneous tissue with small echogenic foci that are compatible with calcifications that were more evident on images obtained with the 10-MHz transducer (not shown). The results of US-guided core-needle biopsy confirmed infiltrating and intraductal carcinoma. Because the extent of tumor was not well characterized mammographically or ultrasonographically, MR imaging was performed before the administration of neoadjuvant chemotherapy. 1 and 2 are measurement labels. (d) Sagittal MR image from a three-dimensional spoiled gradient-recalled acquisition in the steady state (repetition time msec/echo time msec, 11.0/2.3; flip angle, 30°; matrix, 512 x 256; one signal acquired) obtained 1 minute after the intravenous administration of 15 mL of gadopentetate dimeglumine (Magnevist; Berlex Laboratories, Wayne, NJ) with the precontrast image subtracted shows a 6.5 x 5.6-cm lobular enhancing mass (arrow) that occupies most of the upper part of the breast and is compatible with stage III cancer. A small focus of tumor behind the nipple also was noted to be contiguous with the rest of the mass seen on other images. The patient underwent four cycles of chemotherapy with doxorubicin hydrochloride and cyclophosphamide. Three small (<5-mm) residual foci of infiltrating ductal carcinoma mixed with diffuse DCIS were identified at mastectomy.

View larger version (99K): [in this window] [in a new window] [Download PPT slide]   Figure 3b. Diffuse infiltrating and intraductal carcinoma in a 61-year-old woman. (a) Craniocaudal and (b) mediolateral oblique mammograms of the upper outer quadrant of the right breast show dense tissue with diffuse calcifications (arrows in b), many of which layer consistent with milk of calcium. Mammographically, there had been no change for 7 years, but the patient had developed a 6-cm palpable mass in this region. (c) Antiradial sonogram (4-MHz curved-array transducer) of the palpable mass (marked by calipers) shows diffusely heterogeneous tissue with small echogenic foci that are compatible with calcifications that were more evident on images obtained with the 10-MHz transducer (not shown). The results of US-guided core-needle biopsy confirmed infiltrating and intraductal carcinoma. Because the extent of tumor was not well characterized mammographically or ultrasonographically, MR imaging was performed before the administration of neoadjuvant chemotherapy. 1 and 2 are measurement labels. (d) Sagittal MR image from a three-dimensional spoiled gradient-recalled acquisition in the steady state (repetition time msec/echo time msec, 11.0/2.3; flip angle, 30°; matrix, 512 x 256; one signal acquired) obtained 1 minute after the intravenous administration of 15 mL of gadopentetate dimeglumine (Magnevist; Berlex Laboratories, Wayne, NJ) with the precontrast image subtracted shows a 6.5 x 5.6-cm lobular enhancing mass (arrow) that occupies most of the upper part of the breast and is compatible with stage III cancer. A small focus of tumor behind the nipple also was noted to be contiguous with the rest of the mass seen on other images. The patient underwent four cycles of chemotherapy with doxorubicin hydrochloride and cyclophosphamide. Three small (<5-mm) residual foci of infiltrating ductal carcinoma mixed with diffuse DCIS were identified at mastectomy.

View larger version (182K): [in this window] [in a new window] [Download PPT slide]   Figure 3c. Diffuse infiltrating and intraductal carcinoma in a 61-year-old woman. (a) Craniocaudal and (b) mediolateral oblique mammograms of the upper outer quadrant of the right breast show dense tissue with diffuse calcifications (arrows in b), many of which layer consistent with milk of calcium. Mammographically, there had been no change for 7 years, but the patient had developed a 6-cm palpable mass in this region. (c) Antiradial sonogram (4-MHz curved-array transducer) of the palpable mass (marked by calipers) shows diffusely heterogeneous tissue with small echogenic foci that are compatible with calcifications that were more evident on images obtained with the 10-MHz transducer (not shown). The results of US-guided core-needle biopsy confirmed infiltrating and intraductal carcinoma. Because the extent of tumor was not well characterized mammographically or ultrasonographically, MR imaging was performed before the administration of neoadjuvant chemotherapy. 1 and 2 are measurement labels. (d) Sagittal MR image from a three-dimensional spoiled gradient-recalled acquisition in the steady state (repetition time msec/echo time msec, 11.0/2.3; flip angle, 30°; matrix, 512 x 256; one signal acquired) obtained 1 minute after the intravenous administration of 15 mL of gadopentetate dimeglumine (Magnevist; Berlex Laboratories, Wayne, NJ) with the precontrast image subtracted shows a 6.5 x 5.6-cm lobular enhancing mass (arrow) that occupies most of the upper part of the breast and is compatible with stage III cancer. A small focus of tumor behind the nipple also was noted to be contiguous with the rest of the mass seen on other images. The patient underwent four cycles of chemotherapy with doxorubicin hydrochloride and cyclophosphamide. Three small (<5-mm) residual foci of infiltrating ductal carcinoma mixed with diffuse DCIS were identified at mastectomy.

View larger version (203K): [in this window] [in a new window] [Download PPT slide]   Figure 3d. Diffuse infiltrating and intraductal carcinoma in a 61-year-old woman. (a) Craniocaudal and (b) mediolateral oblique mammograms of the upper outer quadrant of the right breast show dense tissue with diffuse calcifications (arrows in b), many of which layer consistent with milk of calcium. Mammographically, there had been no change for 7 years, but the patient had developed a 6-cm palpable mass in this region. (c) Antiradial sonogram (4-MHz curved-array transducer) of the palpable mass (marked by calipers) shows diffusely heterogeneous tissue with small echogenic foci that are compatible with calcifications that were more evident on images obtained with the 10-MHz transducer (not shown). The results of US-guided core-needle biopsy confirmed infiltrating and intraductal carcinoma. Because the extent of tumor was not well characterized mammographically or ultrasonographically, MR imaging was performed before the administration of neoadjuvant chemotherapy. 1 and 2 are measurement labels. (d) Sagittal MR image from a three-dimensional spoiled gradient-recalled acquisition in the steady state (repetition time msec/echo time msec, 11.0/2.3; flip angle, 30°; matrix, 512 x 256; one signal acquired) obtained 1 minute after the intravenous administration of 15 mL of gadopentetate dimeglumine (Magnevist; Berlex Laboratories, Wayne, NJ) with the precontrast image subtracted shows a 6.5 x 5.6-cm lobular enhancing mass (arrow) that occupies most of the upper part of the breast and is compatible with stage III cancer. A small focus of tumor behind the nipple also was noted to be contiguous with the rest of the mass seen on other images. The patient underwent four cycles of chemotherapy with doxorubicin hydrochloride and cyclophosphamide. Three small (<5-mm) residual foci of infiltrating ductal carcinoma mixed with diffuse DCIS were identified at mastectomy.

	DISCUSSION

TOP Abstract Introduction MATERIALS AND METHODS RESULTS DISCUSSION References

The results of several studies (10,11) have shown an increased risk of local recurrence of 25%–40% when the initial disease is multifocal or multicentric compared with an 11% recurrence rate when the initial tumor is unifocal. A higher rate of inadequate or indeterminate margins in specimens with multiple tumors may have confounded these results (11). When clear margins have been achieved and radiation therapy has been administered, similar rates of recurrence have been observed in patients with isolated tumors compared with the recurrence rates in those who had multiple tumors (12,13). The 25%–30% rate of local recurrence in the absence of radiation therapy (14,15) parallels the frequency of multifocal infiltrating tumor. In the National Surgical Adjuvant Bowel Project, 86% of local recurrences that occurred within the first 5 years manifested as a localized mass within or close to the quadrant of the index cancer, and the majority of these recurrent cancers were of the same histologic type and grade as the index lesion, which suggests that they represented overlooked residual cancer (16). Cancers 2.0 cm or larger with high histologic and nuclear grade or intralymphatic extension were associated with an increased risk of recurrence (16).

The prognosis of women with local recurrence within the first 5 years is worse than that of those with late recurrence (61% subsequent 5-year disease-free survival versus 84% in one series [17]); this suggests that the successful identification of patients who need initial wide excision or quadrantectomy is of great clinical importance. Mastectomy is almost uniformly recommended after local recurrence within 5 years, and reconstruction is less successful in the postirradiated breast (18): A woman's best chance for successful breast conservation appears to depend on the accurate preoperative identification and operative management of all local tumor foci. Local excision is contemplated with late recurrence and achieves local control in 92% of cases compared with 49% of cases when there is early recurrence (19).

Postlumpectomy radiation may suffice for some mammographically occult multifocal or multicentric cancers: Additional evaluation of the entire breast may not always be warranted, or it may prompt unnecessary wide excision or mastectomy (2). In one series, the recurrence rate was twofold higher (36% vs 18%) when multicentric disease was preoperatively identified clinically or mammographically compared with the recurrence rate in a group with additional tumor foci that were incidentally found only at histopathologic analysis (11). The observed 11% rate of local recurrence in patients with mammographically unifocal disease (10,11) is far less than the 30%–63% rate of incidental foci identified at histopathologic analysis (3,4) or the 31%–34% rate of additional foci identified at MR imaging (6,7).

Interestingly, in our small series, US depicted unsuspected infiltrating foci in three (15%) of 20 patients who were contemplating lumpectomy for mammographically unifocal disease. In our experience, US proved to be particularly useful in identifying additional foci of infiltrating carcinoma. Identification of all foci of DCIS has proved to be more problematic at both US and MR imaging. In the context of preoperative planning, the clinical distinction between mammographically occult infiltrating carcinoma and DCIS is not yet clear.

It has been suggested that mammography properly performed with magnification views of the index lesion can accurately predict the need for wide excision (20). It is likely, however, that additional foci of tumor have the same likelihood of being mammographically occult as do any other breast cancer. The sensitivity of modern screening mammography has been reported to be 63%–80% in women younger than 50 years and 89%–94% in women aged 50 years and older (21,22). Kerlikowske et al (23) reported a higher sensitivity of mammography in women aged 50 years and older with primarily fatty breasts compared with that in women with primarily dense breasts (98.4% vs 83.7%). Malignant lesions are more difficult to detect in the mammographically dense breast because of technical factors, including reduced image contrast and unsharpness, and because cancers have the same density as normal fibroglandular elements. In our study group, of the nine foci that were seen only at US, eight (89%) were in heterogeneously dense or extremely dense breasts. Adjunctive preoperative imaging probably has a greater diagnostic role in the nonfatty breast.

Whole-breast US has previously been used to identify mammographically occult cancer. Gordon and Goldenberg (24) retrospectively reviewed 12,706 US studies. Of 1,575 incidentally identified solid masses, 44 (2.8%) proved to be malignant, and 16 (36%) of these malignant foci were in patients with multifocal cancer (24). In their study of 3,626 women with dense breasts, normal mammograms, and normal physical examinations, Kolb et al (25) found 11 (0.30%) cancers with screening US. Of these, nine (82%) were 1 cm or smaller. However, another 204 (5.6%) patients had a solid mass that was detected incidentally at US and necessitated fine-needle aspiration (n = 100), surgery (n = 12), or follow-up (n = 92). Overall, 268 (96.0%) of 279 solid lesions identified incidentally at US were either proved or likely to be benign.

To improve the specificity of US interpretation, Stavros et al (26) used a strict classification scheme to predict the benignity of 750 solid masses detected with US. Of the 424 masses that were predicted to be benign, only two proved to be malignant; this yielded a negative predictive value of 99.5%. This is similar to the negative predictive value of 98% for the probably benign lesions seen at mammography in other studies (27,28) and suggests that follow-up is a reasonable alternative to biopsy of lesions that are probably benign on the basis of US findings. Of the 11 nonpalpable, mammographically occult malignancies in the Stavros et al series (26), five (46%) were second foci in patients with multifocal or multicentric disease.

In patients with ipsilateral breast cancer, incidentally detected lesions are more likely to be malignant. In this context, biopsy has been recommended for lesions that would otherwise be considered "probably benign" (29). Rosenblatt et al (30) reviewed their experiences with stereotactic biopsy of multiple synchronous lesions and found a beneficial effect in 20 (80%) of 25 patients; this enabled definitive therapeutic planning. Similar benefits were observed in the series of Liberman et al (31). In our series, with the exclusion of index lesions, of 13 lesions incidentally detected only at US, five (38%) were malignant.

US may be especially helpful in the evaluation of infiltrating lobular carcinoma. The extent of disease has been noted to be more often underestimated mammographically (32), perhaps in part because infiltrating lobular carcinoma generally lacks calcifications (33–35). In their study of the US evaluation of infiltrating lobular carcinoma, Butler et al (36) found 71 (88%) of 81 tumors that were mammographically subtle or occult to be well seen ultrasonographically. In our study, seven (64%) of 11 foci of infiltrating lobular carcinoma were depicted at both mammography and US, two (18%) were depicted only at US, and two (18%) were missed at both mammography and US.

MR imaging is very sensitive for the depiction of cancer; its sensitivity is reported in the literature to be 86%–100% (37–41). Unfortunately, the specificity of MR imaging remains problematic; it ranges from 37% to 97%, depending on whether the entire breast or only the lesion of interest is evaluated (37–41). MR imaging is costly, and MR imaging–directed biopsy is technically demanding. Particularly, there is no simple equivalent to radiography of specimens to confirm successful sampling. Furthermore, some patients—for example, those with pacemakers or aneurysm clips—are not candidates for MR imaging.

Nuclear medicine techniques are evolving in the depiction of mammographically occult breast cancers; technetium 99m sestamibi in particular is being widely evaluated (42). In an initial multicenter trial, the sensitivity of ^99mTc sestamibi scintimammography for the detection of breast cancers smaller than 1 cm was as low as 48%; for the detection of tumors larger than 1 cm, the sensitivity was 74% when the readers were blinded to the mammographic findings; and the overall specificity was higher, 89% (42). In their comparison of MR imaging and sestamibi scintimammography in the differentiation of benign from malignant breast lesions identified mammographically, Helbich et al (43) found MR imaging and sestamibi scintimammography to have similar specificity (82% with MR imaging, 80% with single photon emission computed tomographic [SPECT] scintimammography), but MR imaging had improved sensitivity for the detection of malignancy (96% with MR imaging, 83% with SPECT scintimammography); the average lesion size in that study was 20 mm (range, 5–70 mm). Fenlon et al (44) found the sensitivity of ^99mTc tetrofosmin scintigraphy for the depiction of palpable malignancies to be 95% (20 of 21 cases), which was higher than the 81% (17 of 21 cases) sensitivity of mammography.

Whole-breast US has limitations and certainly should not replace mammography as the initial imaging for breast cancer screening (45). In addition to its lack of specificity as discussed above, US is operator dependent and takes time. The mammogram is essential in providing a "road map" for US. With the current transducers, US is less sensitive for the detection of microcalcifications; as a result, in our series, more than half (nine [56%]) of the 16 foci of DCIS were seen only at mammography. In four (10%) of 40 patients in our study, US would have missed the multicentric disease because the second focus was DCIS that manifested as clustered calcifications only.

We have begun to explore the use of bilateral whole-breast US in patients with breast cancer. Synchronous bilateral cancers have been reported in 0.2%–2.0% of patients (46,47), and metachronous contralateral cancer is reported to occur at a rate of less than 1% per year (48). In one study (49), MR imaging depicted unexpected contralateral carcinomas in three (9%) of 34 women with breast cancer. Bilateral disease may be more common in women with multicentric breast cancer, and increasing size of the primary tumor correlates with frequency of both multicentricity and bilaterality (50). Roubidoux et al (51) found that lesions in the contralateral breast are more likely to be malignant or high risk in women with breast cancer; this suggests that one should use a lower threshold for biopsy of incidentally detected contralateral lesions as well as ipsilateral lesions.

Color Doppler US cannot be performed with the equipment that was used in this study. The presence of demonstrable color flow in a lesion otherwise considered to be probably benign has been suggested as an indication for biopsy (52,53), although there is an overlap of findings in benign and malignant conditions. The presence of increased flow in malignant lesions may be an independent predictor of metastatic potential (54) just as microvessel density has been shown to correlate with likelihood of lymph node metastases (55).

The axilla was not specifically evaluated in our study. Vassallo et al (56) reported US criteria to differentiate benign from malignant lymph nodes, but these criteria have not been widely implemented or verified.

One major advantage of US over MR imaging or ^99mTc sestamibi scintimammography is the ease of guiding core-needle biopsy (57) or needle localization. In their study of 151 women with nonpalpable breast masses, Liberman et al (58) found that US-guided core-needle biopsy spared 128 (85%) women from undergoing a surgical procedure. In our series, US was successful in guiding the biopsy of all but one malignant mass or asymmetric density (39 [98%] of 40 lesions). The one lesion that was missed was not confidently seen at US, and the initial biopsy yielded benign breast tissue; the stereotactic biopsy performed because of mammographic-histopathologic discordance yielded infiltrating ductal carcinoma.

In summary, we propose that whole-breast US is complementary to mammography in the preoperative examination of women with breast cancer in whom breast conservation is planned. At our institution, the subsequent follow-up of patients in whom tumor was depicted better at US includes whole-breast US. The field of breast imaging would benefit from the systematic comparison of whole-breast US, MR imaging, sestamibi scintimammography, and digital mammography in the preoperative evaluation of breast cancer, particularly in women with dense parenchyma.

	Footnotes

 
Abbreviations: BI-RADS = Breast Imaging Reporting and Data System DCIS = ductal carcinoma in situ

Author contributions: Guarantor of integrity of entire study, W.A.B.; study concepts and design, W.A.B.; definition of intellectual content, W.A.B., P.L.G.; literature research, W.A.B., P.L.G.; clinical studies, W.A.B., P.L.G.; data acquisition, W.A.B., P.L.G.; data analysis, W.A.B.; manuscript preparation, editing, and review, W.A.B., P.L.G.

	References

TOP Abstract Introduction MATERIALS AND METHODS RESULTS DISCUSSION References

 

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