Breast imaging and mammography may seem synonymous, but other modalities have important roles in the search for and management of breast cancer. This article reviews these other applications, some established and some experimental, as of mid 2004.

SCREENING

Although the role of mammography in screening for breast cancer is secure, the study has two serious drawbacks: it does not identify all cancers, especially in women with dense breasts, and it reveals many lesions without characterizing them, mandating biopsies that often yield only benign tissue. One line of research in breast imaging is therefore directed at improving breast cancer screening.

An Israeli team used sonography as a second-line screen in 1,517 asymptomatic women with dense breasts and normal mammograms and found seven stage T1 cancers. 1 According to radiologists in Belgium, who compared sonography with mammography in 4,236 women as a means of finding nonpalpable cancers, the two modalities are equivalent in their ability to find low-grade tumors, but sonography was more sensitive both overall, 88% vs 69%, and for high-grade tumors, 88% vs 56%. 2 Sonography was especially helpful in women with dense breasts. Sonography may also be valuable as an adjunct to mammography in women with symptomatic ductal carcinoma in situ. 3

Magnetic resonance imaging may also have some utility. In 41 patients with a high genetic risk of breast cancer, a combination of MR and cytologic examination found a cancer (high-grade ductal carcinoma in situ) that was overlooked by mammography. 4 High-risk premalignant lesions were found in three other patients. In another series of 367 consecutive high-risk patients with normal mammograms examined at Memorial Sloan-Kettering Cancer Center, New York, MRI found 14 cancers, 5 while another 13 women were found to have high-risk premalignant lesions. This same team has reported that MRI may be the only modality that can identify certain benign lesions with a high risk of malignant transformation. 6 Nevertheless, one of these investigators noted in a recent review 7 that the proper clinical role of MRI in breast cancer screening has yet to be defined.

DIFFERENTIAL DIAGNOSIS

Another line of research aims at characterizing indeterminate lesions without biopsy. Several groups are exploring MRI because it can measure tissue vascularity. In a series of 46 patients with breast masses who were studied by axial three-dimensional FLASH protocols, the dynamic contrast enhancement patterns and the rate of progression to maximum signal increase predicted malignancy. 8 Jacobs and colleagues, who studied 36 patients with and without contrast using tissue cluster analysis, concluded that MRI could distinguish benign and malignant lesions and “may enable automated lesion identification and classification.” 9 An experimental technique that measures vascular permeability, feruglose contrast, and determination of the endothelial transfer coefficient and fractional plasma volume had a positive predictive value (PPV) for malignancy of 79%. 10

Other investigators have explored the utility of ultrasonography. In a series of women with palpable breast lesions, color and power Doppler imaging with microbubble contrast medium proved helpful in determining which lesions were malignant. 11 Kook and Kwag used contrast-enhanced power Doppler imaging in 36 patients having indeterminate lesions and generated time-transit profiles. The combination of gray-scale and power Doppler imaging with and without contrast provided the greatest amount of information. 12 Doppler studies with calculation of the acceleration time index 13 and three-dimensional ultrasonography with pixel relation analysis 14 also have shown promise in differential diagnosis.

The newest imaging method to be applied is contrast-enhanced multidetector CT scanning. In a series of 149 women with suspected tumors, 173 lesions were found, of which 131 were malignant. 15 Seven of these cancers were not visible on mammography or sonography. Irregular margins and rim enhancement were universal in the malignant lesions. Tozaki and colleagues had similar results, concluding as well that multidetector CT scans with contrast are “extremely accurate” in identifying intraductal spread and multicentricity. 16

It may also be possible to reduce the negative-biopsy rate using a combination of three-dimensional MRI and positron emission tomography with fluorine 18 fluorodeoxyglucose (FDG-PET). In one series, the two studies reduced the percentage of patients who required biopsy from 55 to 17. 17 The cost of such a protocol is a matter of concern, however, and these investigators suggested using MRI first, with PET being conducted only if the nature of the lesion is still in doubt. Wilczek and associates of the Karolinska Institute in Stockholm found that adding scintimammography with 99mTc-MIBI to clinical examination, mammography, and fine-needle aspiration improved sensitivity for malignancy in both palpable and nonpalpable lesions, although at the cost of reduced specificity. 18

BIOPSY GUIDANCE, AXILLA STAGING

Traditionally, biopsy of breast lesions has involved placement of a marker mammographically to serve as a target for the needle or the surgeon. In a single-stage procedure, Panizza and associates used MRI for real-time guidance of cytologic sampling and biopsy of 14 lesions, 10 of which were visible only by MRI. All of the biopsy specimens and four of the cytologic samples were adequate for histologic diagnosis. The average procedure time was 45 minutes. These workers rated MRI-guided breast biopsy “simple, fast, and safe” and believed it could be recommended for routine use. 19

The practice of identifying a sentinel axillary lymph node for biopsy by injecting blue dye into the primary tumor is well established, but other techniques are being explored.

The ready availability of ultrasonography makes it a desirable option if it is sufficiently sensitive. In patients with operable breast cancers, lymph nodes could be identified sonographically in 103 of 166 axillae of those having invasive cancers and were biopsied with ultrasound guidance. Of the abnormal-appearing nodes, 65% contained cancer. 20

Because of the modality’s ability to depict metabolism, several groups have explored the utility of FDG-PET. One team of investigators studied 200 patients, finding the sensitivity of the technique to be 84% and the specificity 98%. All 17 false-negative studies were associated with low uptake of isotope by the primary tumor, suggesting a low metabolic rate. In 15 patients, the scans revealed possible involvement of the internal mammary nodes. 21 Similar results were obtained in a series from Paris, in which 32 patients with clinically negative nodes underwent FDG-PET. The specificity and PPV of PET were both 100%, but the sensitivity was only 20% and the negative predictive value (NPV) 59%. Like previous authors, these investigators concluded that sentinel node biopsy “can be avoided in patients with positive FDG-PET.” 22

So is routine FDG-PET warranted? Probably not, at least at present. In a multicenter prospective study of 360 women, if at least one probably or definitely abnormal focus of uptake in the axilla was the definition of a positive study, the mean sensitivity of PET was 61%, the mean specificity 80%, the mean PPV 62%, and the mean NPV was 79%. Falsely negative axillae had significantly smaller and fewer tumor-containing nodes than correctly positive axillae: 2.7 vs 51. The authors concluded that “FDG-PET is not routinely recommended for axillary staging of patients with newly diagnosed breast cancer.” 23

To avoid radioisotopes, Minato and associates assessed the accuracy of three-dimensional CT lymphography with subcutaneous injection of 1 mL of iopamidol in stage T1 or T2 breast cancer. The sentinel lymph node was identified in 13 of the 15 cases. 24 In another series, multidetector CT lymphography was used to direct sentinel node biopsy in 17 patients with operable breast cancer. All sentinel nodes could be localized. This Japanese team suggested that preoperative CT lymphography “may be useful for the direction of breast [sentinel lymph node] biopsy.” 25

SURGICAL PLANNING

Patient demand for minimal resection of breast cancer has forced radiologists to try to obtain more accurate pictures of the nature and extent of a tumor than may be possible with mammography.

Sonography may be an option. In 111 consecutive patients with palpable tumors, ultrasonography was significantly more accurate than clinical measurement in determining the size of small tumors (< 3 cm), but both methods tended to underestimate tumors > 3 cm. However, ultrasonography was rated adequate for selecting primary therapy. 26 In another series of 544 symptomatic women, ultrasonography was 92% accurate in depicting the 488 invasive lesions and 85% accurate in demonstrating the 65 intraductal lesions. 27 Park and colleagues, who evaluated 19 consecutive patients with tumors 1 cm or smaller, found ultrasonography excellent for detecting small satellite lesions in the ipsilateral or contralateral breast and suggested that the study has “an important role in the preoperative evaluation of patients for whom breast-conserving surgery is planned.” 28

Nevertheless, routine sonography may not be appropriate. Of 1,385 women with known cancers studied at the Lynn Sage Breast Center at Northwestern University, only 2.8% had their planned management changed as a result of ultrasonography findings. Changes were more likely in younger women and those with higher-grade tumors. 29

Another possible option for determining the extent of the primary tumor is MRI. Of 267 patients with known invasive breast cancer, the planned management in 26% was altered by the results of this study. Changes were more common in women with lobular carcinomas than in those with ductal tumors: 46% vs 24%.30 Similarly, Quan and colleagues reported that “MRI of the breast identifie[d] unsuspected multicentric or contralateral cancer” in 61% of patients with invasive lobular carcinomas. 31

One of the most comprehensive studies of imaging for surgical planning was carried out by Hata and colleagues, who performed mammography, ultrasonography, and dynamic contrast-enhanced MRI in 183 women. The latter study was by far the most sensitive in detecting intraductal spread, although it was less specific. “Magnetic resonance imaging appears indispensable in breast-conserving surgery to minimize local recurrence,” those investigators concluded. 32

Uematsu and colleagues used 3D CT to guide lumpectomy. Imaging guidance reduced the likelihood of positive margins from 42% to 21% and the occurrence of “massively positive” margins from 38% to 9%. “Among patients with positive margins, those with 3D-CT image-guided lumpectomy have less residual cancer” than those in whom the surgery is performed without such guidance, according to these authors. 33

NEOADJUVANT CHEMOTHERAPY

There is growing interest in FDG-PET or MRI to determine whether primary cancers are responding to chemotherapy so that surgery can be performed earlier. In 35 patients with locally advanced cancers, the mean metabolic rate, determined by FDG-PET and (15)O-water PET, showed a greater decline in the responding tumors at 2 months, although the difference was of only borderline significance. However, responding tumors demonstrated an average decline of 32% in blood flow compared with a 48% increase in nonresponding lesions, and the change in flow at 2 months predicted disease-free and overall survival. 34

In 26 women with locally advanced cancers, dynamic contrast-enhanced MR demonstrated two enhancement patterns. Two of the 14 homogeneously enhancing lesions demonstrated a pathologic complete response, and both had at least a 70% reduction in contrast enhancement on scans obtained after two cycles of chemotherapy. Similarly, both of the rim-enhancing lesions that showed a complete response had at least a 40% reduction in early contrast uptake after two cycles of chemotherapy. 35

A team from the NMR Center and Division of Breast Imaging at Massachusetts General Hospital and Harvard Medical School used functional MR imaging with measurement of the extraction flow product after neoadjuvant chemotherapy in 14 women with locally advanced breast cancer and found a difference between responding and nonresponding tumors. Certain of these analytical techniques “appear … to provide functional information” about changes in tumor angiogenesis that may be useful in measuring the chemotherapy response, these investigators concluded. 36

DETECTION OF RESIDUAL CANCER

Another use of imaging is for the detection of cancer remaining locally after irradiation or chemotherapy.

In a series of 72 patients who had undergone breast-conserving surgery and radiation, MRI produced only three false-positive results (biopsy yielding benign tissue), while it revealed residual or recurrent cancer in five irradiated breasts and two contralateral breasts. In the view of these investigators, radiation-induced changes, which may interfere with image interpretation, “are much less severe than reported.” 37 In 21 patients with locally advanced cancers who had received neoadjuvant chemotherapy, MRI showed a 0.75 correlation coefficient with the histologic findings, making it more accurate than physical examination. The imaging study underestimated the size of the residual tumor by > 1 cm in two patients, one of whom had a false-negative examination, and overestimated it by > 1 cm in seven. 38

A team of Japanese investigators used contrast-enhanced CT to help select candidates for breast-conserving surgery after neoadjuvant chemotherapy. In 11 consecutive patients with tumors 3 cm or larger, contrast-enhanced CT before chemotherapy predicted which tumors would eventually prove suitable for conservative resection. 39

DETECTION OF RECURRENCE

Finally, imaging is a cornerstone of monitoring for disease recurrence. Both MRI and FDG-PET have been used.

In a series of 32 patients with suspected local or regional recurrence or suspected contralateral cancer, PET was more sensitive than MRI (100% vs 79%), whereas MRI was more specific (94% vs 72%). The two studies were equally accurate (88% for MR vs 84% for PET), but PET had the advantage of finding metastases outside the MRI field in five patients. 40

A group of Swiss investigators imaged 60 patients with suspected breast cancer recurrence by FDG-PET and found the sensitivity, specificity, and accuracy to be 89%, 84%, and 97%, respectively, for locoregional recurrence and 100%, 97%, and 98% for distant metastases. 41 Importantly, PET was more sensitive than the serum tumor marker CA 15-3, and these radiologists concluded that PET “is a valuable tool in the follow-up of patients with breast cancer.”

Judith Gunn Bronson, MS, is a contributing writer for Decisions in Axis Imaging News.

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