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Annals of Surgical Oncology 10:86-91 (2003)
© 2003 Society of Surgical Oncology

ORIGINAL ARTICLES

Positron Emission Mammography: Initial Clinical Results

Edward A. Levine, MD, Rita I. Freimanis, MD, Nancy D. Perrier, MD, Kathryn Morton, MD, Nadia M. Lesko, MD, Simon Bergman, MD, Kim R. Geisinger, MD, Rodney C. Williams, MS, Connie Sharpe, MBA, Valera Zavarzin, MS, Irving N. Weinberg, MD, PhD, Pavel Y. Stepanov, MS, David Beylin, MS, Kathryn Lauckner, PhD, Mohan Doss, PhD, Judy Lovelace, RN and Lee P. Adler, MD

From the Departments of Surgery (EAL, NDP, JL), Radiology (RIF, KM, NML, CS, RCW), and Pathology (SB, KRG), Wake Forest University School of Medicine, Winston-Salem, North Carolina; PEM Technologies Inc. (VZ, INW, PYS, DB), Bethesda, Maryland; Seleon gmbh (KL), Freiburg, Germany; and Department of Nuclear Medicine (MD, LPA), Fox Chase Cancer Center, Philadelphia, Pennsylvania.

Correspondence: Address correspondence and reprint requests to: Edward A. Levine, MD, Surgical Oncology Service, Wake Forest University, Medical Center Blvd., Winston-Salem, NC 27157; Fax : 336-716-9758; E-mail: elevine{at}wfubmc.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Evaluation of high-risk mammograms represents an enormous clinical challenge. Functional breast imaging coupled with mammography (positron emission mammography [PEM]) could improve imaging of such lesions. A prospective study was performed using PEM in women scheduled for stereotactic breast biopsy.

Methods: Patients were recruited from the surgical clinic. Patients were injected with 10 mCi of 2-[18F] fluorodeoxyglucose. One hour later, patients were positioned on the stereotactic biopsy table, imaged with a PEM scanner, and a stereotactic biopsy was performed. Imaging was reviewed and compared with pathologic results.

Results: There were 18 lesions in 16 patients. PEM images were analyzed by drawing a region of interest at the biopsy site and comparing the count density in the region of interest with the background. A lesion-to-background ratio >2.5 appeared to be a robust indicator of malignancy and yielded a sensitivity of 86%, specificity of 91%, and overall diagnostic accuracy of 89%. No adverse events were associated with the PEM imaging.

Conclusions: The data show that PEM is safe, feasible, and has an encouraging accuracy rate in this initial experience. Lesion-to-background ratios >2.5 were found to be a useful threshold value for identifying positive (malignant) results. This study supports the further development of PEM.

Key Words: Mammography • Breast • Imaging • PET • Cancer • Diagnosis


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
One of the major goals of breast imaging is to detect small breast cancers so that treatment may be initiated when the outlook is most favorable. Once a cancer has been detected, it is useful to demonstrate the extent of the lesion for surgical planning and to identify other foci of tumor in the breast. These tasks are not reliably performed even with the best tools currently in general use (mammography and ultrasound).1 A key reason for the limited efficacy of conventional imaging is the limitation to anatomic depictions. With the addition of functional imaging, however, it is possible that mammographically occult disease may be better characterized, benign lesions may be recognized as such, and unsuspected tumors may be detected.

Positron emission tomography (PET) allows the visualization of functional metabolism in vivo. However, existing commercial PET instruments are not optimal for imaging small breast cancers. PET instruments customized for breast applications have been shown to exhibit superior technical characteristics for imaging small lesions in breast phantoms.2 With the goal of evaluating a dedicated prototype instrument for breast PET, a prospective pilot study was designed to develop methodology. We used this instrument (positron emission mammography [PEM] scanner) mounted on a stereotactic biopsy table.3 To facilitate correlation between PEM findings and pathology results, it was necessary to devise a scanning method that would facilitate both imaging of, and access to, the biopsy site. This article describes our initial experience with this novel imaging modality.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Clinical Protocol
Human subjects were enrolled in an Institutional Review Board approved clinical protocol at Wake Forest University-Baptist Medical Center. All eligible subjects were seen in the breast surgery clinic for suspicious mammogram(s), with or without suspicious physical findings requiring biopsy. Of those patients entered into the protocol, the first set of subjects to have complete data and follow-up (18 breast lesions in 17 breasts from 16 subjects) were selected for analysis.

Following 4 hours of fasting, a sample of blood from each subject was obtained for serum glucose determination. The patient received an intravenous injection of 10 mCi of 18F-fluorodeoxyglucose (FDG). One hour later, the patient was placed prone on the stereotactic biopsy table (Lorad, Danbury, CT). The breast was positioned so that the suspicious lesion was in the field of view of the biopsy window.

The prototype PEM scanner consists of detector heads placed on each side of the compressed breast and associated acquisition and display electronics. One mounting frame is attached to the compression paddle and the other to the back of the detector plate of the prone x-ray table to allow rapid insertion and removal of the components (Fig. 1).1 This prototype device has a field of view of 5.6 by 5.6 cm, similar to the images obtained on stereotactic prone x-ray tables equipped with digital spot mammography. Spatial resolution is better than 3-mm full-width at half-maximum,2 significantly better than can be achieved with conventional whole-body PET scanners. The PEM detector heads can be removed from the x-ray table and replaced within seconds, without requiring release of the subject’s breast from compression.



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  		FIG. 1. PEM detectors mounted on a sterotactic breast biopsy system. Illustrated are: 1 (compression paddle), 2 (back plate), and 3 and 4 (detectors).

 
The following imaging procedure was performed for each subject on the stereotactic biopsy table. A flood field calibration examination of the PEM device was obtained using a flat phantom filled with 18FDG (100 mCi) placed midway between the PEM detector heads. The flood field was imaged between 4 and 10 minutes. The PEM camera heads were then attached to the compression paddle and back plate (Fig. 1). A 120-second position calibration check of the PEM device was performed with a cardboard insert containing two Na-22 positron-emitting point sources. The PEM camera heads were removed and an x-ray image of the two point sources was taken. This position calibration was applied to insure detector efficiency and x-ray/PEM alignment. The PEM camera heads are then reattached to the compression paddles. The patient was then placed in the prone position on the table, resting on a 2-mm thick layer of sheet lead placed under the table’s cushion. The subject breast was then inserted into the table aperture, and a scout x-ray view of the subject’s breast was taken confirming that the mammographic abnormality is visible in the field-of-view. Without releasing breast compression, the PEM detector heads are then reintroduced on both sides of the compressed breast, and a 4-minute examination of the suspicious area is obtained. The PEM detector heads were then removed from the table, and the subject underwent biopsy of the mammographically suspicious lesion. Routine stereo, prefire, and postfire views were obtained. Using standard sterile procedure, breast biopsy was performed with an 11-gauge vacuum-assisted core biopsy needle (Mammotome, Ethicon Endo-Surgery, Cincinnati OH). Cores of breast tissue were taken sequentially at 12 locations around the clock at 2-hour intervals (e.g., 2:00, 4:00, 6:00, 8:00, 10:00, 12:00, 1:00, 3:00, 5:00, 7:00, 9:00, 11:00). Each core was examined by a pathologist without knowledge of the PEM study results. For those subjects who were biopsied on the table, the coordinates of the lesion location were recorded for later analysis. In one case, a subject with an obvious cancer was not biopsied on the table on the day of the PEM examination. Subjects did not report untoward effects as a result of the examinations with the PEM device.

Data Acquisition Protocol
The PEM device recorded a file of gamma ray events acquired by the PEM detector heads. This list-mode file included coincident events, as well as delayed coincident events (i.e., randoms) for postprocessing randoms correction. Back-projected images taken with the PEM camera were visible within 2 minutes of acquisition. X-ray images were ported from the stereotactic biopsy computer to the PEM computer using a file transfer protocol-like protocol implemented with data transfer from the biopsy table computer parallel port, as described previously.2

Data Analysis
The list-mode data acquisition files were reconstructed with an iterative maximum likelihood estimation method using median filtering and 2-mm in-plane pixel size. In deference to the standard system for spatial localization on the biopsy unit, the planes were assigned x- and y-axes, and the vector between the compression paddles was assigned to the z direction. Twenty-four equidistant z planes of reconstruction were selected that were parallel to the compression paddles. Due to variable breast thickness as indicated by the width of compression on the biopsy table, the z width of each plane varies in thickness from approximately 2 to 3.5 mm, depending on compression distance. Visualization is accomplished using IDL software (IDL version 5.4, Research Systems, Boulder, CO). Using the point source images for both PEM and x-ray to correct for x-y shift and magnification, the two image modalities were co-registered.

For those subjects undergoing stereotactic biopsy (17 breasts/18 lesions), the target x, y, and z coordinates of the biopsy site of interest were recorded by the biopsy computer. These biopsy locations were displayed on the PEM slices and on the x-ray image. In the one subject who did not have a stereotactic biopsy, a biopsy location was drawn on the co-registered PEM and x-ray images in the approximate center of an obvious lesion that was diagnosed by fine-needle aspiration then removed with a mastectomy.

Image Analysis
Regions of interest (ROI) were created on the PEM images (Fig. 2) at two locations. The first location corresponds to the site of stereotactic core biopsy and the second to a representative background region of comparable size and tissue thickness. The biopsy site ROI was centered at the biopsy location specified by x, y, and z coordinates for the biopsy procedure. The most clinically significant (malignant) histology in the biopsy cores is recorded as the "gold standard" result, and the PEM value recorded for that tissue is the highest pixel intensity in the volume of tissue biopsied. This three-dimensional biopsy ROI measurement was designed to model the sample geometry of the core biopsy. The sampled volume maximally includes tissue approximately 1 cm in diameter around the biopsy core needle in the x-y plane and approximately 19 mm along the biopsy z-axis, centered around the z coordinate. To mathematically model the geometry of the biopsy sampling for histopathology, the measurement of the value of the biopsy ROI was computed as the maximum value of the five slices surrounding the biopsy z value, where each slice represents approximately 2 mm thickness.



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  		FIG. 2. Representative clinical images (subject 6b in Table 1). Images from a patient study illustrating (from left to right) digital x-ray (with location of biopsy and background ROIs), reconstructed PEM image from central plane of biopsy, and overlaid PEM/x-ray image. The lesion was invasive ductal carcinoma by histology. True positive.

 

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  		TABLE 1. Patient data
 
For the background ROI determination, the z slice selected corresponded to a depth comparable to that determined by the biopsy target slice (z location). Two board-certified radiologists collaborated in identifying a representative background region in that slice which corresponded to an area of low attenuation (i.e., fatty breast tissue) as identified by the digital x-ray of the breast, at a site of comparable thickness to the site of biopsy. The mean and minimum pixel count intensities were calculated. There are several possible methods of selecting the appropriate value for the background ROI. To model the physiological concept of lesion-to-background ratio with the highest fidelity, the minimum pixel value is used because this would represent the lowest degree of malignancy in the ROI. The mean value for the background should provide better counting statistics than does the minimum value. As PET images typically have few counts per pixel in the breast, the mean value has previously been used in the PET literature.4 However the mean value determination may vary more with user selection of the region of interest than would the minimum value. The count statistics advantage are likely to be less important in the PEM images than with conventional PET scanners because count efficiency for activity in the breast are much higher in the PEM scanner than in a whole-body PET scanner.2 For these reasons, results from both methods (mean and minimum) are reported.

PEM lesion-to-background ratios are calculated for biopsy location using both mean and minimum background values. These ratios were compared with the histological findings. The left-uppermost corner of the receiver operating characteristic (ROC) curves was used to identify the cutoff threshold ROI ratio for optimal sensitivity and specificity in identifying the presence or absence of malignancy.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The PEM lesion-to-background ratios for the 18 lesions in 17 breasts (16 patients) studied are listed in Table 1. The average age of the 16 women was 57 years, with a range of 34 to 84 years. Of the 16 study subjects, 4 were black and 12 were white. No adverse reactions to FDG or the PEM imaging procedures were encountered. Among the 18 breast lesions evaluated, there were a total of 7 with carcinoma (5 ductal and 1 each of the lobular and mucinous types) and 11 with benign findings. The lesion-to-background ratios for the PEM studies varied between 1.32 and 7.7. Representative images are shown in Figures 1–4. The average ratio for the malignant lesions was 3.95 vs. 1.94 for the benign lesions, P = .0032 (by Wilcoxon rank sum test).



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  		FIG. 3. Subject 11. Fibroadenoma and sclerosing adenosis. Ratio 2.53. True negative.

 


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  		FIG. 4. Subject 6b. Invasive ductal carcinoma. Ratio 7.7. True positive.

 
An ROC curve was generated for the lesion-to-background data (using mean pixel density to determine the background value). Selecting the left-most and upper-most corner of the ROC curve, a cutoff lesion-to-background ratio threshold of >2.5 was selected to segment benign from malignant lesions. With this cutoff, there was one false positive and one false negative, with a sensitivity in the detection of malignancy of 86%, specificity of 91%, and overall diagnostic accuracy of 89%. Using the minimum background pixel value to calculate lesion-to-background ratios, but with a different cutoff lesion-to-background ratio threshold (i.e., 2.95), resulted in the same accuracy. Figures 3 and 4 are exams selected as representative of typical results.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Previous FDG-PET scan studies of patients with suspected breast cancer have reported relatively low sensitivity in the detection of primary breast cancer.4,5 The sensitivity of FDG-PET is lowest for small lesions.5 By using high-resolution components to improve spatial resolution and reduce inter-detector distance, count rate statistics are improved. The goal was to improve diagnostic accuracy in the detection and characterization of primary carcinoma in the breast. The results reported here are preliminary, obtained with a prototype PEM scanner. The results reported here are semi-quantitative. Even higher accuracy in characterizing mammographic findings may be obtainable with PEM scanners if quantitative analysis is achieved. To correlate x-ray (mammographic) and functional PEM data, it is critical that the images be co-registered accurately. This cannot be accomplished with conventional PET, and successful PEM devices must be adapted to mammographic units to permit simultaneous or sequential analysis without releasing compression.

For the single false negative in the series, (case 13 in Table 1) it is interesting to note that she had an invasive lobular lesion. The lobular histology has been reported to be associated with false-negative FDG-PET.5 Further, the subject had discontinued estrogen therapy approximately 1 week before the PEM study. This may have altered the results, although the effect of hormonal replacement on the results of the PEM scans will not be known without additional research. It is also possible that the low-lesion uptake reflects low-angiogenic activity, as has been described in the magnetic resonance imaging literature to explain the lowered sensitivity of magnetic resonance imaging for some breast cancers.6 The development of larger field-of-view detectors or absolute quantitative indices of uptake could overcome this limitation.

The marriage of functional and conventional imaging has substantial potential impact. In addition to evaluation for regional7,8 and distant disease,9 FDG-PET may give insight into tumor response to systemic therapies.10–12 The PEM device dovetails nicely with conventional mammography for analysis of suspicious mammographic lesions. In addition to finding early malignancy, such analysis could serve as a guide to the surgeon in planning breast-conserving surgery. Further, the PEM device may be able to assess changes in proliferative rates of ductal cells, potentially serving as a surrogate marker for hyperplasia.

This pilot study with a prototype PEM scanner suggests that quantitative comparisons of lesion-to-background FDG concentration result in promising sensitivity, specificity, and accuracy in the characterization of breast lesions. Further work is required to implement absolute quantification with scatter correction, to develop larger field-of-view detectors, and to systematically identify patient factors that could enhance or complicate our ability to detect breast cancer with PEM. Additional studies seem warranted and are required to determine whether this promising performance is borne out with larger cohorts of patients.


   Footnotes
 
Presented at the Society of Surgical Oncology meeting, Denver, CO, March 15–17, 2002.

Initial clinical results using a positron emission mammography device for evaluation of women with mammographic anomalies was undertaken. Good sensitivity, specificity, and accuracy were found suggesting that further evaluation of positron emission mammography is warranted.

Received for publication March 15, 2002. Accepted for publication August 5, 2002.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Kerilikowske K, Grady D, Barclay J, et al. Variability and accuracy in mammographic interpretation using the American College of Radiology Breast Imaging and Reporting System. J Natl Cancer Inst 1998; 90: 1801–9.[Abstract/Free Full Text]
  2. Weinberg IN, Majewski S, Weisenberger AG, et al. Preliminary results for positron emission mammography: real-time functional breast imaging in a conventional mammography gantry. Eur J Nucl Med 1996; 23: 804–6.[CrossRef][Medline]
  3. Weinberg IN, Zawarzin V, Pani R, et al. Implementing PET-guided biopsy. Integrating functional imaging data with digital x-ray mammography cameras. In: Mun SK, ed. Medical Imaging 2001: Visualization, Display, and Image-Guided Procedures. Vol. 4319. Proc. Bellingham: SPIE, 82–7.
  4. Adler LP, Crowe JP, Al-Kaisi NK, Sunshine JL. Evaluation of breast masses and axillary lymph nodes with [F-18] 2-deoxy-2-fluoro-D-glucose PET. Radiology 1993; 187: 743–50.[Abstract/Free Full Text]
  5. Avril N, Schelling RM, Dose J, et al. Breast imaging with positron emission tomography and fluorine-18 fluorodeoxyglucose: use and limitations. J Clin Oncol 2000; 18: 3495–3502.[Abstract/Free Full Text]
  6. Knopp MV, Weiss E, Sinn HP, et al. Pathophysiologic basis of contrast enhancement in breast tumors. J Magn Reson Imaging 1999; 10: 260–6.[CrossRef][Medline]
  7. Smith IC, Ogston KN, Whitford P, et al. Staging of the axilla in breast cancer accurate in vivo assessment using positron emission tomography with 2-(fluorine-18)-fluoro-2-deoxy-D-glucose. Ann Surg 1998; 228: 220–7.[CrossRef][Medline]
  8. Greco M, Crippa F, Agresti R, et al. Axillary lymph node staging in breast cancer by 2-fluoro-2-deoxy-D-glucose-positron emission tomography: clinical evaluation and alternative management. J Natl Cancer Inst 2001; 93: 630–5.[Abstract/Free Full Text]
  9. Council on Scientific Affairs. Positron emission tomography in oncology. JAMA 1988; 259: 2126–31.[Abstract]
  10. Smith IC, Welch AE, Hutcheon AW, et al. Positron emission tomography using [18F]-fluorodeoxy-D-glucose to predict the pathologic response of breast cancer to primary chemotherapy. J Clin Oncol 2000; 18: 1676–88.[Abstract/Free Full Text]
  11. Schelling M, Avril N, Nahrig J, et al. Positron emission tomography using [18F] Fluorodeoxyglucose for monitoring primary chemotherapy in breast cancer. J Clin Oncol 2000; 18: 1689–95.[Abstract/Free Full Text]
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