Affiliations of authors: M. Greco, R. Agresti, R. Giovanazzi, S. Asero, C. Ferraris, M. Gennaro (General Surgery BBreast Unit), F. Crippa, E. Seregni, A. Gerali, E. Bombardieri (Nuclear Medicine Unit), A. Micheli (Epidemiology Unit), N. Cascinelli (Scientific Director), National Cancer Institute, Milan, Italy.
Correspondence to: Marco Greco, M.D., General Surgery BBreast Unit, National Cancer Institute, Via Venezian 1, 20133 Milan, Italy (e-mail: r.agresti{at}iol.it).
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ABSTRACT |
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INTRODUCTION |
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In this study, our goal was to use FDGPET prospectively to investigate whether PET could be used to identify involved axillary lymph nodes and thus to identify patients who might avoid ALND.
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PATIENTS AND METHODS |
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We studied 167 consecutive patients with T1 (20 mm) or T2 (2150 mm) breast carcinomas at the National Cancer Institute of Milan, Italy, who were scheduled to receive ALND. The average age of the patients was 54 years (range = 2884 years). Axillary status was clinically classified as N0 (patients without axillary metastases) or N1 (patients with axillary metastases). Patients underwent complete (all three levels) ALND in addition to mastectomy or quadrantectomy as reported previously (20). The average tumor size, measured after sectioning for histology, was 21 mm (range = 550 mm). No patient had distant metastasis when the PET scan and breast surgery were done. Written informed consent was obtained from all of the patients considered in this study. This study was performed after approval by our Institutional Review Board.
PET Examinations
PET studies using a 4096 WB Plus scanner (General Electric Co., Milwaukee, WI) were performed on patients 17 days before surgery was scheduled. Before the PET examination, all patients fasted for at least 5 hours and had normal fasting blood glucose levels. In our previous report (20), an additional patient with massive undetected axillary metastatic involvement was described; despite having a normal blood glucose level during the PET examination, this patient was later found to be diabetic. This patient had a false-negative PET result (20) and was not included in the present evaluation. Her data emphasize the need for an accurate blood glucose history for all patients. About 400 MBq (or 11 mCi) of FDG was injected into a vein contralateral to the tumor side. Positioning of the breast and axillary regions in the field of view of the scanner was checked by a built-in laser guide. Most patients were studied in the supine position with their arms raised. Before FDG injection, two contiguous, 10-minute transmission scans were acquired in the bed position with a rotating 68Ge rod source to correct for attenuation of the mammary and axillary regions. Two 20-minute static emission scans were acquired at the transmission positions 4560 minutes after FDG injection. Patients were repositioned by use of markers placed on the skin before the transmission scans.
PET results were analyzed on attenuation-corrected emission images reconstructed by filtered back-projection by use of 2-mm pixels in a 256 x 256 matrix and a 4.2-mm Hanning filter (General Electric Co.). Images were considered to be positive if axilla took up more FDG than the surrounding tissue. All individuals analyzing PET scans were blinded to the histopathologic findings at surgery. PET scans were evaluated as negative or positive by three nuclear medicine physicians, who concurred in the final evaluation. PET results were evaluated for sensitivity, specificity, accuracy, and positive- and negative-predictive values relative to the histopathologic diagnosis.
Pathology
Breast tumor size was measured on histologic sections, and tumors were classified as T1ab (10 mm), T1c (1120 mm), or T2 (2150 mm). Lymph nodes isolated from axillary fat tissue were formalin fixed, paraffin embedded, and stained with hematoxylineosin. Depending on size, each lymph node was sectioned into two or three parts, and one or more sections were prepared from each part. The results of the histologic report were used as a reference to evaluate the ability of the FDGPET examination to detect axillary metastases.
Statistical Methods
We used the Wilson method as proposed by Agresti and Coull (22) to calculate 95% confidence intervals (CIs) for the percentages of measures of cross-classification in the detection of the axillary metastases. The Wilson approach guarantees better coverage properties than the standard exact method [see also Newcomb (23)]. The two-sample test on the equality of proportion was used when relevant. All statistical analyses were done with the computer program Stata 6.0 (1999; Stata Corporation, College Station, TX) and with parts developed by Gleason (24) for CI estimation of proportions. All statistical tests were two-sided.
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RESULTS |
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Table 1 summarizes the PET results in the detection of the axillary metastasis for all 167 patients and for patients grouped by clinical axillary status. For PET, overall sensitivity, specificity, and accuracy were 94.4% (PET detected 68 of 72 patients with axillary involvement; 95% CI = 86.0% to 98.2%), 86.3% (PET detected 82 of 95 patients without axillary involvement; 95% CI = 77.8% to 91.9%), and 89.8% (PET detected 150 of all 167 patients; 95% CI = 84.2% to 93.6%), respectively. The positive- and negative-predictive values were 84.0% (68 patients with histologically positive lymph nodes of 81 patients with a positive FDGPET scan; 95% CI = 74.2% to 90.5%) and 95.3% (82 patients with histologically negative lymph nodes of 86 patients with a negative FDGPET scan; 95% CI = 88.2% to 98.5%), respectively. Between the groups of patients, specificity of PET was not homogeneous, but the difference was not statistically significant between N1 patients and N0 patients (75.0% for N1 versus 87.4% for N0). Of the 72 patients with axillary involvement, PET identified 27 (37.5%) with limited pathologic axillary lymph node involvement (three or fewer metastatic lymph nodes). About 80% of these 27 patients had no clinically palpable axillary lymph node but did have a wide range of microscopic involvement, as shown by histopathologic examination, from single microembolic metastasis (four patients) to massive lymph node metastases (nine patients), and the remaining 14 patients had pluriembolic and/or partial lymph node metastases. This range of patterns of lymph node metastases is consistent with the patterns routinely encountered in clinical practice.
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DISCUSSION |
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The 167 breast cancer patients in this study include 68 patients whose data have been previously reported (20). Results from those 68 patients are consistent with the results of the entire series of 167 patients; the new estimates of sensitivity, specificity, and accuracy are within the 95% CIs of the previous estimates. The present study of the 167 patients indicates that FDGPET can safely predict axillary lymph node status and is a reliable and accurate noninvasive method for identifying patients who might avoid ALND. The high rate of detecting axillary lymph nodes with metastases and the acceptably low false-negative rate suggest that PET appears to be an important landmark in axillary staging. In addition to an overall sensitivity of 94.4% and an accuracy of 89.8%, the negative-predictive value of PET was 95.3% for all 167 patients and 97.3% (36 of 37 patients with negative FDGPET scan; 95% CI = 84.7% to 99.9%) for patients with T1ab breast cancers. In this subgroup, the risk of lymph node metastases is very low (about 10%), so that a high negative-predictive value was expected. By contrast, the ability of PET to identify T1c patients with no involved axillary lymph nodes (negative-predictive value) was essentially the same (93.5%; 29 of 31 patients with negative FDGPET scan; 95% CI = 78.0% to 99.1%). In this group, the rate of metastatic axillary involvement is more than 30%. The overall reliability of FDGPET was confirmed by the results from patients with T2 breast carcinoma. For these patients, FDGPET had a negative-predictive value of 94.4% (17 of 18 patients with negative FDGPET scan; 95% CI = 72.0% to 99.9%), with an expected axillary metastatic involvement of more than 60%. For T1 breast carcinoma, the high negative-predictive values and the ability of PET to detect minimal metastatic involvement may be sufficient to determine whether ALND could be avoided.
Initial PET studies of axillary lymph nodes and breast cancer (2831) examined a small number of patients with a prevalence of large tumors. More recently, two larger studies have found negative-predictive values of 95% (32) and 96% (33), which are consistent with the value determined in this study. The relative clinical impact of the false-negative results remains debatable, especially the issue of missing a few minimally involved axillary lymph nodes versus the overall lower morbidity resulting from avoiding ALND. In this study, only four patients had negative PET results but positive histologic results showing a limited number of metastatic cells in the axillary lymph nodes (5.6%; four of 72 patients with axillary involvement; 95% CI = 1.8% to 14.0%). We doubt that this undetected embolic nodal metastatic involvement represents the limit of detection for PET (34). However, it has been argued (34) that the sensitivity of PET imaging depends on the extent of lymph node involvement and that PET cannot provide the spatial resolution necessary to accurately assess axillary status. Although PET spatial resolution is an important technical challenge with a wide margin for improvement (35), PET imaging is a function not only of anatomic tumor size but also of FDG uptake. FDG uptake is the amount of radioactivity inside the tumor, defined as the standardized uptake value. The median standardized FDG uptake value for carcinomas with axillary metastases is considerably higher (4.6 times) than that for carcinomas without metastases (2.9 times) (20). There is an association between the standardized uptake value and the number of involved axillary lymph nodes (36). Moreover, there is a statistically significant correlation between FDG uptake and histologic grade (21,37) and tumor p53 levels (21). The glycolytic rate in neoplastic tissue is generally higher in aggressive and proliferating tumors, so that even a few metastasized cells in an axillary lymph node can be detected, and the signal may be amplified by activated nodal leukocytes around the metastatic lesion. In our previous report (20), an additional patient with massive, undetected axillary metastatic involvement was described. After publication of the report, this patient, despite having a normal blood glucose level for the PET examination, was found to be diabetic, which accounted for this false-negative PET result (20). Although data from this patient were not included in the present evaluation, these results do emphasize the importance of an accurate blood glucose history, even for borderline diabetic alterations. A study on experimental breast carcinoma in rodents (38) has suggested that, if blood glucose levels are substantially elevated, tumor imaging may be impaired. Before FDGPET studies are conducted, patients should fast, and their blood glucose concentration should be taken into account when the FDGPET results are evaluated (39). Thus, potential pitfalls associated with diabetic patients must be considered, and, in general, diabetics should be excluded from FDGPET analysis.
We believe that a small number of patients with microembolic axillary metastases undetected by PET should be expected. Questions about the relevance of lymph node micrometastases and their therapeutic implications have been raised because of the introduction of sentinel lymph node biopsy, which detects such micrometastases at a higher rate. Concern has been expressed about potential "upstaging" of many patients and about possible overtreatment if a micrometastasis in the sentinel lymph node represents the only axillary involvement (40). However, when the sentinel lymph node biopsy detects a micrometastasis, a complete ALND is done. After a median follow-up of 5 years in our prospective nonrandomized series of 401 patients with T1 or T2, N0 breast cancer who were treated with breast surgery without axillary dissection, only 27 (6.7%) of the patients had a recurrence of breast cancer with involved axillary lymph nodes. This result indicates that only a few microembolic axillary metastases become clinically evident during such a follow-up, and further analysis of these patients (7) revealed that these axillary relapses had no major impact on overall survival.
Sentinel lymph node biopsy has a non-negligible false-negative rate of 1%15% in almost all studies (1016). Moreover, no statistically significant differences have been shown between the two principal technical approaches (i.e., the blue-dye method and lymphoscintigraphy with intraoperative -probe detection) in terms of the rate of individualization of the sentinel lymph node. The negative-predictive value for the sentinel lymph node biopsy (1016) is similar to that of this study and of most large PET studies (32,33). Moreover, sentinel lymph node biopsy is a nonselective method to determine whether the first regional lymph node that drains a tumor is metastatically involved. Lymphoscintigraphy alone cannot provide information on the status of the lymph node visualized, whereas PET can specifically visualize the metastatic lymph node and thus can provide direct information on the axillary status. In addition, the sentinel lymph node method requires that several specialists closely coordinate their work. We believe that it will be useful to compare FDGPET and the sentinel lymph node method in terms of invasiveness, time, and hospitalization costs. One study (32) has calculated the potential cost savings and improved patient care found by using PET imaging before considering ALND for patients with breast carcinoma. When we used the median costs reported in that study (32) and PET imaging as the method to identify patients who could avoid axillary surgery, we calculated a savings of $3000 (U.S. dollars) per patient for our entire series and a savings of up to $5000 (U.S. dollars) for patients with T1ab breast cancer. This cost saving is clear when PET and ALND are compared, but it is less evident or absent when PET and sentinel lymph node biopsy are compared. However, the best evidence to support the use of PET, even compared with sentinel lymph node biopsy, is the great improvement in the patient's quality of life because of the noninvasive nature of PET.
To date, sentinel lymph node biopsy represents a facet of surgical planning because the information derived from this method is principally used for determining the need for axillary dissection. In fact, detection of microfoci of metastatic cells in the sentinel lymph node is normally followed by the recommendation for complete ALND because about 50% of patients may have other involved lymph nodes (11). By contrast, PET imaging can identify patients who might avoid axillary dissection, can provide staging information with a complete regional evaluation of the disease (i.e., internal mammary chain and supraclavicular lymph nodes) and information on all three axillary levels, and can quantify metastatic involvement. Moreover, PET can provide prognostic information (41), and, because it is a reproducible method, patients who do not undergo ANLD can be monitored during follow-up. Finally, multifocal or multicentric tumors or previous breast biopsy examinations do not affect PET performance. Our study lacked the ability to determine whether PET scans could be used to identify patients requiring adjuvant treatment because of low positive-predictive values for T1 patients and the small number of patients with lymph node-positive T1ab and T1c tumors (six and 14 patients, respectively).
We know that a single institution study may be a limitation; thus, we encourage multicenter studies to confirm the validity of routine use of PET in clinical practice to obtain information for the treatment of breast cancer. Our data do show that FDGPET can safely predict axillary status in patients with breast cancer and thus is a reliable, accurate, and noninvasive method to identify patients who can avoid ALND.
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NOTES |
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We are deeply indebted to Dr. Marco Sandri (Center for Scientific Calcolus, University of Verona, Italy) for mathematical help.
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Manuscript received July 12, 2000; revised January 30, 2001; accepted February 7, 2001.
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