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© 2000 American Society for Clinical Oncology Breast Imaging With Positron Emission Tomography and Fluorine-18 Fluorodeoxyglucose: Use and LimitationsFrom the Departments of Nuclear Medicine and Gynecology, Technische Universität München, Munich; and Department of Gynecology, University Hospital Eppendorf, Hamburg, Germany. Address reprint requests to Norbert Avril, MD, Department of Nuclear Medicine, Klinikum rechts der Isar, Technische Universität München, Ismaningerstr 22, 81675 München, Germany; email n.avril{at}lrz.tu-muenchen.de
PURPOSE: To evaluate the diagnostic value of positron emission tomography (PET) using fluorine-18 fluorodeoxyglucose (FDG) for the diagnosis of primary breast cancer. PATIENTS AND METHODS: Preoperatively, 144 patients with masses suggestive of breast cancer underwent PET imaging of the breast. To identify breast cancer by increased metabolic activity, parametric FDG-PET images were analyzed for increased tracer uptake applying conventional image reading (CIR) and sensitive image reading (SIR). One hundred eighty-five breast tumors were evaluated by histology, revealing 132 breast carcinomas and 53 benign masses. RESULTS: Breast carcinomas were identified with an overall sensitivity of 64.4% (CIR) and 80.3% (SIR). The increase in sensitivity (SIR) resulted in a noticeable decrease in specificity, from 94.3% (CIR) to 75.5% (SIR). At stage pT1, only 30 (68.2%) of 44 breast carcinomas were detected, compared with 57 (91.9%) of 62 at stage pT2. A higher percentage of invasive lobular carcinomas were false-negative (65.2%) compared with invasive ductal carcinomas (23.7%). Nevertheless, positive PET scans provided a high positive-predictive value (96.6%) for breast cancer. CONCLUSION: Partial volume effects and varying metabolic activity (dependent on tumor type) seem to represent the most significant limitations for the routine diagnostic application of PET. The number of invasive procedures is therefore unlikely to be significantly reduced by PET imaging in patients presenting with abnormal mammography. However, the high positive-predictive value, resulting from the increased metabolic activity of malignant tissue, may be used with carefully selected subsets of patients as well as to determine the extent of disease or to assess therapy response.
MANY BREAST TUMORS are initially detected by breast examination, either in a clinical routine examination or by self-examination. However, depending on the size of the breast and the density of breast tissue, most tumors do not become palpable until greater than 1 cm in diameter.1 Therefore, a number of imaging procedures have been introduced to improve diagnosis of breast cancer. There are two crucial areas that need improvement: (1) the detection of breast cancer at early stages, before the disease becomes systemic, and (2) accurate characterization of breast abnormalities. It is generally accepted that screening mammography reduces mortality by more than 30% in women who are older than 50 years.2,3 A smaller but still significant benefit has been reported for younger women.4 Identification of microcalcifications and irregular-shaped breast masses offers high sensitivity and identifies 80% to 90% of patients with breast cancer.5,6 On the other hand, benign tissue alterations often display similar image appearance, thus resulting in a low specificity for mammography.7 Only between two and four of 10 patients with abnormal mammography who undergo surgery are found to have breast cancer on histology.7,8 In addition, approximately 10% of breast carcinomas cannot be identified by mammography even when they are palpable.9 Ultrasound allows immediate differentiation between cystic and solid lesions if the lesion has smooth walls, sharp anterior and posterior borders, and no internal echoes.10 Sensitivity to detect breast carcinomas is comparable to that of mammography in palpable masses, whereas specificity seems to be higher. However, characteristics that typically represent malignant tissue, such as irregular-shaped hypoechoic masses with posterior acoustical shadowing and ill-defined demarcation against surrounding breast tissue, do not allow for accurate differentiation between benign and malignant tumors.11 Magnetic resonance imaging provides three-dimensional visualization of breast tissue with high spatial resolution. Paramagnetic contrast agents have been found to be essential to identify breast masses.12 The increase in signal intensity over time reflects regional proton density and depends on density and permeability of tumor capillaries. Regional signal enhancement provides a high sensitivity to detect breast cancer, in most studies more than 90%, whereas the specificity of magnetic resonance imaging is reported to be lower compared with that of mammography.12-14 Because of these limitations, many women with breast masses that are suggestive of cancer still undergo invasive procedures for accurate diagnosis. Imaging of metabolic tissue pattern is gaining increasing clinical importance among diagnostic procedures for patients with oncologic diseases (see overview in Rigo et al15 and Weber et al16 ). Enhanced glycolysis of cancer cells is well known since the reports from Warburg17 and Warburg et al17,18 in the early twenties. Positron emission tomography (PET) using the radiolabeled glucose analog 2-(fluorine-18)-fluoro-2-deoxy-D-glucose (FDG) enables three-dimensional visualization of regional glucose metabolism within the body. After intravenous injection, the tracer is taken up by tissue and trapped intracellularly due to phosphorylation by hexokinase, thus reflecting exogenous glucose consumption.19 Initial studies that included patients with advanced disease suggested high accuracy for the detection of primary breast carcinomas. Wahl et al20 correctly identified breast carcinomas in 10 patients with tumor sizes between 3 and 6 cm. In a series of 28 patients, Adler et al21 found a sensitivity of 96% studying breast masses larger than 1 cm in diameter. In an earlier report of this study, including a subset of 51 patients, primary breast cancer was identified with a sensitivity between 68% and 94%, depending on criteria used for image interpretation.22 The aim of the following study was to address the limitations of breast imaging with PET regarding potential clinical applications based on a larger patient population.
Patients Women referred to the department of gynecology for breast surgery were asked to participate in this study. Inclusion criteria were abnormal mammographic findings or palpable breast masses. Patients were excluded if they had had prior surgery to the breast, chemotherapy, or radiation therapy within the last 3 months. Patients were not studied if they were pregnant, had known diabetes, or were younger than 18 years. Details of the study were explained by a physician and written informed consent was obtained from all patients. The study protocol was approved by the Committee for Human Research at the Technische Universität München. PET scanning of the breast was performed on 144 patients (mean age, 50.6 ± 10.3 years). Sixty patients were clinically identified as premenopausal, 18 as perimenopausal, and 66 as postmenopausal.
PET Imaging Patients were required to fast for at least 4 hours before PET imaging. The serum glucose level was measured before the intravenous administration of 240 to 400 MBq (approximately 10 mCi) FDG. All patients were studied in prone position following comfortable positioning on the scanner table using foam rubber support, arms placed at their sides. For optimal tumor localization, a hole in the foam ensured no deformation of the breast. In all patients, emission scans of the breast, acquired in one bed position, were obtained from 40 to 60 minutes after tracer injection (20 minutes’ duration).
Image Analysis
Histopathologic Evaluation
Histology Of 144 patients, a total of 185 breast masses were evaluated by histology, revealing 132 breast carcinomas and 53 benign breast tumors. Eighteen breast cancer patients presented with multifocal or multicentric tumor localizations, accounting altogether for 41 breast carcinomas. The size of breast carcinomas ranged from 0.3 to 12.0 cm, with a mean diameter of 3.1 ± 2.1 cm. Twelve tumors were found to be in situ carcinomas (10 ductal and two lobular), 97 were invasive ductal carcinomas (IDCs; mean diameter, 3.0 ± 1.9 cm), and 23 were invasive lobular carcinomas (ILCs; mean diameter, 3.4 ± 2.2 cm). A summary of the histologic findings is given in Table 1. Miscellaneous benign lesions comprised one case of ductal adenoma, inflammatory tissue, necrosis, granular cell tumor, and hematoma.
PET Imaging Visual analysis identified a total of 88 focal tracer accumulations within the breast, classified as grade 3 (definitely malignant). Thirty-one lesions were classified as grade 2 (probably malignant), and 66 lesions were classified as grade 1 (unlikely to represent breast cancer). Table 2 lists the statistical analysis for CIR and SIR. Comparing these two approaches for PET image interpretation, the number of false-positive results increased from three (CIR) to 13 (SIR), whereas the number of false-negative results decreased from 47 (CIR) to 26 (SIR). Overall accuracy for CIR and SIR was 73.0% and 78.9%, respectively (Figs 1 through 4).
Depending on tumor size, there was considerable variation in diagnostic accuracy. Table 3 lists the number of false-negative findings for different tumor stages. Sensitivity was found to be low for tumors smaller than 1 cm. Zero of four tumors at stage pT1a (0.5 cm) and only one of eight breast carcinomas at stage pT1b (> 0.5 to 1.0 cm) were classified as grade 3 (definitely malignant). Nevertheless, for breast carcinomas at stage pT2 (> 2.0 to 5.0 cm), sensitivity increased to 80.6% (CIR) and 91.9% (SIR), respectively. Of note, 12 of 62 pT2 tumors did not display focal FDG accumulation, and five tumors were completely negative in PET scans. Three of 14 breast carcinomas larger than 5 cm (stage pT3) were false-negative by CIR, but were all identified by SIR. Because of limited anatomic information in PET images, stage T4 tumors were categorized depending on their size in this study.
Of 18 patients presenting with multicentric or multifocal breast cancer, only five (27.8%) were correctly identified by CIR and nine (50%) by SIR. Based on the total number of histologically verified lesions, 18 (43.9%) of 41 breast carcinomas were identified by CIR and 26 (63.4%) by SIR. There was considerable variation between identification of ILCs and IDCs. Fifteen (65.2%) of 23 ILCs were false-negative compared with 23 (23.7%) of 97 IDCs applying CIR. Histology showed noninvasive breast cancer in 12 patients, including 10 ductal carcinoma-in-situ and two lobular carcinoma-in-situ. Zero of six noninvasive carcinomas smaller than 2 cm in the greatest dimension were identified by CIR, and only one lobular carcinoma-in-situ with a diameter of 1.8 cm by SIR. CIR identified three of six larger in situ carcinoma and SIR identified four of six. When applying CIR with PET imaging of the breast, false-positive findings were infrequent. Only three of 53 benign lesions showed focal increased tracer uptake: one case with severe chronic inflammation, one fibroadenoma, and one ductal adenoma. However, the number of false-positive lesions increased to 13 for SIR (additionally, seven cases with dysplastic tissue, two fibroadenomas, and one inflammation were false-positive). The figures demonstrate true-positive (Fig 1), false-negative (Fig 2), false-positive (Fig 3), and true-negative (Fig 4) findings.
Malignant transformation of cells is often associated with increased metabolic activity. Therefore, imaging metabolic pathways has been proposed as a novel approach to improve the diagnostic strategies applied to patients with breast masses that are suggestive of abnormality. However, our study demonstrates that PET using the radiolabeled glucose analog FDG does not provide sufficient accuracy to exclude breast cancer in patients who present with abnormal mammography or palpable breast masses. Diagnostic accuracy was dependent on tumor size and increased from 68.2% (pT1) to 91.9% (pT2) and approached 100% for tumors larger than 5 cm (pT3). These results suggest that the number of unnecessary invasive procedures may not be significantly reduced by the use of currently available PET imaging techniques. PET scans of the breast may be analyzed using different visual and quantitative approaches.22 Intensity of tracer uptake is the most pronounced diagnostic criteria to differentiate benign from malignant tumors. As previously shown, visual analysis of SUV-normalized PET images results in a diagnostic accuracy comparable to quantitative analysis using the region of interest technique.22,24 Visual image analysis was made first by regarding only definitely positive (grade 3) regional tracer uptake as criteria for malignancy, referred to as CIR, and second, by including probably positive (grade 2) and definitely positive (grade 3) lesions, known as SIR. As a result of an inverse relationship between sensitivity and specificity of imaging modalities, reading images more sensitively (SIR) increased sensitivity at the cost of specificity (Table 2). When applying the results of this study to the clinical application of breast imaging with PET, the prevalence of breast cancer in the patient group studied must be taken into account. This study was based on a preselected patient population referred to a highly specialized breast cancer center for breast surgery, thus resulting in a bias for malignant tumors. In a patient group with a significantly lower prevalence of breast cancer, SIR positive-predictive values will significantly decrease compared with CIR. Thus the diagnostic gain of PET imaging compared with other imaging modalities, providing a high positive-predictive value for breast cancer, may only be accomplished by CIR. Overall sensitivity in this study was 64.4% for CIR and 80.3% for SIR. Forty-seven (35.6%) of 132 breast carcinomas were false-negative in CIR, and 26 (19.7%) could still not be identified by SIR. Earlier studies have found a lower rate of false-negative PET results. Adler et al21 reported one (4%) of 27 patients, Nieweg et al26 one (9%) of 11 patients, and Tse et al27 two (14%) of 14 patients that could not be identified with PET. Scheidhauer et al28 studied 30 women and identified 21 (91%) of 23 breast carcinomas with PET. However, the number of patients included in these studies was small and inclusion criteria were different, eg, small tumors were excluded. We found that the major limitation for the application of PET in breast imaging is a poor detection rate for small (pT1a and pT1b) breast carcinomas. Independent of the cost and availability of PET imaging, one of the major goals of imaging procedures is to detect breast cancer in the early stages, and this cannot currently be achieved by PET. Zero of four tumors at stage pT1a (0.5 cm) and only one of eight breast carcinomas at stage pT1b (> 0.5 to 1.0 cm) was identified (Table 3). Furthermore, the ability to detect noninvasive breast cancer was low, with a sensitivity of 25% for CIR and 41.7% for SIR. Although the number of patients studied in this group was small, these findings suggest that detection of in situ carcinomas may not be improved by PET imaging. Multicentric breast cancer is a significant limitation for use of breast-conserving therapy. Identification of multicentricity was suggested to be improved by means of PET imaging.28 Even by applying SIR, we could only identify nine (50%) of 18 patients with multifocal or multicentric breast cancer. Sensitivity for CIR was only 27.8%. In contrast, magnetic resonance imaging (MRI) is reported to provide a greater sensitivity for the detection of multicentric breast cancer. Kramer et al29 compared clinical breast examination, sonography, mammography, and MRI in 38 patients and found the highest sensitivity (89%) to be for MRI. On the other hand, specificity of MRI was the lowest, showing eight false-positive contrast enhancements within the breast. However, before breast-conserving therapy, the sensitive detection of breast abnormalities may be more important than the specific characterization, even if lesions identified by MRI are found to be benign on frozen section. Nevertheless, in our experience, PET was often helpful in identifying malignant lesion(s) and therefore aided the surgical strategy. An important finding of this study was that ILCs were overrepresented in the false-negative group. Approximately 6% to 10% of invasive breast carcinomas are ILC.30 In this study, 65.2% of ILC were false-negative compared with 23.7% of IDCs. This result cannot be explained by differences in tumor size (mean diameter of IDCs is 3.0 ± 1.9 cm v 3.4 ± 2.2 cm for ILCs). In general, ILCs are more difficult to diagnose using imaging procedures. Physical examination is often nonspecific, and even large tumors may not be palpable.31 Because of its diffuse growth pattern and tendency to form lesions with opacity equal to or less than surrounding parenchyma, lobular carcinomas can be extremely difficult to detect mammographically.32 In addition, the infrequency of suspicious microcalcifications contrasts markedly with ductal carcinoma.33 Paramagul et al34 found a variety of appearances of ILC by ultrasound, and only 16 (68%) of 19 presented as a distinct lesion. In MRI, ILCs also accounted for a considerable number of false-negative cases.13 Lower microvessel density has been suggested as an explanation. Hohenberger et al35 studied tumor oxygenation and found no difference in histology. This observation is important because FDG uptake in tissue is affected by regional oxygenation. Incompletely metabolized glucose in hypoxic tissue to lactate subsequently increases FDG uptake. Different growth patterns of ILC, such as lower tumor cell density and diffuse infiltration of surrounding tissue, may explain lower FDG uptake. In addition to the biologic behavior of tumors, partial volume effects are important components affecting the visualization of malignant tumors by FDG PET imaging. There is little information available regarding the relationship between metabolic activity and tumor extension. Glucose metabolism and subsequent FDG uptake may initially be low, increasing with tumor growth, thus preventing the detection of small tumors. Moreover, partial volume effects impact on the accuracy of radioactivity measurement in small lesions by causing a spread of the signal over a larger area than it actually occupies.36 Depending on the spatial resolution, which was between 5 and 8 mm for the PET scanners used in this study, the tracer accumulation is significantly underestimated in small tumors. In phantom studies, we found only 28% of the true radioactivity concentration in spheres of 1 cm in diameter.24 This means that at small sizes, only highly metabolic active tumors can be visualized. Torizuka et al37 compared the average FDG uptake in breast and lung cancer and found a significantly lower phosphorylation of FDG by hexokinase in breast cancer tissue. Additionally, FDG uptake in surrounding normal tissue is much higher in the breast compared with in the lung, resulting in decreased image contrast and detectability of tumors. Further improvements in spatial resolution will be provided by new generations of PET scanners, and dedicated breast imaging devices are currently being developed. However, the diagnostic limitations linked to partial volume effects cannot be expected to be completely resolved. We found only three of 53 benign breast masses presenting with intense tracer uptake. Therefore, this study confirmed previous findings of the high positive-predictive value of increased tracer accumulation to represent breast cancer. It must be emphasized that numerous malignancies are characterized by elevated glucose metabolism, and therefore PET cannot distinguish between different malignant tumors. However, neither does mammography, sonography, or MRI. One case of inflamed breast tissue demonstrated focal FDG uptake. Cellular infiltrates of granulocytes and macrophages may result in an increased glycolysis. Therefore, false-positive PET findings have been reported in abscesses, soft tissue infections, tuberculosis and sarcoidosis.38,39 However, inflammation of the breast does not represent a major diagnostic problem. We found that PET imaging provided a high accuracy in the differentiation of fibroadenomas from malignant tumors. Fibroadenomas are the second most common benign tumor, and only one of nine showed increased tracer uptake. Moreover, dysplastic tissue that often accounts for false-positive results in MRI predominantly showed little or moderate diffuse FDG uptake. Only one case of 35 accounted for a false-positive PET result. Interestingly, one rare case of a ductal adenoma presented with clear increased tracer uptake without a conclusive explanation. The limited ability of PET to detect small tumors does not allow screening of asymptomatic women for breast cancer. However, it is important to note that no imaging modality currently available provides the accuracy of an open biopsy and subsequent histologic tissue examination; even fine-needle aspiration cytology and core-needle biopsy can be affected by sampling errors.40 Thus the number of invasive procedures required by patients presenting with breast masses suggestive of abnormality cannot be reduced by PET imaging. On the other hand, PET excels with high positive-predictive values (resulting from increased metabolic activity of tumor tissue) that are superior to mammography, ultrasound, and MRI. It must be emphasized that PET is not affected by the density of breast tissue, which often reduces the diagnostic value of mammography. In our experience, breast surgery, radiation therapy, breast augmentation, or breast implants do not impair the image quality of PET. Moreover, dysplastic tissue, which often accounts for false-positive results in MRI (due to significant contrast enhancement), is true-negative in PET imaging. Therefore, PET may be helpful in a carefully selected subgroup of patients for whom findings are inconclusive after conventional diagnostic procedures. In patients with known breast cancer, specific identification of tumor tissue by metabolic imaging may be used to preoperatively determine the extent of disease. PET can identify not only primary tumors but also locoregional lymph nodes and distant metastases.41 We reported previously on the high diagnostic accuracy of PET imaging in identifying axillary lymph node metastases.42 When comparing the imaging modalities currently available, PET offers the greatest diagnostic accuracy in the assessment of locoregional lymph node status.41 Moreover, Moon et al43 found in patients with suspected recurrent or metastatic breast carcinoma that whole-body PET imaging offered a sensitivity and specificity of 93% and 79%, respectively. Bender et al44 correctly identified 28 (97%) of 29 patients with lymph node involvement, 15 (100%) of 15 patients with bone metastases, five (83%) of six patients with lung metastases, and two of two patients with liver metastases. These studies clearly indicate the potential clinical application of PET as a highly effective method for the staging of breast cancer patients. Recently, primary chemotherapy has been introduced to improve the management of patients with locally advanced breast cancer. FDG PET imaging has been found to be highly valuable for monitoring the effects of chemotherapy.45-47 Assessment of therapy response on the basis of the glucose metabolism of breast cancer was possible earlier than with any other method. Schelling et al48 found that FDG PET predicted the histologic response, assessed after completion of chemotherapy, as early as after the first course of chemotherapy. Assessment of chemosensitivity in vivo, using FDG-PET, would help to identify nonresponding patients and avoid ineffective chemotherapy. Therefore, while taking into account its limitations, PET imaging proves to be a valuable tool in the management of breast cancer patients.
We gratefully acknowledge the effort of the cyclotron and radiochemistry staff. Furthermore, we thank the PET technicians for excellent technical support, and Jodi Neverve for editorial help, and Leishia Tyndale-Hines for preparation of this manuscript.
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
