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Breast Imaging |
1 From the Departments of Clinical Oncology, Medical Physics Division (D.K.W.Y.), Diagnostic Radiology and Organ Imaging (H.S.C.), and Anatomical and Cellular Pathology (G.M.K.T.), Prince of Wales Hospital, 30-32 Ngan Shing St, Shatin, Hong Kong, China. Received July 25, 2000; revision requested September 13; final revision received January 4, 2001; accepted January 11. Address correspondence to D.K.W.Y. (e-mail: dkyeung@hkstar.com).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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MATERIALS AND METHODS: Examinations were performed at 1.5 T with use of a standard breast coil. Contrast-enhanced MR imaging was performed in 30 consecutive patients (mean age, 50 years; age range, 20–80 years) who had nonspecific lesions (>1.5 cm in diameter) on sonograms or mammograms. Single-voxel 1H MR spectroscopy was performed in the enhancing lesions by using a point-resolved spectroscopic sequence with echo times of 38, 135, and 270 msec. MR spectroscopic and histopathologic findings were determined in blinded fashion and compared.
RESULTS: Twenty-four patients had carcinoma of the breast (tumor size, 2.0–11.2 cm; mean, 4.7 cm), and six had benign lesions (lesion size, 1.8–3.8 cm; mean, 2.7 cm). Choline was detected in 22 patients with carcinoma. Choline was not detected in five patients with benign lesions and in two patients with carcinoma. The preliminary results indicate that this technique had a sensitivity of 92%, specificity of 83%, and accuracy of 90%.
CONCLUSION: Choline can be reliably detected in less than 45 minutes in large contrast-enhanced breast lesions by using a multiecho point-resolved spectroscopic protocol. The presence of water-soluble choline metabolites obtainable with 1H MR spectroscopy could complement MR imaging findings to improve specificity and to reduce the number of unnecessary biopsies.
Index terms: Breast neoplasms, diagnosis. 00.31, 00.32 • Magnetic resonance (MR), contrast enhancement, 00.12143 • Magnetic resonance (MR), spectroscopy, 00.121411, 00.121413, 00.121415, 00.12143, 00.12145 • Metabolism, 00.59
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Recent studies of in vitro (9–11) and in vivo (12–15) 1H MR spectroscopy of the breast have shown high levels of choline-containing compounds at 3.2 ppm in malignant lesions but low levels in normal breast tissues and benign lesions. Roebuck et al (12), using a stimulated-echo acquisition mode, or STEAM, sequence to obtain absolute concentration measurements in contrast-enhanced lesions, found choline in seven of 10 patients with malignant lesions and no choline in six of seven patients with benign lesions. They had only one false-positive finding, which was in a patient with a rare benign tubular adenoma.
However, in a recent study by Kvistad et al (13) who used a precontrast acquisition strategy and a detection method based on the presence of choline with use of a point-resolved spectroscopic (PRESS) sequence, choline was found in nine of 11 carcinomas and two (one fibrocystic disease and one fibroadenoma) of 11 benign lesions. Differences in the number of false-positive and false-negative findings in these studies may be due to the effect of contrast agents on the detection of choline (16), the lower signal sensitivity of the stimulated-echo acquisition mode sequence compared with that of the PRESS sequence (17), and the use of different custom-built breast coils.
Detection of choline with absolute measurement methods (12,18) requires an external standard because neither fat nor water can be used as an internal reference. When an external standard placed near the breasts is used, variations in signal amplitudes measured in lesions and the reference due to magnetic field inhomogeneities may lead to uncertainties in the concentration estimation (19). In addition, the performance of a combined MR imaging and spectroscopic examination with an absolute concentration protocol requires an average imaging time of 75 minutes (12), making the procedure clinically unattractive. In comparison, the acquisition strategy and detection method described by Kvistad et al (13), with use of the PRESS sequence, is more sensitive and requires a shorter imaging time (45 minutes). However, correct positioning of the volume of interest in suspicious lesions is more difficult without image guidance provided by contrast-enhanced MR imaging. Together, findings of these in vivo studies indicate that the clinical role of in vivo 1H MR spectroscopy is still unclear, and further investigation is necessary.
The aim of the present study was to examine whether in vivo detection of choline by using 1H MR spectroscopy performed with contrast-enhanced MR imaging could help in the differentiation of benign and malignant breast lesions.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The examinations were performed with a 1.5-T whole-body MR imaging system (Gyroscan ACS-NT; Philips, Best, the Netherlands). A standard receive-only double-breast coil covering both breasts was used for both MR imaging and MR spectroscopy. The patients were examined in the prone position with the breasts suspended in the breast coil. The body coil was used as the transmitter to generate a homogeneous B1 field over the sensitive volume of the breast coil.
MR imaging was performed in the transverse and sagittal planes. Transverse images were obtained by using a T1-weighted spin-echo sequence (repetition time msec/echo time [TE] msec, 450/12; 4-mm section thickness with no gap; field of view, 350 mm; 256 x 256 matrix; two signals acquired) with spectral presaturation with inversion recovery for fat saturation. This sequence required approximately 5 minutes. Thirty transverse images covering the whole breast were obtained before administration of contrast material. After the patient was given a bolus intravenous injection of gadopentetate dimeglumine (Magnevist; Schering, Berlin, Germany), 0.2 mmol per kilogram of body weight, a contrast-enhanced transverse MR image was acquired. Image subtraction was then performed to show enhancing lesions on the subtracted images. Contrast-enhanced sagittal images were obtained in the affected breasts by using a T2-weighted turbo spin-echo spectral presaturation with inversion recovery sequence (2,000/100; 4-mm section thickness with 10% gap; 256 x 256 matrix; three signals acquired; imaging time, approximately 4 minutes).
By using the PRESS sequence (2,000/38, 2,000/135, and 2,000/270), three water-suppressed spectra were acquired for each volume of interest 15–20 minutes after the administration of contrast material for MR imaging. The radiologist (H.S.C.) carefully positioned the volume of interest (mean volume, 11.4 cm3; range, 1–95 cm3) within the enhancing breast lesions, as demonstrated on the subtraction images. Automated parameter optimization consisted of frequency and receiver gain adjustment, shimming, and gradient tuning. Water suppression was achieved with selective inversion recovery, starting the measurement at the zero-crossing of the water signal. Data were acquired at a spectral bandwidth of 1,000 Hz, and 64 signals were averaged for each water-suppressed spectrum to achieve an adequate signal-to-noise ratio. The time required to complete the MR spectroscopic examinations was approximately 20 minutes.
All MR spectra were analyzed with the time domain–fitting routine variable projection, or VARPRO, method (20) implemented with the MR user interface, or MRUI, software package (A. van den Boogaart, Katholieke Universiteit Leuven, Belgium; available at www.mrui.uab.es/mrui.mruiHomePage.html) (21). Residual water was first removed by using the Hankel-Lanczos singular value decomposition (HLSVD) (22) method to obtain a reduced free-induction decay that is completely free from water signal. The resonance frequency and line width of choline were selected manually; these values were used as the prior knowledge input in the fitting process. The criterion used to determine whether or not was present in a lesion was that the peak at 3.2 ppm should be clearly identifiable in at least two of the three spectra acquired at different TEs.
Histopathologic diagnoses of suspicious lesions seen on contrast-enhanced MR images were established with mastectomy in 15 patients, hook-wire–guided excision in one, core biopsy with a 16-gauge Monopty needle (C. R. Bard, Covington, Ga) in nine, and fine-needle aspiration cytology in five. Tissue samples were collected by one radiologist (H.S.C.), and histopathologic examinations of samples were performed by one pathologist (G.M.K.T.). Both the radiologist and the pathologist were double-blinded to the MR spectroscopic measurements performed by the physicist (D.K.W.Y.).
The MR spectroscopic results were compared with histopathologic and surgical information. True-positive, true-negative, false-positive, and false-negative detection rates, as well as sensitivity and specificity, were determined.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Six patients had benign lesions, including three fibrocystic changes, one fibroadenoma, one papilloma, and one hamartoma. The mean size of these lesions was 2.7 cm (range, 1.8–3.8 cm). The Table summarizes the MR spectroscopic and histopathologic findings of the contrast-enhanced breast lesions in the 30 patients. In 22 patients with carcinoma, a resonance at 3.2 ppm attributed to a choline-containing compound was detected. In five of the six patients with benign lesions, no choline signal was detected. Choline was found in one benign lesion (fibroadenoma), and choline was not detected in two malignant lesions (one infiltrating ductal carcinoma and one medullary carcinoma). Eighteen of the 23 positive choline findings were made based on the spectra with all three TEs, and the remaining five positive findings were based on two TEs. All seven negative choline findings were confirmed on the basis of the absence of any identifiable signal in the 3.2-ppm region above the baseline noise on the spectra with all three TEs.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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We had only one false-positive result (Fig 2a) among the six benign lesions found in our patients. It is unclear why this fibroadenoma had a detectable choline level above those of other benign lesions. Kvistad et al (13) also reported the in vivo detection of choline-containing compounds in a fibroadenoma. In addition, Mackinnon et al (9), in an ex vivo 1H MR spectroscopic study of fine-needle breast biopsy specimens, found that three of the 15 fibroadenomas contained detectable levels of choline. The dissimilar spectral pattern of the two fibroadenomas shown in Figure 2a could not be explained in terms of acquisition differences, as both spectra were obtained by using the same voxel size and imaging protocol. One possible explanation lies perhaps in the age difference of the patients. The patient (patient 10) with the false-positive choline level was 20 years old, and the other patient (patient 2) was 42 years old. Choline was detected at the time when an increase in lesion size was documented on consecutive US scans obtained about 21 months apart. Her repeat MR spectroscopic examination performed a year later was negative for choline, while the lesion was shown to be static in size and less hyperintense on T2-weighted images. The absence of the choline peak at the second MR spectroscopic study might thus be a reflection of reduced metabolic activity within the lesion or of reduced cellularity. This remains speculative because excision of the lesion was not performed; histopathologic findings were not available because the patient refused biopsy, the benign diagnosis had been determined with only fine-needle aspiration cytologic evaluation. Fine-needle aspiration cytologic evaluation is not helpful for preoperative diagnosis because of the substantial number of cases in which insufficient tissue is obtained and because of the considerable number of false-negative results (25).
The number of false-negative results in our study was lower than the numbers reported by Roebuck et al (12) and Kvistad et al (13). However, due to the small population in each study, there were insufficient data to test whether these differences were significant. One of the two malignant lesions with no detectable choline (Fig 3a) was a medullary carcinoma, and it is unclear whether the absence of choline observed is in any way related to the prognosis of this variant of ductal carcinoma. The medullary carcinoma was diagnosed on the basis of the established histologic criteria of a rounded border, mononuclear cells infiltrate, lack of tubule component, a syncytial growth pattern, and necrosis of less than 25% of the tumor area. Medullary carcinoma has been shown (26,27) to possess a better prognosis and survival than ductal carcinoma. Although the underlying mechanism remains unknown, the high rate of apoptosis in medullary carcinoma has been suggested to contribute to the better prognosis (28). This may account for the false-negative choline uptake in our case. No satisfactory explanation could be found for the false-negative result in one patient (patient 11) with invasive ductal carcinoma, but misregistration artifacts seen on her subtraction MR image (Fig 3c) suggest that patient motion might be a factor.
We did not include healthy subjects in this study because it is well-documented that choline-containing compounds are not detectable in vivo in the normal breast by using 1H MR spectroscopy at 1.5 T (13–15). The choline resonance at 3.2 ppm detected in vivo in breast cancer lesions is most probably phosphocholine, as high-spectral-resolution in vitro studies (10,11,29) have clearly shown. Phosphocholine is known to accumulate 16–27 times more in breast cancer cell lines than in normal mammary epithelial cells (30,31). Together, these results strongly support the argument that choline may serve as a metabolic marker for human breast malignancy. However, a recent report by Kvistad et al (13) showed that choline could also be detected in volunteers who were breast-feeding, raising the possibility that choline is an indicator of high metabolic activity rather than a marker of malignancy. Given the limited spectral resolution achievable with in vivo 1H MR spectroscopy at 1.5 T, it is impossible to identify the relative contributions of phosphocholine and free choline in the broad resonance seen at 3.2 ppm (Fig 1). Chao et al (32), in their work on the uptake of choline by mammary-gland epithelial cells of lactating rats, showed that most of the choline that was taken up by the cells was in the form of free choline.
The water-fat ratio (15) was not used in our analysis, since recent reports (12,13) have shown that this ratio is not useful for the characterization of breast lesions. The presence of broad and intense fat signals, however, represents a challenge to the correct identification of choline with short-TE spectra of the breast (Fig 1). In addition, patient motion during data acquisition may also cause a decrease in signal intensity because of signal averaging of spectra acquired with different phases. The multiecho acquisition strategy described in this work may partially overcome the effect of patient motion, as detection was made on the basis of evidence obtained from more than one spectrum. A more elegant method was recently described by Star-Lack et al (33), whereby both motion correction and lipid suppression are incorporated into a PRESS-based localization sequence for body 1H MR spectroscopy. The in vivo breast MR spectroscopic illustrations from their work are promising, and the future clinical application of their new sequence remains to be seen.
Early detection of breast cancer is the key to improving patient outcome. The ability to acquire reliable spectra from smaller breast lesions (<1 cm3) identified on contrast-enhanced MR images would probably improve the diagnostic value of in vivo 1H MR spectroscopy. One limitation of this study was that most spectra were acquired by using a nominal voxel volume of 3.4 cm3, as our prestudy test have shown that the signal-to-noise ratio was unacceptably low when a 1-cm3 voxel volume is used. The double-breast coil available with our imager and used in this study is not as sensitive as the single-breast coil, as a smaller coil volume has a better filling factor.
Another limitation of this study was the relatively small patient population— in particular, those with benign lesions. Most of the patients selected were referred to MR imaging with lesions previously detected with either mammography or US. This may reflect the large lesion size found in our patients, and the artificially higher incidence of malignant lesions. The sensitivity and specificity results in this study are preliminary and can be applied only to breast lesions larger than 1.5 cm in diameter. It is beyond our capacity in the present study performed at 1.5 T to predict the usefulness of the technique to detect choline in smaller breast lesions by using MR imaging systems with higher field strengths.
In conclusion, our results demonstrated that choline can be reliably detected in contrast-enhanced breast lesions in vivo by using a multiecho PRESS acquisition method. Using the presence of choline at 1H MR spectroscopy to test for breast cancer in 30 patients, we found a sensitivity of 92%, specificity of 83%, and an accuracy of 90%. The additional information provided by 1H MR spectroscopy may complement other investigations, such as signal intensity time-course data (5,6) and high-spatial-resolution contrast-enhanced MR imaging (7), to improve the diagnostic specificity of the MR examination. This could lead to a reduction in the number of unnecessary biopsies of benign lesions and an improvement in the treatment of patients with breast cancer.
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FOOTNOTES |
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Author contributions: Guarantors of integrity of entire study, H.S.C., D.K.W.Y., G.M.K.T.; study concepts, H.S.C., D.K.W.Y.; study design, D.K.W.Y.; literature research, D.K.W.Y.; clinical studies, H.S.C., G.M.K.T., D.K.W.Y.; data acquisition, D.K.W.Y., H.S.C., G.M.K.T.; data analysis/interpretation, D.K.W.Y., H.S.C.; statistical analysis, D.K.W.Y.; manuscript preparation, D.K.W.Y.; manuscript definition of intellectual content, D.K.W.Y., H.S.C.; manuscript editing, H.S.C., G.M.K.T.; manuscript revision/review, D.K.W.Y.; manuscript final version approval, D.K.W.Y., H.S.C., G.M.K.T.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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