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Nuclear Medicine |
1 From the Department of Radiology, Duke University Medical Center, Room 24244b, Hospital South, Durham, NC 27710. From the 2003 RSNA Annual Meeting. Received April 12, 2004; revision requested May 18; revision received August 3; accepted August 26. Supported by DOD Concept Award DAMD17–01-1–0517. Supported in part by the Office of Biological and Environmental Research of the Office of Science of the U.S. Department of Energy. Address correspondence to E.L.R. (e-mail: eric.rosen@duke.edu).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTS DISCUSSIONREFERENCES |
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MATERIALS AND METHODS: Institutional review board approval was obtained for this study, and all patients provided written informed consent prior to participation. Subjects were recruited from a cohort of patients in whom diagnostic mammography and/or ultrasonography demonstrated lesions that were highly suggestive of malignancy. Twenty-three patients who met the inclusion criteria were subsequently imaged by using a dedicated PET mammography unit that was developed in conjunction with the Thomas Jefferson National Accelerator Facility (Newport News, Va). One hour after administration of 2.0–2.5 mCi (74.0–93.5 MBq) of fluorodeoxyglucose, 5-minute PET mammography of the affected breast was performed. Images were processed and reconstructed in the transverse craniocaudal and coronal planes. For each lesion, image-guided core-needle biopsy was performed immediately after PET mammography. Conventional mammography results and histologic findings were correlated with PET mammography images. The sensitivity, specificity, negative predictive value, and positive predictive value of PET mammography for demonstrating malignant lesions were calculated.
RESULTS: PET mammography demonstrated 20 focal abnormalities, of which 18 were malignant and two were benign. Both benign lesions represented areas of fat necrosis. Three of 20 malignant lesions demonstrated at conventional mammography were not demonstrated at PET mammography. The overall sensitivity of PET mammography for malignancy was 86% (95% confidence interval: 65%, 95%), with a positive predictive value of 90% (95% confidence interval: 70%, 97%). The calculated specificity was 33% (95% confidence interval: 2%, 79%), and the negative predictive value was 25% (95% confidence interval: 1%, 70%).
CONCLUSION: These pilot data suggest that PET mammography can demonstrate small primary breast malignancies.
© RSNA, 2005
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS DISCUSSIONREFERENCES |
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Although imaging studies performed with whole-body PET imaging scanners have established the feasibility of using FDG PET to identify and characterize breast malignancy, findings from these same studies also highlight the limitations that are inherent in currently available PET imaging techniques. Specifically, whole-body PET scanners have a limited ability to depict small lesions, and breast abnormalities that are demonstrated with these scanners can be difficult to localize anatomically. Moreover, whole-body PET is expensive, and, while the number of scanners is increasing rapidly, access to this modality, when compared with conventional mammography for example, is still limited nationwide.
Recently, PET imaging units have been developed exclusively for breast imaging in an attempt to overcome the limitations of whole-body PET for the depiction of breast cancer (9–12). Dedicated PET mammography units that can image positron-emitting tracers in the breast have several potential benefits over whole-body tomography, including high sensitivity for the emitted radiation, improved spatial resolution, substantially reduced attenuation, and reduced cost (9–11,13,14). These dedicated units are also much more compact than conventional PET units and could be incorporated directly into a breast imaging facility, thereby making such units more readily available than whole-body PET units. The purpose of this pilot study was to prospectively assess a dedicated, large field of view PET mammography device for the imaging of primary breast carcinoma.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS DISCUSSIONREFERENCES |
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Study Population
Subjects were recruited from a cohort of patients who underwent diagnostic mammography and/or US at our institution and who demonstrated lesions that were highly suggestive of malignancy (Breast Imaging Reporting and Data System assessment category 5) (15,16). Patients with category 5 lesions were initially informed of the pilot study at the time of their diagnostic imaging examination. Patients who were interested in participating were formally contacted by the clinical coordinator, who explained the procedure in detail. If patients agreed to participate, PET mammography was scheduled for the same day immediately prior to core-needle biopsy. Patients who were younger than 40 years, who were pregnant, or who had a prior history of breast cancer or radiation to the ipsilateral breast were excluded from this study. During November 2002 to July 2003, 23 patients (mean age, 58 years; age range, 39–78 years) with 23 lesions who met the inclusion criteria and who had lesions that were highly suggestive of malignancy were subsequently imaged. These patients represented the study population. Six of 23 lesions were palpable at the time of diagnosis, and 17 of 23 were depicted at conventional mammography.
PET Mammography
A dedicated PET mammography unit that was developed in conjunction with the Thomas Jefferson National Accelerator Facility (Newport News, Va) was used for imaging (17). This system consists of two 15 x 20-cm planar detectors and 3 x 3 x 10-mm lutetium gadolinium oxyorthosilicate scintillator elements. The detectors are positioned above and below the compressed breast and are typically separated by 6–9 cm. The large angular coverage of the device not only yields good sensitivity but also allows full three-dimensional image reconstruction, which provides well-delineated transverse images that are created by using an iterative reconstruction algorithm.
Unlike whole-body PET imaging systems, devices such as the one used in our study have no accepted standards for measuring basic performance. By using a non–three-dimensional backprojection method with 1.5-mm image pixels, we measured a transverse spatial resolution of 4.1 mm. While iterative algorithms yield substantially better results, such algorithms result in a less objective measure. (For this reason, iterative algorithms are not used in the standard performance measures for whole-body systems.)
Ultimately, the spatial resolution of the final image and the resulting ability to depict small lesions depends largely on the number of counts obtained. Because of the excellent geometric sensitivity and the low photon attenuation factors of PET mammography (compared with whole-body imaging, in which only about 5% of photon pairs make it out of the body), it was determined that a 2.0-mCi (74.0-MBq) injected dose of FDG and an imaging time of 5 minutes would be appropriate for this system. This injection dose is low compared with doses used for whole-body examinations 1.0–2.0 mCi (37.0–74.0 MBq). There are also many benefits to being able to use such low doses, including cost and availability of the radiotracer and radiation exposure to the patient and technologists.
Approximately 2.0 mCi (74.0 MBq) represents a good maximum dose for this system in its current configuration; any higher amount can result in considerable count losses as a result of dead time and can yield diminishing returns. This system is used in conjunction with a conventional analog or full-field digital x-ray mammography unit (Fig 1). The compression paddle from the mammography unit provides mild compression against the lower PET mammography detector. However, substantially less compression is used with the PET mammography unit than with conventional mammography. The upper detector can be moved vertically toward or away from the lower detector to adjust for breast size and compression (Fig 2), and the PET mammography detector pair can be rotated to accommodate oblique views with the x-ray gantry. Finally, the entire gantry can be moved up and down by using a motorized control to adjust to the height of each patient.
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Image Interpretation and Comparisons
The reconstructed PET mammography images were all evaluated in conjunction with prior conventional mammography images by one experienced breast imaging radiologist (E.L.R.) to determine if the highly suggestive mammographic abnormality was demonstrated by PET mammography. For this study, only visually conspicuous foci that had increased FDG accumulation compared with that of the background at the site of the known lesion were considered a positive result; nonfocal or patchy regions of FDG activity were disregarded. Focal areas of increased FDG activity that were identified on both the transverse and coronal reconstructed images were used to spatially localize and correlate PET mammographic abnormalities with conventional mammographic abnormalities seen on craniocaudal and mediolateral oblique images. In addition, PET mammography images were also evaluated for other conspicuous yet incidental foci of increased FDG accumulation located within the ipsilateral breast in areas geographically distinct from the primary mammographic abnormality.
Conventional mammographic results and histologic findings were compared with PET mammography images by the same radiologist (E.L.R.). For each lesion, mammographic size was recorded at conventional mammography as the maximum lesion dimension. For mixed lesions (those composed of both a mass and microcalcifications), the mammographic size included measurements of both the mass and microcalcifications. The histologic size was defined as the single largest dimension of invasive carcinoma as was recorded in the pathology report. If ductal carcinoma in situ was present in addition to invasive carcinoma, the histologic size was recorded as the largest dimension as was stated in the pathology report. However, the ductal carcinoma in situ size measurement was not consistently reported, especially when ductal carcinoma in situ was present in addition to invasive carcinoma. This inconsistency resulted in several cases, such as those of mass lesions and associated calcifications, in which the mammographic lesion size was substantially larger than the histologic size.
All patients were initially evaluated with image-guided core-needle biopsy performed with either mammographic or US guidance. As is our standard practice, all biopsy results were reviewed in conjunction with imaging findings. Discordant benign core-needle biopsy findings were referred for surgical excision. Patients with concordant malignant histologic findings at core-needle biopsy were referred to a breast oncologist for further evaluation and consultation.
Lesion type (microcalcifications, mass, or architectural distortion), maximum dimension (mammographic and histologic), and histologic type were recorded for each lesion. For this study, PET mammography results were considered true-positive if focal areas of increased FDG activity were demonstrated at the site of the conventional mammographic abnormality during PET mammography or US and if the histologic results demonstrated either in situ or invasive malignancy. PET mammography results were considered false-positive if focal areas of increased FDG activity were demonstrated at the site of the conventional mammographic lesion during PET mammography but the histologic findings demonstrated a benign lesion. PET mammography results were considered false-negative if no increased FDG activity was demonstrated at the site of abnormality during PET mammography and if histologic findings revealed carcinoma. PET mammography results were considered true-negative if no lesion was demonstrated at the site of the abnormality during PET mammography and if histologic findings revealed a benign lesion. If other incidental foci of increased FDG accumulation were noted, these foci were evaluated, as appropriate, with additional diagnostic mammography, US, and US-guided core-needle biopsy.
Statistical Analysis
The mean size, standard deviation, and size range for all lesions were calculated on the basis of both mammographic and histologic appearance. In addition, the sensitivity, specificity, negative predictive value, and positive predictive value of PET mammography for demonstrating malignant lesions were calculated (Excel; Microsoft, Redmond, Wash).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS DISCUSSIONREFERENCES |
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Three of the 23 lesions were histologically benign. Of these three lesions, two (masses) were fat necrosis and one was a benign calcification present in fibrocystic changes. Both cases of fat necrosis were confirmed with findings from surgical excision after initial core-needle biopsy. The benign calcification was not surgically excised on the basis of subsequent review of radiologic and histologic findings, which suggested that the histologic findings were concordant with the imaging findings and that representative calcifications were retrieved and submitted to pathologic examination.
PET Mammography
In one patient, an unsuspected focus of increased FDG activity was demonstrated at a site distant from the known mammographic abnormality (Fig 3). To evaluate this patient further, diagnostic mammography and directed US were performed. At the site of the abnormality depicted at PET mammography, an 8-mm oval solid mass was demonstrated at US. Subsequent US-guided core-needle biopsy revealed a 4-mm noninvasive papillary carcinoma.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS DISCUSSIONREFERENCES |
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We enrolled a subset of patients with highly suspiscious mammographic abnormalities who were scheduled for image-guided core-needle biopsy. The 86% sensitivity of our device is similar to the reported sensitivities of both whole-body PET and other PET mammography units (1,10,12,18). In contrast to most other studies, however, which typically evaluated large and palpable abnormalities, our study evaluated cases in which the majority of lesions were 2.5 cm or smaller. In fact, our device demonstrated several lesions less than 1.0 cm in size, including an unsuspected 0.4-mm noninvasive papillary carcinoma in a patient with mammographically dense breasts who was scheduled to undergo biopsy in another quadrant of the breast. Our data suggest that the large field of view of this PET mammography device is capable of imaging small and, anecdotally, mammographically occult breast malignancy.
Despite multiple studies reporting both high sensitivity and specificity of whole-body FDG PET for breast imaging, whole-body FDG PET has not been incorporated into clinical breast imaging. Studies of whole-body PET typically include a large percentage of palpable and locally advanced malignancies, which are not representative of the types of lesions depicted at screening.
A meta-analysis evaluated 13 studies of whole-body FDG PET for the depiction of breast carcinoma and showed an overall sensitivity of 89% (79%–100%), a specificity of 80% (50%–100%), a false-negative rate of 12.1%, and a negative predictive value of 87.9% (18). The mean tumor size across the studies included in this meta-analysis ranged from 2 to 4 cm. Overall, the authors of this meta-analysis conclude that FDG PET with whole-body imaging should not be used clinically to determine the need for breast biopsy because of the unacceptable rate of false-negative findings, which would lead to a delay in the diagnosis of some cancers (18). The authors of this analysis also conclude that most of the studies omit a critical segment of patients—those with nonpalpable, mammographically depicted lesions (18). Although findings from these studies suggest both a high sensitivity and a high specificity of FDG PET imaging for breast cancer, these studies have limited clinical application because the lesions that were evaluated do not parallel the typical lesions that are depicted at imaging, nor do the lesions represent the type of lesion for which additional imaging information is likely to benefit diagnosis.
On the other hand, and despite limitations, whole-body FDG PET imaging has already demonstrated promise as a local staging modality for women recently evaluated for breast cancer. Reiber et al (8) evaluated 43 patients with biopsy-proved primary breast carcinoma by using conventional mammography, MR imaging, and conventional whole-body FDG PET. Of the 43 patients, 12 (28%) had ipsilateral multifocal malignancies, and three (7%) had contralateral occult malignancies that were confirmed with histologic findings. FDG PET correctly identified 28 unifocal, three bifocal, and six multifocal ipsilateral carcinomas and identified three of three contralateral malignancies. In that study (8), there was no statistically significant difference demonstrated between MR imaging and whole-body FDG PET; both modalities were shown to be superior to conventional mammography in their ability to accurately demonstrate the local extent of primary breast carcinoma and to depict otherwise occult contralateral malignancy.
Findings from previous reports evaluating FDG PET mammography have demonstrated both a high sensitivity and a high specificity for breast cancer. Levine et al (12) demonstrated an 86% sensitivity and a 91% specificity for 17 lesions evaluated with PET mammography. Murthy et al (10) reported an 80% sensitivity and a 100% specificity for 14 lesions evaluated with PET mammography. The 86% sensitivity is similar to the sensitivities reported for other PET mammography units. One important difference, however, is that we relied solely on visually conspicuous uptake as the sole indicator of abnormality. The other two studies used semiquantitative methods to detect abnormalities. In addition, our study design was different than the design of these two studies because we recruited only patients with lesions likely to be malignant; we also imaged the entire breast and not just the targeted lesion.
Although our design did not allow accurate determination of specificity, our goal was to determine the ability of PET mammography to depict primary malignancies. One indirect indicator of the high specificity of our unit, however, is the lack of false-positive incidental lesions observed during this pilot study. The main advantage of our PET mammography unit when compared with other units is the large field of view, which permits the entire breast to be imaged in a single acquisition. Our unit has a useful 15 x 20-cm field of view compared with the 6.5 x 5.5-cm and 5.6 x 5.6-cm field of view of previously reported PET mammography units (10,12). Our initial data suggest that our FDG PET mammography unit is at least as sensitive for malignancy as other PET mammography prototypes but that our unit has the advantage of having a large field of view, which permits evaluation of the whole breast in a single acquisition.
Several potential benefits and limitations of FDG PET mammography were demonstrated during this pilot study. We confirmed that our dedicated PET mammography unit is both sensitive for primary breast malignancy and capable of depicting small invasive and noninvasive malignant lesions. In fact, the unit demonstrated focal areas of abnormal FDG uptake in several lesions that were smaller than 1.5 cm, and in one patient we identified a mammographically occult 0.4-cm focus of noninvasive carcinoma located in a quadrant other than that of the index tumor. In this patient, the lesion was successfully identified with directed US and was sampled with core-needle biopsy. All malignancies in our study manifested as focal areas of increased FDG activity and were identified without the aid of quantitative assessment.
One potentially important, and not unexpected, limitation is that lesions located in the far posterior portion of the breast may not be successfully imaged. In our series, all three of 20 false-negative cases (15%) were from posteriorly located lesions. This finding is explained by both the smaller range of acceptable angles of coincidence for a lesion near the edge (vs the center) of the detector and the physical limitations imposed by the detector plates, which exclude far posterior lesions from the field of view.
Another potential limitation is false-positive FDG activity resulting from fat necrosis at sites of prior breast biopsy. Both of the false-positive cases that we encountered resulted from areas of fat necrosis, one at the site of a prior core-needle biopsy and another at the site of an excisional breast biopsy.
In summary, these pilot data suggests that PET mammography is capable of demonstrating primary breast malignancies and can be performed in the breast clinic by using a low dose of FDG and a 5-minute acquisition time. Additional research is required to determine the sensitivity and specificity of PET mammography for demonstrating malignancy for all nonpalpable lesions and not just for category 5 lesions.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Authors stated no financial relationship to disclose.
Author contributions: Guarantor of integrity of entire study, E.L.R.; study concepts, E.L.R.; study design, E.L.R., T.G.T., R.E.C.; literature research, E.L.R.; clinical and experimental studies, E.L.R., T.G.T.; data acquisition, E.L.R., T.G.T.; data analysis/interpretation, E.L.R.; statistical analysis, E.L.R.; manuscript preparation, E.L.R., T.G.T.; manuscript definition of intellectual content, E.L.R.; manuscript editing, R.E.C., M.S.S., J.A.B.; manuscript revision/review, T.G.T., E.L.R., R.E.C.; manuscript final version approval, all authors
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS DISCUSSIONREFERENCES |
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