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A Prospective Evaluation of Positron Emission Tomography Scanning, Sentinel Lymph Node Biopsy, and Standard Axillary Dissection for Axillary Staging in Patients with Early Stage Breast Cancer

From the Department of Surgery (PJL, SDC, CHG, VRT), Surgical Outcomes Research Centre, McMaster University and St. Joseph’s Healthcare; Department of Pathology (VC), McMaster University and St. Joseph’s Healthcare; Department of Nuclear Medicine (GC), McMaster University and Hamilton Health Sciences; Cancer Care Ontario (MNL, KS, VRT), Hamilton Regional Cancer Centre; Department of Clinical Epidemiology and Biostatistics (CHG, MNL, VRT), McMaster University; Centre For Evaluation of Medicines (CHG), St. Joseph’s Healthcare, Hamilton, Ontario; and Department of Surgical Oncology (CL), Toronto Sunnybrook Regional Cancer Centre, Toronto, Ontario.

Correspondence: Address correspondence and reprint requests to: Peter J. Lovrics, MD, St. Joseph’s Healthcare, 50 Charlton Avenue East, Hamilton, Ontario, Canada, L8N 4A6; Fax: 905-521-6042; E-mail: lovricsp{at}mcmaster.ca

	ABSTRACT

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Background: Positron emission tomography (PET) is a noninvasive imaging modality that can detect malignant lymph nodes. This study determined the sensitivity, specificity, predictive values, and likelihood ratios of PET scanning compared with standard axillary lymph node dissection (ALND) and sentinel lymph node biopsy (SLNB) in staging the axilla in women with early stage breast cancer.

Methods: Women with clinical stage I or II breast cancer had whole body PET scanning before ALND and SLNB, in a prospective, blinded protocol. ALND were evaluated by standard hematoxylin and eosin (H&E) staining techniques, while sentinel nodes were also examined for micrometastatic disease.

Results: A total of 98 patients were recruited. PET compared with ALND demonstrated sensitivity of 0.40 (95% CI, 0.16, 0.68), specificity 0.97 (CI, 0.90, 0.99), positive likelihood ratio 14.4 (CI, 3.21, 64.5), positive predictive value 0.75 (CI, 0.35, 0.97), and false–negative rate of 0.60 (CI, 0.32, 0.84). Test properties were similar for PET compared with sentinel nodes positive by H&E staining. A few false–positive scans (0.028, CI, 0.003, 0.097) were seen. Multiple logistic regression analysis found that PET accuracy was better in patients with high grade and larger tumors. Increased size and number of positive nodes were also associated with a positive PET scan.

Conclusions: The sensitivity of PET compared with ALND and SLNB was low, whereas PET scanning had high specificity and positive predictive values. The study suggests that PET scanning cannot replace histologic staging in early stage breast cancer. The low rate of false–positive findings suggests that PET can identify women who can forego SLNB and require full axillary dissection.

Key Words: Breast cancer • PET scanning • Sentinel node biopsy • 18 FDG • Staging

	INTRODUCTION

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Surgical treatment of patients with early stage breast cancer has evolved from radical mastectomy, to modified radical mastectomy, and, most recently, to breast conservation with axillary dissection. Breast irradiation after lumpectomy and adjuvant systemic therapy (chemotherapy and tamoxifen) are now mainstays of treatment. Throughout this evolution, the status of the regional axillary lymph nodes has remained the single most important independent variable in predicting prognosis, both for disease recurrence and survival. Although axillary lymph node dissection (ALND) is currently the standard of care in staging, it is an imperfect prognostic tool with clinically important morbidity. Numerous studies have documented the short- and long-term complications of ALND, and have found that ALND is a major cause of decreased cancer-specific quality of life.^1–7

Furthermore, effective regional disease control can be attained with nodal irradiation. These factors have led some authors to advocate a more restricted use of ALND in patients with early breast cancer,^8,9,10 and for the development of less invasive, and noninvasive means to stage the axilla. This is supported by the trend toward offering systemic therapy to women who are node-negative, and by the steady decrease in average primary tumor size as a result of screening and early detection, making the risk of axillary spread even lower in many women.^11,12

Development of sentinel lymph node biopsy (SLNB) has enabled precise axillary staging through a minimally invasive and less morbid surgical approach.^13–16 Lymphatic mapping used to identify the sentinel lymph node allows more precise and consistent identification of the node with the highest pathological yield, and enables more detailed analysis for micrometastatic disease.¹⁷ It still involves a surgical procedure, however. A noninvasive imaging test that can accurately stage the axilla in early stage breast cancer would be ideal.

Positron emission tomography (PET) scanning is a nuclear medicine imaging modality that demonstrates biochemical and physiologic activity, in addition to an anatomic image. It has been applied to clinical oncology because it has been shown that malignant cells exhibit increased glycolytic activity and are imaged preferentially by PET scanning. A radiolabeled glucose analog, 2-(fluorine-18)-fluoro-deoxy-D-glucose (18 FDG), injected intravenously, is preferentially taken up by malignant cells and trapped there, as tumor cells lack the capability to further metabolize 18 FDG. The emerging role of PET scanning in clinical oncology has been reviewed.^18,19 The available literature examining the utility of PET scanning in staging the axilla compared with ALND in early stage breast cancer is limited. The studies are small in size, have a number of methodological limitations, and the results are inconsistent.²⁰ PET scanning has not yet been adequately evaluated against SLNB in staging the axilla.

This study was conducted to evaluate the diagnostic accuracy of preoperative PET scanning in determining the presence or absence of tumor in axillary lymph nodes in women with biopsy-proven early stage breast cancer in comparison with both ALND and SLNB.

	PATIENTS AND METHODS

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Study Design and Patients
This was a prospective, blinded cohort study. Consecutive women with histologically proven adenocarcinoma of the breast scheduled to have an ALND as part of their surgical staging and management were evaluated for enrollment between December 1999 and January 2003. Exclusion criteria were (1) male gender; (2) clinical stage III or IV disease; (3) uncontrolled diabetes mellitus; (4) known multiple or multicentric breast cancer; (5) inflammatory breast cancer; (6) prior ALND; (7) pregnancy; and (8) participation in another research project. Written informed consent was obtained at enrollment and the institutional research ethics boards approved the research protocol.

Intervention
PET Imaging
Patients were required to fast for 4 hours, and to have two glasses of water 30 to 60 minutes before scanning. Plasma glucose level was checked via glucometer; if the level was >10 mmol/L, insulin was given at the discretion of the nuclear medicine physician. Patients were injected intravenously with 5 mCi 18 FDG in the contralateral hand; 45 minutes after injection, patients were positioned in the scanner with their arms above their heads. Whole body scans were performed in an ECAT ART (CTI/Siemens) PET scanner, with 47 slices per bed position (mean of five positions), overlap of 5 cm, spatial resolution 6 mm, and axial field of view 15 cm. Attenuation correction of images was not performed. A single nuclear physician, aware of the diagnosis of breast carcinoma and side involved but blinded to final pathology results, interpreted the scans. Interpretation was by visual and semiquantitative analyses as described previously.²¹ Visual analysis compares the axilla with background on a five-point confidence scale, whereas semiquantitative analysis compares counts per pixel of the lesions with background, generating a ratio.²¹ A final interpretation of negative, positive, or indeterminate was provided.

Surgery
Definitive surgery was performed within 14 days of the PET scan. SLNB was performed, followed by standard ALND (level I and II) and breast-conserving resection or modified radical mastectomy. The SLNB technique is as described by Bass et al.²² The morning of surgery or the afternoon of the day before surgery, 1.0 mCi of technetium 99 sulfur colloid was injected peritumorally or around the previous excision site. Lymphoscintigraphy was not routinely performed. Intraoperatively, vital blue dye (isosulfan or patent blue dye) was injected peritumourally, and the sentinel node was identified with the aid of a hand-held gamma probe. The surgeon was unaware of the PET scan result.

Histologic Evaluation
Pathological evaluation was by one of two dedicated pathologists, blinded to the PET scan results. All specimens were submitted in formalin. Number and size of sentinel nodes were documented. Sentinel nodes >0.5 cm in maximal dimension were serially sectioned transversely; those <0.5 cm were bisected. Three hematoxylin and eosin (H&E) stained slides at 50 µm apart were examined. If no metastases were identified in the original H&E slides, the sections were stained with the immunohistochemical cytokeratin marker Cam 5.2. If the Cam 5.2 stain was negative, serial sections (at 50 µm) were taken at three further levels. Micrometastatic disease was defined as any sentinel lymph node with a defined cluster of cells staining positive with Cam 5.2 that could subsequently be confirmed histologically on H&E sections or disease <2 mm in extent. Tissue from the ALND was submitted in formalin; nodes were numbered and measured. Nodes were sectioned as the sentinel node. Standard H&E examination was performed. The primary tumor was likewise submitted in formalin (lumpectomy or mastectomy), and evaluated after H&E staining. Size, grade, margins and estrogen and progesterone status were determined.

Statistical Analysis
Sensitivity, specificity, positive and negative predictive values, false–positive and false negative rates, and likelihood ratios were calculated comparing PET scanning to SLNB and standard ALND using StatXact 4.0 statistical software (Cytel Software Corporation, Cambridge, MA).

Likelihood ratios (LR) measure the accuracy of a diagnostic test and, therefore, the clinical usefulness of a diagnostic test. LR express the probability of a positive or negative test result in "diseased" people compared with the probability of the same test result in "non-diseased" people. They are the preferred analysis to evaluate the usefulness of a diagnostic test as they are not dependent on prevalence rates.^23,24 LR >1 increase the probability that the disease is present: the higher the LR, the greater this increase. Conversely, LR <1 decrease the probability that disease is present. LR >10 or <0.1 generate large and often conclusive changes from pretest probabilities. Values between 2 to 0.5 alter probability to a very small and rarely relevant degree.²⁴ Confidence intervals of 95% were calculated for each test characteristic. Univariable and multivariable logistic regression were used to establish the relationship between independent variables (i.e., tumor stage, tumor grade, histologic type, age, quadrant, estrogen receptor status, and intraductal component) and PET scan visualization, using SigmaStat 2.03 statistical software (SPSS Inc., Chicago, IL). Statistical significance was set at the 5% level.

	RESULTS

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A total of 155 consecutive patients were approached and 115 gave informed consent. Seventeen patients subsequently withdrew consent because of anxiety and perceived inconvenience before PET scanning, leaving 98 participating patients. Six patients did not have PET scanning because of machine or FDG unavailability. Two more patients could not complete their PET scan because of acute anxiety. Thus, 90 patients had both PET scanning and full ALND. In four patients, a sentinel node could not be found, whereas in 1 patient a sentinel node was found but was not included in the SLNB calculations because of unclear labeling. In five patients, SLNB was not attempted because of gamma probe or radiocolloid unavailability, leaving 80 patients with successful SLNB and ALND. Of these 80 patients, 8 did not complete PET scanning, leaving 72 patients with SLNB, ALND, and PET scans.

Patient and primary tumor characteristics are detailed in Table 1. More than 40% of women required needle localization, whereas 14% of women opted for modified radical mastectomy despite being candidates for partial mastectomy. A total of 14 patients had previous diagnostic excisional biopsy of the primary tumor before enrollment. Of tumors, 80% were T1 lesions; one lesion was found to be a T3 lesion on final pathology. Six patients were found to have multifocal disease on final pathology.

Test properties of PET scanning compared with ALND, ALND + SLNB by routine H&E staining, and compared with SLNB (routine H&E and micrometastatic disease) alone, are presented in Table 2. In the 90 patients with PET scans, the scan was interpreted as positive in 9 of the 25 patients where the standard ALND or SLNB was positive by routine H&E staining (sensitivity 0.36, false–negative rate 0.64)(Fig. 1). The PET scan was interpreted as positive in 2 patients where the standard ALND and SLNB were negative (2 of 90; specificity 0.97, false–positive rate 0.03). The PET scan was interpreted as indeterminate in 3 patients, 2 of whom had previous excisional biopsies. Both patients with N2 disease had positive PET scans. In seven patients, the PET scans were negative despite having malignant nodes >1.5 cm in diameter. Scans were also negative in five patients with three or more nodes positive by routine H&E; one patient had eight malignant nodes, grade III, and a negative PET scan (Fig. 2). Of true positive PET scans, 50% were grade III tumors, whereas 42% of the false–negative findings occurred in grade I tumors.

View larger version (59K): [in this window] [in a new window]   FIG. 1. A woman 51 years of age with a 2 cm, grade III tumor in the lower, outer quadrant of the left breast. Coronal, transaxial, and sagittal positron emission tomography images demonstrate the primary tumor (single arrow), and multiple positive axillary nodes (double arrows). A total of 13 nodes were positive in the full axillary node dissection.

View larger version (63K): [in this window] [in a new window]   Fig. 2. A woman 81 years of age with a 2.5 cm, grade III tumor in the upper, inner quadrant of the right breast. Coronal, transaxial, and sagittal positron emission tomography images demonstrate the primary tumor (single arrow), and the false–negative axilla. Final pathology revealed eight malignant nodes in the axilla.

Table 4 summarizes visualization of the primary tumor by PET scanning. Only 51.3% of the primary tumors were visualized. Multivariable logistic regression (Table 5) showed that only primary tumor grade and size are independent predictors of PET scan visualization of the primary tumor (P < .01). Odds ratios calculated for tumor grade indicate that a woman with a grade III lesion was four times more likely to have a positive PET scan (odd ratio = 4.07; CI 95%, 1.47, 11.26; P = .007) compared with a grade 1 lesion, and that a T2 lesion was more than four times more likely to have a positive PET scan than a T1a/b lesion (odd ratio = 4.17; CI 95%, 1.57, 10.62; P = .002).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
This study determined the accuracy of PET scanning compared with both complete ALND and SLNB in staging the axilla in women with early stage breast cancer. The sensitivity of PET compared with ALND and SLNB was low (Table 2). On subgroup analysis, poorly differentiated tumors, large tumors, and increased size and numbers of positive axillary nodes were more likely to be associated with a positive PET scan. Our study did show that PET scanning had high specificity and false–positive findings were rare. The positive likelihood ratios of PET compared with ALND and SLNB were high, indicating that a positive PET scan is a highly accurate diagnostic test compared with surgical staging. The corresponding negative LR were low, indicating that a negative PET scan does not accurately reflect nodal status.

A number of studies have examined the accuracy of PET scanning compared with ALND. Many of these were small in sample size and were limited by their methodology.^25–30 In contrast with our study, Greco et al.³¹ reported a sensitivity of 94% and a specificity of 86% in 167 patients having ALND. In Greco et al.,³¹ more than 40% of patients had T2 tumors and 43% of patients had positive nodes, suggesting a group of patients with more advanced disease. In the T1a/b population (48 patients), the sensitivity was 86% and specificity was 88%. Schirrmeister et al.,³² reported on PET scans in 117 women. In their study, sensitivity was 79% and specificity was 92%, with a false–negative rate of 20% in comparison with ALND. Only 89 of the patients, however, were found to have breast cancer. Furthermore, in the subgroup with confirmed malignancy, 55% were stage II, and 17% stage III, again suggesting a group of patients with more advanced disease. Similar to our series, Danforth et al.³⁰ noted poor sensitivity (42.9%) in stage I or II disease in a series of 46 patients. Sensitivity increased to 83% in stage III and IV disease.

Few studies have compared preoperative PET scanning with SLNB and this study represents the largest reported series. PET scanning specificity was high (0.96, CI, 0.86, 0.99); however sensitivity was poor: 0.27 (CI, 0.11, 0.50), and the false–negative rate was 72%. Three previous reports of smaller series of patients yielded similar sensitivities (25% to 43%) and low false–positive rates.^33–36 As in our series of patients, PET scanning was occasionally able to identify sentinel nodes with micrometastatic disease, but the overall sensitivity was very low.

Proponents of staging the axilla with PET scanning have put forward various algorithms in the management of patients with breast cancer.^{14,29,31,35,36} In studies where sensitivity is high and false–negative findings rare, it has been suggested that a negative PET scan can obviate the need for surgical staging. In our study, however, the false–negative rates for PET scans compared with the gold standard ALND, with ALND and SLNB positive by routine H&E staining, and with only SLNB positive by H&E and immunohistochemistry were high, and sensitivities were low (Table 2). Thus, PET scanning is not sensitive enough to replace surgical staging in early breast cancer. Although PET seems to be more accurate with larger and more advanced lesions, it is the patient in the early stage of disease who is most clinically relevant. Women with advanced local or regional disease will be offered systemic therapy and full nodal dissection in most settings. Our results did demonstrate that PET scanning had high specificity and positive likelihood ratios versus both ALND and SLNB (Table 2). Accordingly, a positive scan could be considered an indication for a full ALND. The use of PET scanning in advanced breast cancer (stage III and IV) has also been suggested. Small series have been reported, where PET scanning is used before and after systemic therapy to assess axillary and distant metastases.^30,34,36,37 Our study did not include patients with stage III or IV disease.

Factors that determine PET scan visualization of malignant lymph nodes in breast cancer have not yet been precisely determined. In a study by van der Hoeven et al.,³⁵ a statistically significant correlation was found between axillary tumor load and PET accuracy, and PET accuracy also paralleled visualization of the primary tumor. Avril et al.³⁶ and Greco et al.³¹ also found a correlation between size of the primary tumor and axillary visualization. Our study results are consistent with these findings. PET accuracy was improved in the subset of patients where the primary tumor was visualized, and PET scan sensitivity correlated with tumor grade, primary tumor size, and number of involved axillary lymph nodes.

Technical differences in PET scanning are a potential limitation to this study. The ECAT ART (CTI/Siemens) provides high sensitivity and high resolution. It operates with a three-dimensional reconstruction algorithm. In contrast with most publications comparing PET scanning and surgical axillary staging, in this study scanning and interpretation occurred without attenuation correction. Attenuation correction involves the correction of PET data for the attenuation of the 511 Kev gamma rays by body tissue, and may improve the interpretation of the images. In three recent publications, however, non-corrected images were either superior or comparable to PET interpretation using attenuation correction.^21,38,39 In our study, all scans were interpreted by a single, experienced nuclear medicine physician, blinded to the final pathology, according to a standardized scale.²¹ Further evolution of PET scanners is occurring; however, it is likely that current and foreseeable developments will lead to faster image acquisition. Improved resolution and sensitivity may depend on both technologic advances in PET imaging and the development of new radiopharmaceutical labels in the future.

Our prospective evaluation of PET scanning in patients with early stage breast cancer suggests that PET scanning cannot replace surgical staging and histologic confirmation of nodal status provided by the gold standard ALND and PET imaging does not offer the enhanced staging potential of sentinel lymph node biopsy. In our study, the false–positive rate of PET was very low. Hence it is possible that a positive PET can identify women who require ALND and could forego SLNB, but this requires further study. Although possible roles for PET scanning in breast cancer may evolve, it should not be offered routinely as a noninvasive way to stage the axilla in early stage breast cancer.

	ACKNOWLEDGMENTS

 
Funding for this study was provided by a Canadian Breast Cancer Research Initiative IDEA grant (CBCRI), a Father Sean O’Sullivan Research Centre (FSORC) Seed Grant, St. Joseph’s Healthcare Hamilton and funds from Department of Surgery, McMaster University. The authors would like to thank Sheila Sprague, Luann Wu, Dana Wood and Abigail D’Sa for their assistance with data collection.

	FOOTNOTES

 
Positron emission tomography (PET) offers the capability to noninvasively stage breast cancer in patients. This prospective, cohort study yielded low sensitivity and high specificity when PET was compared with axillary dissection and sentinel lymph node biopsy in women with early stage breast cancer.

Received for publication November 21, 2003. Accepted for publication June 8, 2004.

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