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1 Department of Radiology, Boca Raton Community Hospital, 800 Meadows Rd., Boca
Raton, FL 33486.
2 Department of Biostatistics and Epidemiology, The Cleveland Clinic, Cleveland,
OH.
Received December 18, 2003;
accepted after revision August 2, 2004.
Address correspondence to J. I. Wiener
(JWiener{at}bocaradiology.com).
Abstract
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SUBJECTS AND METHODS. Contrast-enhanced bilateral breast MRI was performed prospectively on 65 patients with highly suspicious imaging findings (BI-RADS category 4 or 5). All enrolled patients were believed to be candidates for breast conservation on the basis of clinical examination, mammography, and sonography. The primary index lesion's characteristics, size, and extent were assessed. Also, additional lesions detected by MRI that could represent potential malignancies in both the ipsilateral and contralateral breast were evaluated. Morphologic assessment and kinetic analysis were performed on each lesion using dedicated postprocessing and display software. The patients were reevaluated as to whether they were still candidates for breast-conservation therapy after the MRI examination and subsequent biopsies.
RESULTS. There were 46 patients (71%) whose primary breast lesion (detected by mammography, sonography, or both) was found to be malignant (39 invasive breast cancers, five intraductal cancers, and two lymphomas). For the primary index lesions, the sensitivity for MRI was 100% (44/44) for predicting a breast malignancy and the specificity was 73.7% (14/19) for predicting benign lesions. MRI detected an additional 37 lesions, of which 23 were cancerous, beyond those suspected on mammography or sonography. One or more additional ipsilateral breast cancers were detected in 32% (14/44) of breast cancer patients and contralateral breast cancers in 9% (4/44) of the breast cancer patients. MRI also resulted in an incremental recommendation of mastectomy in 18% (8/44) of the pathologically confirmed breast cancer patients. MRI resulted in additional biopsy of only 14 benign lesions, six of which were shown to be atypical ductal hyperplasia.
CONCLUSION. When added to the standard evaluation of clinical examination, mammography, and sonography in patients thought to have early-stage breast cancer, contrast-enhanced MRI using both a kinetic and morphologic analysis will often result in changes in recommended patient management and better treatment planning and will result in no significant increase in biopsies of benign lesions. In addition, there is a significant detection rate of occult contralateral breast cancers.
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After a review of our experience and the literature, we decided that both morphologic and kinetic data must be assessed to maintain not only high sensitivity but also adequate specificity. Also, both breasts must be evaluated because of the high incidence of breast cancer, particularly in high-risk groups such as those with known or prior breast cancer. Breast cancers are known to show certain morphologic patterns including regional and ductal spread. Also, larger lesions and those with irregular borders are more likely to be malignant. On breast MRI, enhancing nodules are almost certainly malignant when they show early intense enhancement and progressive signal loss over time. Lesions that show less intense enhancement and less signal loss over time (washout) or those that have a signal that remains relatively constant over time can also be malignant and are therefore indeterminate, whereas lesions showing progressive enhancement over time are more likely to be (but are not always) benign.
In this study, we standardized the MRI parameters and the time points of the 3D bolus gadolinium acquisition similar to the three–time point (3TP) method [14] while maintaining high bilateral spatial resolution. Postprocessing of the data can yield color parametric maps allowing pixel-by-pixel kinetic analysis throughout the 3D data sets over multiple time points. This technique allows more accurate assessment of variations of kinetics within the lesions. The 3TP method using red–blue–green color mapping that emphasized the washout curves showed a relatively high specificity of 84% in individual lesions in a prospective study of unilateral breast imaging, although a diminished sensitivity of only 87% was obtained [12].
We sought to test the hypothesis that by implementing a combined analysis of both morphologic and kinetic MRI data with a different postprocessing algorithm using a different thresholding and color mapping, we could more accurately assess morphology and kinetics of lesions thought to be potentially malignant on mammography or sonography. This would allow a more accurate assessment of lesions as to their likelihood of cancer as well as their size and extent. We also sought to assess the frequency of additional malignant lesions in the breast of interest and in the opposite breast and how often these findings would significantly impact patient management including biopsy and surgical treatment planning.
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Patients and Inclusion Criteria
A total of 515 patients were found to have indeterminate lesions on
mammography, sonography, or both (category 4 or 5 BI-RADS classification
scheme [15]) between April 23,
2001, and April 26, 2002. Of this group, 392 patients with one or more
potential malignant lesions were also thought to be candidates for
breast-conservation therapy on the basis of the size and extent of the lesion
or lesions and the patient's preferences. A total of 67 women (mean age, 56.6
years; SD, 13.3 years; range, 30–82 years) agreed to be enrolled in this
study during that time period. One patient in the study had bilateral
suspicious lesions on mammography, and one patient refused to subsequently
undergo the MRI examination because of claustrophobia.
Of the 65 patients who underwent MRI, 18 had indeterminate microcalcifications and the remaining 47 had discrete masses. Seventeen patients had lesions thought to 1 cm or smaller; 32 patients, 1–2.0 cm; and 16 patients, greater than 2 cm. Twenty-eight of the 65 patients had predominantly or entirely fatty breasts (BI-RADS category 1 or 2), and the remaining 37 patients had heterogeneously dense or extremely dense breasts (BI-RADS category 3 or 4) on mammography. All patients signed informed consent in compliance with the institutional review board at our hospital. MRI was performed within 2 weeks of the initial lesion detection and during the first 2 weeks of the menstrual cycle in premenopausal patients.
Any patients thought to have cancers larger than 5 cm, to have multicentric disease (i.e., in more than one quadrant), to not be a candidate for radiation therapy, or to have a small breast compared with lesion size (i.e., cosmetic outcome thought to be unacceptable) were excluded from the study.
Final patient management recommendations and individual lesion characterization were based on imaging-guided biopsy, excisional biopsy, or follow-up for at least 2 years. Follow-up consisted of mammography, sonography, and MRI at intervals of 6 months for the first 2 years. All lesions thought to be possibly malignant by any of the imaging techniques underwent biopsy (even if thought to be clearly benign on MRI) unless the lesion could not be localized or the patient refused.
Breast MRI Technique
Imaging was performed on a 1.5-T whole-body system (Symphony with quantum
gradients using a bilateral CP 4 channel breast array coil, Siemens Medical
Solutions). An IV angiocatheter, 22-gauge or greater if possible, was placed
into an antecubital fossa vein and connected to a power injector (model
SDU200, Medrad) before the patient was placed in the prone position in the
breast coil within the magnet. No compression plates were applied to the
breasts during diagnostic imaging.
The imaging protocol consisted of an initial rapid gradient-echo scout localization sequence acquired in all three orthogonal planes through both breasts. Noncontrast sequences of the two breasts, axilla, and chest wall included a turbo STIR coronal sequence (20 sections; each section, 4 mm and skip, 1 mm; 340-mm field of view; TR/TE, 6,000/36; inversion time, 150 msec; turbo factor, 7; matrix, 256 x 256; and 1 acquisition) and a turbo T2-weighted axial sequence (24 sections; each section, 4 mm and skip, 1 mm; 340-mm field of view; 4,250/139; turbo factor, 7; matrix, 256 x 256; and 1 acquisition).
After the initial precontrast sequences, the patient was reinstructed to remain perfectly still for the dynamic 3D fast low-angle shot contrast-enhanced series performed using the following parameters: radiofrequency spoiled gradient-echo; no fat suppression; five measurements (series); 80 sections; each section, 5 mm interpolated to 2.5-mm intervals; matrix, 317 x 512; 340-mm field of view; 10/4.5; flip angle, 25°; and 1 acquisition (measurement). The scanning time was 2 min 39 sec per series time point. The first time point was acquired before contrast administration. During a subsequent pause of 30 sec, a single dose of gadopentetate dimeglumine (0.1 mmol/kg, Magnevist, Berlex) was injected at a rate of 2 mL/sec and was immediately followed by a 20-mL normal saline flush injected at a rate of 1 mL/sec. Series 2–5 were then acquired sequentially with no interscan delays. The resulting total imaging time for the dynamic series was 13 min 43 sec. Centric spatial encoding was used for all sequences.
Postprocessing of the Data
The image data were than transferred to a softcopy reading station (MTJADE,
Mevis Technologies) running in Windows 2000P (Microsoft) with MTDYNA software
(Mevis Technologies)
[16–18].
The raw data dynamic 3D series images were then automatically postprocessed
yielding whole-volume and moving slab maximum intensity projection (MIP),
image subtraction, and color parametric maps of the relative changes in each
pixel's signal intensity over time overlaying the raw image data.
Three time points were used to determine the color coding: the precontrast,
first postcontrast (arterial phase), and final time point (equilibrium phase).
Enhancement of the initial postcontrast time point relative to the baseline
precontrast time point (relative wash-in) determined an initial color category
(yellow, > 200%; red, > 100%; blue, > 50%; no color, 
50%). The
final displayed colors (total of nine hues, three within each primary color
category) for each pixel overlay were determined by the signal of the last
time point relative to that of the arterial phase: continuing rise in signal
or plateau (< 20% change from the pre-contrast time point signal) versus
declining signal (reflecting a relative washout) (Figs.
1A,
1B,
1C,
1D, and
1E). The software also allowed
interactive single-pixel and region-of-interest signal intensity measurements
with the corresponding signal intensity curves for confirmation and closer
interrogation and magnification of lesions.
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Correlative Imaging Studies and Clinical Information
All patients initially underwent bilateral diagnostic mammography with spot
and magnification views as indicated. Targeted high-frequency sonography of
the primary lesion was used to further characterize the morphology, size, and
extent. Sonography was not routinely used to screen for other suspicious
lesions within either breast. However, additionally, detected lesions on
sonography were recorded.
Patients thought to have malignancies were referred to breast surgeons for consultation and physical examination. Those patients who were thought to possibly have early-stage breast cancer and to be candidates for breast-conservation therapy were offered bilateral contrast-enhanced breast MRI at no additional charge. All patients signed informed consent under the guidelines of our institutional review board and were counseled as to the possibility of MRI detecting other suspicious lesions resulting in additional imaging studies and procedures.
All of the clinical and imaging data were available to the radiologists at the time of the breast MRI interpretation.
Data Analysis
Each patient and each individual lesion were initially assessed with
mammography and sonography by one of two board-certified radiologists
specializing in breast disease. Each lesion was characterized as benign
(BI-RADS category 1, 2, or 3) or suspected malignant (BI-RADS category 4 or
5). Lesion morphology, maximum lesion size dimension, and extent were
recorded. The breast parenchyma on mammography was also characterized as to
density, again using BI-RADS criteria—fatty or scattered densities (1 or
2) versus heterogeneously or extremely dense (3 or 4).
Each patient and individual lesion were reassessed at the time of the MRI interpretation by one board-certified radiologist with additional training and experience in mammography, breast sonography, and MRI in the same fashion as described earlier using BI-RADS classification. No interobserver statistical analysis was performed. Additional lesions detected in either breast were also assessed in terms of morphology, size and extent, and enhancement kinetics. Lesion morphology was assessed using the following criteria: maximal lesion size; well-circumscribed, round, or lobular versus irregular; and distribution (focal vs branching, regional, or clumped).
Each lesion's kinetic characteristics were assessed by the color overlays. Colors that extended over an area of at least 4 pixels were considered to represent a significant portion of the lesion and assumed not due to motion artifact. The most malignant color within each lesion determined the category to which the lesion belonged. For example, if the lesion showed predominantly progressive enhancement on later time points with initial enhancement of greater than 200% to the precontrast time point (displayed in orange) but also contained regions of relative washout on the last time point (displayed in yellow), the lesion overall was considered to show washout (i.e., considered a probable malignancy). Progressive enhancement was defined as a relative increase of greater than 20% in signal between the first postcontrast time point and the last time point. A relative loss of signal between the first postcontrast time point and the last time point of greater than 20% was defined as declining enhancement—that is, as washout.
Lesions were classified as malignant on MRI if they met the criteria for one of the following three groups. The first was discrete lesions greater than 3 mm with initial enhancement within portions of the lesion greater than 200% and areas of persistent or declining enhancement (contained bright yellow or intermediate yellow regions [Figs. 1A, 1B, 1C, 1D, and 1E]) or initial enhancement of the lesion greater than 100% with declining signal intensity on subsequent time points (displayed as pink). The second was irregular lesions greater than 7 mm and initial enhancement within portions of the lesion greater than 200%, with or without washout. The third group was lesions with asymmetric branching or regional areas of enhancement of greater than 200%.
After MRI interpretation, the size and extent of the primary index lesion and any additional lesions' sizes were conveyed to the patient's breast surgeon. The patient was then referred back to the women's center affiliated with our hospital for imaging-guided biopsy. Retrospective targeted sonography and targeted diagnostic mammography when also indicated were performed on all lesions considered suspicious (BI-RADS category 4 or 5) by any of the imaging techniques, including those initially detected only by MRI. Suspicious lesions that could be definitively identified on sonography subsequently underwent biopsy under sonography guidance. Indeterminate microcalcifications and suspicious lesions better seen on mammography were biopsied under X-ray stereotactic guidance (MammoTest Select Breast Biopsy System, Fischer Imaging). All the cases were biopsied with an 11-gauge needle and a handheld device (Mammotome, Ethicon Endo-Surgery). Those lesions detected by MRI that could not be definitely located on sonography or mammography even in retrospect were followed with serial imaging studies at intervals of 6 months for at least 2 years. An MR-guided localization and biopsy coil were not available at the time of the study.
Treatment recommendations (breast conservation vs mastectomy, lesion excision vs 6-month imaging follow-up) were then given to each patient by their breast surgeon. Histologic analysis of each lesion and lesion size and extent on surgical specimens (when possible after the previous biopsy) were compared with the predictions of the imaging techniques.
Statistical Methods
Only lesions that had definitive histology were included in the statistical
analysis. For the primary lesions (detected initially on mammography,
sonography, or both), we calculated the sensitivity (defined as a BI-RAD score
of 4 or 5 for a biopsy-proven malignant lesion), specificity (defined as a
BI-RAD score of 1, 2, or 3 for a biopsy-proven benign lesion), and receiver
operating characteristic (ROC) curve for MRI. The nonparametric estimate of
the area under the ROC curve
[19] was computed because
parametric algorithms could not fit the data. Asymptotic 95% confidence
intervals (CIs) were constructed for each measure of accuracy; the rule of
three [20] was applied for
constructing the CI for sensitivity because the estimated sensitivity was
1.0.
For the secondary lesions detected by MRI, we calculated sensitivity, specificity, and area under the ROC curve for MRI using the same definitions described earlier. Methods to handle multiple lesions from the same patient [21, 22] were used for constructing CIs.
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There were 54 secondary lesions with a pathologically confirmed diagnosis: 23 cancers and 31 noncancers. Combining primary and secondary lesions, the sensitivity of MRI was 68/69 (0.986) with a 95% CI of 0.958–1.0. The specificity was 36/50 (0.720) with a 95% CI of 0.578–0.862. The area under the ROC curve estimated for all lesions (n = 119) was 0.898 with a 95% CI of 0.841–0.955.
A total of 118 lesions (primary and secondary) had pathologic analysis, and the distribution is given in Table 2. One primary index lesion (indeterminate calcifications), thought initially to be a BI-RADS category 4 lesion on mammography but later believed to be a BI-RADS category 3 lesion on the basis of its character and stability, remained stable for more than 2 years; the patient had refused biopsy. Another six lesions (three thought to be benign and three small contralateral malignancies) had follow-up for more than 2 years but were excluded from the statistical analysis. Accuracy results for the imaging techniques are given in Tables 3 and 4.
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MRI resulted in 11 patients undergoing biopsies of 14 benign lesions not detected by mammography or sonography. Six of those lesions were atypical ductal hyperplasia. On the other hand, MRI correctly predicted benign histology in 11 well-circumscribed nodules among the 14 primary benign lesions (three were indeterminate calcifications), and biopsy could have been avoided if those patients had not been enrolled in this study. An example of a benign lesion is shown in Figure 2.
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A total of 23 additional malignant lesions, including 21 breast cancers, were detected by MRI in this series of 44 patients with proven breast cancer. Additional malignant lesions in the same breast with the primary lesion (multicentric disease) were detected in 14 patients (32%) on MRI (Figs. 3A, 3B, 3C, and 3D). When combined with increased estimated lesion size, these findings resulted in eight (18%) of 44 of the pathologically confirmed breast cancer patients being excluded from recommendations for breast-conservation therapy. Four (50%) of these eight patients had predominantly fatty breasts. One of the patients elected to have segmental resection and had positive margins at pathologic analysis requiring a second operation (mastectomy).
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Contralateral malignancies were suspected in four (9%) of the 44 confirmed
breast cancer patients on MRI. One was proven malignant on biopsy. Three other
small lesions ( 8 mm) with typical malignant enhancement curves (rapid
washout) could not be definitively localized on sonography. All three patients
received adjuvant chemotherapy for their primary lesions after lumpectomy. On
follow-up MRI examinations, the contralateral lesions had all disappeared.
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In our study, we used the principles of the 3TP method for data acquisition with high bilateral spatial resolution and a kinetic post-processing and display software package, thereby more effectively combining the assessment of lesion size, morphology, and enhancement kinetics to improve the specificity of MRI, while maintaining excellent sensitivity. We chose not to use fat suppression because we were performing bilateral examinations and fat suppression would not have been reliably homogeneous over the entire imaging volume. Also, we were concerned that because of variations in fat suppression over time, the kinetic curves could be significantly altered.
In our study, all lesions thought to be potentially malignant on any of the techniques underwent biopsy. The specificity of MRI in our series of patients in assessment of breast lesions could have allowed avoiding the unnecessary biopsy of many lesions previously detected by mammography or sonography, which had typical benign kinetic characteristics on MRI. Therefore, performing MRI using our methods in breast cancer diagnostic evaluations would not necessarily result in any incremental increase in the biopsy of benign lesions and in fact could lower the rate of biopsy of benign lesions.
The imaging parameters and time points of a dynamic bolus gadolinium data acquisition could be standardized for a multicenter trial. This would allow replication of this technique with different MRI equipment and pulse sequence parameters because the time points could be adjusted to maintain similar contrast enhancement characteristics.
Our soft-copy reading software performed automatic postprocessing, generated color parametric maps, and thereby allowed the radiologist to quickly detect and accurately characterize enhancing lesions. Most cases were interpreted in less than 5 min. Individual pixel signal intensity measurements and enhancement curves could be easily obtained from the raw data and could be correlated with subtracted and MIP images. Lesions showing only partial or regional malignant enhancement curves were correctly diagnosed as malignant in our study. Prior published studies likely suffered from region-of-interest sampling errors [10], because breast cancers are known to be pathologically heterogeneous. This would help explain why our method allowed a higher specificity over those previously published methods emphasizing kinetic analysis.
Also, unlike the published 3TP method of kinetic analysis using a red–green–blue color overlay display [12, 14], which emphasizes the relative signal washout over time, the initial relative enhancement on both the first time point and the later time points was more equally weighted in our kinetic analysis color parametric mapping method. This would explain the increased sensitivity over the published 3TP method. For these reasons, we believe that our methods do allow a more rapid and accurate breast MRI interpretation.
There are several limitations in our study. First, we assessed only a relatively small number of patients and could not localize and biopsy all the suspicious smaller lesions including three typical small cancers with malignant enhancement curves in the contralateral breast and four benign-appearing lesions. We did not compare the ability of sonography with MRI to stage breast cancer [26, 27]. It is possible that sonography, which can be performed at a much lower cost, would have accuracy approaching that of MRI. However, sonography is generally thought to have poor specificity, is highly operator-dependent, and is therefore not currently used at most centers for breast cancer staging and screening.
For MRI interpretation, observers were not blinded to the results of other imaging examinations because MRI was performed as a diagnostic ancillary tool and not as a screening examination. Also, only one radiologist interpreted each case. We did not assess interobserver variability or reliability. This is, however, how breast MRI is generally used in clinical practice. The primary focus of this study was to determine the incremental value of performing breast MRI in breast cancer diagnosis and staging.
We could not and did not apply statistical analysis to lesion size at pathology compared with lesion size on mammography, sonography, and MRI because many of the lesions were small and had already been reduced in size or completely removed by the initial Mammotome biopsy before definitive surgical excision.
No motion-correction algorithm for image subtraction and kinetic analysis was available to us at the time of the study. Motion could have obscured or significantly altered the observed kinetics in smaller lesions. We now have a commercialized version of this software (DYNA-CAD, In Vivo), which can perform 2D and 3D rigid and elastic motion-correction algorithms. We plan to study whether these algorithms will improve the accuracy of breast MRI.
We also did not assess whether adding breast MRI examinations altered breast cancer patient outcomes. This would require a large prospective randomized trial with a significant subset of patients not having the MRI examinations. This study would be costly and take many years. Based on the large number of additional detected cancers on MRI in our series and the ability to obviate biopsy of benign lesions in many patients, we think that breast MRI performs a valuable role in evaluating patients with suspected breast cancer who are being considered for breast conservation.
A recently published study showed no difference in long-term survival between lumpectomy and mastectomy even though the patients in those studies did not have sophisticated preoperative imaging (sonography, MRI, or both) [28]. In another study, adjuvant radiation did decrease the local recurrence rate of breast cancer from 15% to 4% [29]. Because of the large number of additional cancers detected by breast MRI in our study, we suspect that radiation treatment and chemotherapy must destroy many of the additional cancers that breast MRI would detect if it were routinely used. Otherwise, recurrence rates should be higher.
Interestingly, we did detect many additional larger cancers that adjuvant therapy may not effectively eliminate. In addition, some patients will have recurrences and some ultimately will die of their breast cancer, despite what is thought to be early-stage breast cancer at initial diagnosis and adequate therapy. Perhaps some of these patients have occult cancers remote from the primary breast cancer in the same or opposite breast that metastasize before ever being detected. Performing breast MRI in known breast cancer patients may reduce the risk of recurrence or interval development of new breast cancers.
Our study population consisted of patients thought to potentially have breast cancer. As a result, a large percentage of the lesions were malignant with many invasive cancers. The accuracy of our MRI methods can therefore not be assumed for detection of early-stage cancer (e.g., ductal carcinoma in situ) or in a low-risk screening population. MRI will likely prove efficacious as a screening tool in difficult-to-image or high-risk populations such as gene carriers; patients with atypia, atypical ductal hyperplasia, or lobular carcinoma in situ on biopsy; patients with dense breasts; and those with a strong family history or a personal history of breast cancer. Although MR-guided needle localization is now available at some centers, quick and accurate MR-guided breast biopsy methods using instruments for removal of tissue samples adequate for reliable histology are necessary to minimize incremental costs associated with MRI screening for detection of occult lesions on mammography and sonography. We have now implemented MR-guided large-gauge-needle vacuum-assisted breast biopsy at our center, and we plan to perform a screening trial in high-risk patients using our described MRI methodology.
In summary, our study showed that breast MRI using a combined 3TP kinetic analysis and morphologic analysis detected many occult cancers and thereby altered and allowed more confident treatment planning. Our methods also yielded a high specificity and did not result in a significant incremental increase in biopsy of benign lesions. We believe that future prospective multicenter trials should further evaluate the relative roles of high spatial resolution, morphologic assessment, and kinetic analysis in determining the accuracy of breast MRI as a staging technique in patients with breast cancer. Also, standardization and implementation of computer-aided diagnosis algorithms will prove helpful. Breast MRI is now clinically accepted and routinely used by the local breast surgeons and oncologists in our region for preoperative breast cancer staging regardless of breast density on mammography.
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