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© 2001 American Society for Clinical Oncology 18Fluorodeoxyglucose Positron Emission Tomography to Detect Mediastinal or Internal Mammary Metastases in Breast CancerByFrom the Departments of Radiology, Nuclear Medicine, Oncology, and Radiation Oncology, University of Washington School of Medicine; and Department of Radiology, Puget Sound Health Care System, Seattle, WA; and Department of Mathematics, University of Wyoming, Laramie, WY. Address reprint requests to William B. Eubank, MD, Department of Radiology (114), Puget Sound Health Care System, 1660 S Columbian Way, Seattle, WA 98108-1597; email: weubank{at}u.washington.edu
PURPOSE: To determine the prevalence of suspected disease in the mediastinum and internal mammary (IM) node chain by 18fluorodeoxyglucose (FDG) positron emission tomography (PET), compared with conventional staging by computed tomography (CT) in patients with recurrent or metastatic breast cancer. PATIENTS AND METHODS: We retrospectively evaluated intrathoracic lymph nodes using FDG PET and CT data in 73 consecutive patients with recurrent or metastatic breast cancer who had both CT and FDG PET within 30 days of each other. In reviews of CT scans, mediastinal nodes measuring 1 cm or greater in the short axis were considered positive. PET was considered positive when there were one or more mediastinal foci of FDG uptake greater than the mediastinal blood pool. RESULTS: Overall, 40% of patients had abnormal mediastinal or IM FDG uptake consistent with metastases, compared with 23% of patients who had suspiciously enlarged mediastinal or IM nodes by CT. Both FDG PET and CT were positive in 22%. In the subset of 33 patients with assessable follow-up by CT or biopsy, the sensitivity, specificity, and accuracy for nodal disease was 85% , 90%, and 88%, respectively, by FDG PET; 54% , 85%, and 73%, respectively, by prospective interpretation of CT; and 50%, 83%, and 70%, respectively, by blinded observer interpretation of CT. Among patients suspected of having only locoregional disease recurrence (n = 33), 10 had unsuspected mediastinal or IM disease by FDG PET. CONCLUSION: FDG PET may uncover disease in these nodal regions not recognized by conventional staging methods. Future prospective studies using histopathology for confirmation are needed to validate the preliminary findings of this retrospective study.
METASTASIS TO INTERNAL mammary (IM) or mediastinal nodes is a common occurrence in breast cancer patients with locally advanced or recurrent disease.1-6 Internal mammary node metastasis is often clinically occult. A parasternal mass is a rare manifestation at the site of first treatment failure in patients with locally advanced disease.7-9 However, the status of these nodal regions is generally unknown because tissue sampling of these nodes is not routinely performed in patients with breast cancer. Unsuspected disease in the mediastinum or IM nodal chain may be responsible for some treatment failures and the development of distant metastases in patients thought to have only locoregional disease based on clinical and conventional imaging findings. For the case of IM nodal evaluation, this hypothesis is supported by several investigations that have shown a significantly worse prognosis in terms of disease-free and overall survival rates among patients with histologically proven IM nodal metastasis.1,4,5,9,10 We hypothesized that the use of 18fluorodeoxyglucose (FDG) positron emission tomography (PET) could improve the detection of disease in the IM chain and mediastinum, improving on conventional modalities used for nodal staging in patients with recurrent or metastatic breast cancer, thereby revealing unrecognized disease. This hypothesis is driven by FDG PET’s demonstrated ability to detect axillary nodal metastasis in patients with breast cancer11-13 and mediastinal lymph nodes in patients with non–small-cell lung cancer.14-21 In particular, for staging of patients with non–small-cell lung cancer where mediastinal node sampling is routinely used, a number of investigations have shown that FDG PET is significantly more accurate than computed tomography (CT) in detecting mediastinal disease, compared with conventional staging by CT and verified against pathology.14,16-21 Our anecdotal experience in restaging patients with recurrent or metastatic breast cancer also points to an increase in the prevalence of abnormal findings in the IM chain and mediastinum at FDG PET compared with clinical and conventional imaging methods, including CT. We, therefore, retrospectively evaluated a group of patients with advanced breast cancer who underwent both FDG PET and CT as part of their diagnostic work-up. The main goal of this study was to compare the prevalence of suspected disease in mediastinal and IM nodes based on abnormal findings by FDG PET versus conventional staging by CT. In a subset of patients with confirmation by biopsy or follow-up imaging, we also reported sensitivity, specificity, and accuracy values of these two imaging tests.
Study Design A single-institution retrospective evaluation of CT and FDG PET in assessing the prevalence of mediastinal and IM lymph node abnormalities based on prospective clinical interpretations in patients with known breast cancer was performed. The sensitivity, specificity, and accuracy of CT and FDG PET examinations were compared in a subset of the patients who had confirmation with pathology or follow-up imaging. Blinded reviews of the CT data were also performed.
Patient Population The primary reasons for FDG PET referral were to restage patients after suspected treatment failure and to assess disease response to therapy. Sixty-two patients (85%) had had prior mastectomies or lumpectomies with axillary lymph node dissection. Of these patients, 36 (58%) were undergoing chemotherapy or hormonal therapy, and 26 (42%) were not being treated with systemic therapy at the time of FDG PET. Eleven patients (15%) had no prior surgery but were undergoing neoadjuvant chemotherapy (n = 8) at the time of FDG PET or had finished a regimen of systemic therapy (n = 3) before FDG PET. The clinical stage at the time of FDG PET was I in four patients (6%), II in 20 patients (27%), III in nine patients 0(12%), and IV in the remaining 40 patients (55%). The high frequency of advanced disease reflects (1) the nature of the patients referred to our tertiary care center and (2) the use of FDG PET in our practice to clarify staging in patients in whom conventional staging has been equivocal. Clinicopathologic information was extracted from the patients’ medical records, including node status at time of initial diagnosis, location (central/medial or lateral) of tumor, steroid receptor status of tumor, size of primary tumor, presence or absence of chest wall recurrence at initial presentation or after primary treatment, and therapeutic history after diagnosis. The average time interval between initial diagnosis of cancer and FDG PET was 44.1 months (SD, 38.3; range, 0 to 161 months). CT was performed before FDG PET in 43 patients (mean, 13.7 days; range, 1 to 30 days), FDG PET was performed before CT in 28 patients (mean, 11.7 days; range, 1 to 29 days), and on the same day in two patients. All patients signed a written consent stating that FDG PET was being used for investigational purposes in the staging of breast cancer patients at our institution.
Thoracic CT Technique
FDG-PET Technique Transmission scans were performed with a rotating 68Ge rod source. Quantitative analysis was applied to the attenuation-corrected images by computing the standard uptake value (SUV) of areas of focal FDG accumulation.25 Images were reconstructed onto a 128 x 128 matrix using a Hanning filter, which resulted in an effective in-plane resolution (full width at half maximum) of approximately 10 to 12 mm.23,24 The reconstructed images were displayed in axial, coronal, and sagittal planes on a workstation, as needed.
Image Interpretation The prospective FDG PET interpretation was based on the nonindependent consensus interpretation of two or more nuclear medicine physicians experienced in FDG PET imaging. The images were interpreted primarily on a qualitative basis. Nodal status was considered negative if no mediastinal or hilar foci above the mediastinal blood pool background were detected or if uptake was borderline (close to mediastinal blood pool by visual inspection) and was felt unlikely to represent metastasis in the overall impression of the interpretation. Nodal status was considered positive if activity was greater than mediastinal blood pool. Nuclear medicine physicians had access to CT interpretations if CT was performed before FDG PET. For CT performed at our institution after FDG PET, the results of FDG PET were available to the interpreting radiologists. Blinded review of CT data. To evaluate inconsistent CT interpretation as a potential cause of lowering sensitivity for detecting mediastinal and IM disease, we conducted a separate, blinded review of the CT examinations by two experienced observers in cross-sectional thoracic imaging. The two observers (J.T. and H.V.), independently overread 86% of the CT examinations (63 of 73 scans, mediastinal windows only). The readers were aware that all of the patients had breast cancer but were given no additional information. The readers indicated their degree of suspicion of intrathoracic nodal metastasis by nodal station using the map of Naruke,26 based primarily on the size of the node in short axis. The following scale for suspicion was used: 1, definitely benign (0 to 5 mm); 2, probably benign (5 to 8 mm); 3, equivocal (9 to 10 mm); 4, probably malignant (11 to 15 mm); and 5, definitely malignant (greater than 15 mm). Nodal features other than size, including presence of fatty hilum, calcification, or enhancement were also used to determine the suspicion level. A rating of 4 or 5 was considered positive for the purpose of calculating the prevalence of suspected disease, sensitivity, specificity, and accuracy values. Any discrepancy between individual observers that resulted in difference of benign versus malignant interpretation on patient-by-patient basis (n = 5) was decided by consensus reading.
Standard of Reference Follow-up FDG PET was used for confirmation in a small subset of patients (n = 7) who received continuous chemotherapy between two FDG PET examinations. A significant increase or decrease in the SUV of a focus of mediastinal or IM node in combination with similar SUV change at other sites of confirmed disease (eg, axillary node, chest wall, liver metastases) was considered positive for malignancy. Results from these patients are reported separately.
Statistical Analysis
The prevalence of suspected disease in mediastinal or IM nodes by CT and FDG PET in all 73 patients is presented in Table 1. The prevalence of suspected mediastinal or IM nodal disease was 40% (29 of 73 patients) by FDG PET and 23% (17 of 73 patients) by CT based on prospective interpretation. The prevalence of suspected nodal disease based on blinded observer interpretation of CT data was slightly higher (19 of 63 patients or 30%) compared with the prospective interpretation. Mediastinal abnormalities were present on both CT and FDG PET in 22% of the patients (16 of 73). Based on prospective interpretation, findings at CT and FDG PET were concordant in 81% (16 of 73 were CT+PET+, and 43 of 73 were CT-PET-) and discordant in 19% (13 of 73 were CT-PET+, and one of 73 was CT+PET-) of patients. Based on blinded observer review of CT data, findings at CT and FDG PET were concordant in 78% (15 of 63 were CT+PET+, and 34 of 63 were CT-PET-) and discordant in 22% (10 of 63 were CT-PET+, and four of 63 were CT+PET-) of patients. Figure 1 is an example of concordant CT and FDG PET findings in the mediastinum in a 57-year-old female with inflammatory breast cancer with clinically apparent chest wall and axillary recurrence. Figure 2 is an example of discordant CT and FDG PET findings in the mediastinum in a 45-year-old female diagnosed with inflitrating ductal carcinoma in the right breast and positive axillary node and undergoing neoadjuvant chemotherapy. Figure 3 is an example of false-positive CT and FDG PET in a 52-year-old female with metastatic disease to the liver despite high-dose chemotherapy and bone marrow transplantation.
In the subset of 33 patients with node status confirmed by biopsy or follow-up CT, the sensitivity (95% confidence interval [CI]), specificity (95% CI), and accuracy for nodal disease was 85% (73%, 97%), 90% (80%, 100%) and 88%, respectively, by FDG PET; 54% (37%, 71%), 85% (73%, 97%), and 73%, respectively, by prospective interpretation of CT; and 50% (33%, 67%), 83% (70%, 96%), and 70%, respectively, by blinded observer interpretation of CT (P < .05 for difference in accuracy between CT and FDG PET) (Fig 4). With the inclusion of patients whose node status was confirmed by follow-up FDG PET (n = 40), the sensitivity (95% CI), specificity (95% CI), and accuracy for nodal disease was 85% (74%, 96%), 90% (81%, 99%), and 88%, respectively, by FDG PET; 40% (25%, 55%), 85% (74%, 96%), and 63%, respectively, by prospective interpretation of CT; and 39% (24%, 54%), 83% (71%, 95%), and 61%, respectively, by blinded observer interpretation of CT (P < .05 for difference in accuracy between CT and FDG PET) (Fig 5). Four patients had histologic confirmation of mediastinal nodes in this study. FDG PET correctly identified the node status in three of these patients (neoplastic [n = 2] and benign [n = 1]) and was falsely positive in a patient with invasive aspergillus infection (Fig 3). CT was correct in only one of these patients (benign status), falsely negative in two patients, and falsely positive in the patient with infection.
Thirty-three (45%) of the 73 patients were suspected of having only locoregional disease (ipsilateral breast, axillary node, supraclavicular node, or chest wall involvement) based on clinical examination and conventional imaging before FDG PET (Table 2). In this subset of patients suspected of locoregional disease, 10 (30%) had positive and 23 (70%) had negative findings in the mediastinum or IM chain at FDG PET (Table 2). Among the standard risk factors evaluated in this subset of patients, those associated with the greatest likelihood of abnormal FDG uptake in the mediastinum or IM chain include more than three positive axillary nodes or chest wall invasion (P = .05 for each condition), and estrogen receptor–negative tumors (P = .06) (Table 3). There were no statistically significant differences found in location, size of primary tumor, or prior radiation to chest wall or IM nodal chain.
There was good agreement between the prospective CT interpretation and the two blinded observers (weighted kappa, 0.54 and 0.59) and only slightly improved agreement between the two blinded observers (weighted kappa, 0.63). Interpretations between prospective reading and blinded observer review were discordant (benign v malignant node status) in nine (14%) of 63 patients. Six of the nine patients with discordant CT results had confirmation (all were positive by follow-up imaging and positive at FDG PET), and there were an equal number of true-positive (n = 3) and false-negative (n = 3) results among cases interpreted prospectively and those interpreted by blinded observer. Therefore, the sensitivity and specificity values for prospective versus blinded observer CT interpretations were not affected by the majority of these discordant CT results.
In a retrospective evaluation of patients with recurrent or metastatic breast cancer, we demonstrated that the prevalence of abnormal FDG uptake in the mediastinum or IM chain approximates twice that of abnormal CT findings in these nodal regions. This suggests that disease in the mediastinum and IM chain may be underdiagnosed by current methods, namely clinical examination and CT. In the subset of patients where confirmation was obtained (slightly less than one half of the total patients), the accuracy of FDG PET is similar to the accuracy of FDG PET in staging mediastinal nodes in patients with non–small-cell lung cancer.14,16-21 The higher prevalence rate of suspected nodal disease at FDG PET demonstrated in this study warrants further investigation with a prospective trial using histopathology for confirmation of nodal status. The largest potential impact of FDG PET on clinical staging was the upstaging of patients suspected of having only locoregional disease, based on clinical examination and conventional imaging, including CT. The FDG PET results were positive in the mediastinum or IM chain in 10 (30%) of 33 of these patients. Assuming a specificity of 90%, FDG PET would have correctly upstaged at least nine of these patients (27%). The recognition of disease in the IM or mediastinal region may have important implications for the clinical management of patients with recurrent breast cancer. For patients suspected of having locoregional recurrence after definitive treatment of primary tumor, detection of disease in the IM or mediastinal nodal basins may (1) change local therapy by extending radiation fields to include these nodal regions, (2) change systemic therapy to a more aggressive regimen, and (3) identify patients who are prone to more widespread relapse of disease. Detection of IM nodal disease in patients with early breast cancer may have even more important implications with regard to individual patient management. Metastasis to the IM chain in women with operable breast cancer occurs in 17.6% to 22% of cases1,10,28 and is associated with poor prognosis.1,5,9,10,20 Currently, these nodes are not routinely biopsied, so their status is generally unknown. Provided findings from FDG PET are validated with histopathologic confirmation in future studies, this noninvasive imaging modality could aid both in detection of IM nodal disease and direct local radiotherapy. Although the treatment of locoregional nodes with radiation is controversial, two recent, large, prospective randomized trials have demonstrated a significant disease-free survival benefit in patients with stage II and III (all axillary node–positive) breast cancer treated with postmastectomy locoregional radiotherapy (including the IM nodal chain) and adjuvant chemotherapy, compared with those who received only adjuvant chemotherapy.29,30 To determine which patients with suspected locoregional recurrences might benefit most from FDG PET restaging, we looked for risk factors associated with abnormal FDG uptake in the mediastinum or IM chain. Two risk factors associated with positive FDG uptake in the mediastinum or IM chain in these patients, more than three positive axillary nodes and chest wall invasion, reached statistical significance. This is not surprising because positive axillary node status has been shown by several investigators to be associated with an increase risk of IM nodal metastasis.4,31 One group of investigators has recently shown a two-fold risk of systemic relapse in patients with high-risk medial tumors compared with patients with tumors located in the lateral half of the breast.32 Dissemination of disease from untreated IM node metastases is one reasonable explanation of their findings. We did not find a significant association between tumor location and positive FDG uptake in the IM chain or mediastinum. However, we studied patients with much more advanced disease. The main limitation in our study was the lack of pathologic confirmation in mediastinal and IM nodes. These nodes are not routinely biopsied in breast cancer patients, especially in patients with other sites of disease. Despite the limited number of cases with pathologic confirmation, accuracy for nodal staging using CT and FDG PET in our patient group was similar to values from studies comparing CT and FDG PET in non–small-cell lung cancer, where pathologic confirmation was strictly used.14,16-21 For cases confirmed by follow-up CT or FDG PET, the 6-month minimum follow-up period may have been too short to allow nodes containing micrometastases to be detected by either modality. This could be a source of false-negative cases in our study and result in an overestimation of sensitivity for both modalities. The effect of ongoing chemotherapy for control of locoregional or distant disease in the majority of the patients also may have contributed to the underestimation of nodal disease prevalence. Nevertheless, this does not diminish our most significant result, that the prevalence of suspected disease in the mediastinum or IM chain is underestimated by conventional staging. Whether findings from FDG PET are accurate can only be addressed in a prospective study with tissue sampling for pathologic confirmation. We studied a heterogenous group of patients with regard to clinical stage. Patients were referred for FDG PET at our institution primarily to better define extent of disease when the clinical examination or conventional imaging is confusing or to monitor response to ongoing therapy. This referral pattern introduced a selection bias toward patients with more advanced stages of breast cancer. This tended to provide a higher rate of mediastinal and IM metastases than in a population with earlier stage disease and also put CT at an inherent disadvantage when comparing its accuracy directly with FDG PET. Another limitation of our study is that more than one third of the patients had CT performed at an outside facility, where the CT technique was not uniform. Also, the prospective interpretations of these CT examinations were rendered by many different radiologists with various levels of experience in thoracic imaging. Both of these factors influence the accuracy of CT interpretation for mediastinal or IM node disease. To address this, we performed a blinded review of the CT data by observers experienced in thoracic imaging. Differences in CT technique were minor. Only 11% of the CT examinations interpreted by the blinded observers were performed with incremental rather than helical technique, so this factor probably did not have a significant effect on the overall accuracy of the CT interpretations. There was good agreement (weighted kappa, 0.54, 0.59) between the two blinded observers and the prospective readings. The level of agreement and accuracy between prospective and blinded review of CT data was not significantly different, suggesting that potential differences in interpreter skill level had little impact on our results. The role of FDG PET in imaging breast cancer patients has been proven valuable by other investigators for axillary node staging11-13 evaluating response to chemotherapy33-37 and in the detection of distant metastases.38 Our study shows that the prevalence of abnormal findings in mediastinum and IM chain was about two-fold greater with FDG PET than by conventional CT staging in patients with recurrent or metastatic breast cancer. Patients with undiagnosed disease in the mediastinum or IM chain likely have a worse prognosis than those without malignant involvement of these nodes. FDG PET may play an important role in the noninvasive evaluation of mediastinal and IM nodes and directing therapy to nodes involved with neoplasm, particularly in patients with earlier-stage disease. The benefit of local treatment of disease in the IM chain and mediastinum is still in debate and needs further investigation. However, improved staging by FDG PET is likely to be helpful in future clinical therapy trials attempting to address this issue.
Supported in part by National Institute of Health grant nos. CA42045 and CA72064.
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ABSTRACT
INTRODUCTION
