REPORT

Axillary Lymph Node Staging in Breast Cancer by 2-Fluoro-2-deoxy-D-glucose–Positron Emission Tomography: Clinical Evaluation and Alternative Management

Marco Greco, Flavio Crippa, Roberto Agresti, Ettore Seregni, Alberto Gerali, Riccardo Giovanazzi, Andrea Micheli, Salvatore Asero, Cristina Ferraris, Massimiliano Gennaro, Emilio Bombardieri, Natale Cascinelli

Affiliations of authors: M. Greco, R. Agresti, R. Giovanazzi, S. Asero, C. Ferraris, M. Gennaro (General Surgery B—Breast 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 B—Breast Unit, National Cancer Institute, Via Venezian 1, 20133 Milan, Italy (e-mail: r.agresti{at}iol.it).


    ABSTRACT
 Top
 Notes
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Background: Surgical removal of axillary lymph node and histologic examination for metastases are used to determine whether adjuvant treatment is necessary for patients with breast cancer. Axillary lymph node dissection (ALND) is a costly procedure associated with various side effects, and 80% or more of patients with tumors of 20 mm or less are lymph node negative and might avoid ALND. In this study, we evaluated whether an alternative, noninvasive method—i.e., positron emission tomography (PET) with 2-[18F]fluoro-2-deoxy-D-glucose (FDG)— could be used to determine axillary lymph node status in patients with breast cancer. Methods: One hundred sixty-seven consecutive patients with breast cancers of 50 mm or less (range = 5–50 mm; mean = 21 mm) scheduled for complete ALND were studied preoperatively with FDG–PET, and then PET and pathology results from ALND were compared. All statistical tests were two-sided. Results: The overall sensitivity, specificity, and accuracy of lymph node staging with PET were 94.4% (PET detected 68 of 72 patients with axillary involvement; 95% confidence interval [CI] = 86.0% to 98.2%), 86.3% (82 of 95 patients without axillary involvement; 95% CI = 77.8% to 91.9%), and 89.8% (150 of 167 patients with breast cancer; 95% CI = 84.2% to 93.6%), respectively. Positive- and negative-predictive values were 84.0% (68 patients with histologically positive lymph nodes of 81 patients with positive FDG–PET scan; 95% CI = 74.2% to 90.5%) and 95.3% (82 patients with histologically negative lymph nodes of 86 patients with negative FDG–PET scan; 95% CI = 88.2% to 98.5%), respectively. When PET results for axillary metastasis were analyzed by tumor size, the diagnostic accuracy was similar for all groups (86.0%–94.2%), with higher sensitivity for tumors of 21–50 mm (98.0%) and higher specificity for tumors of 10 mm or less (87.8%), and the range was 93.5%–97.3% for negative-predictive values and 54.5%–94.1% for positive-predictive values. Among the 72 patients with axillary involvement, PET detected three or fewer metastatic lymph nodes in 27 (37.5%) patients, about 80% of whom had no clinically palpable axillary lymph nodes. Conclusions: Noninvasive FDG–PET appears to be an accurate technique to predict axillary status in patients with breast cancer and thus to identify patients who might avoid ALND. These results should be confirmed in large multicenter studies.



    INTRODUCTION
 Top
 Notes
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Management of the axilla in patients with operable breast cancer is currently one of the most controversial areas in clinical oncology. During the last decade, many groups have attempted to simplify surgical procedures. Currently, axillary lymph node dissection (ALND) is recommended for all patients with invasive tumors of 20 mm or less (stage T1), despite the well-known morbidity, its cost, and the presence of axillary metastases in only 3%–20% of these patients (i.e., >=80% of patients with such tumors are lymph node negative), suggesting that ALND is unnecessary in the overwhelming majority of patients with stage T1 breast cancer (15). Nevertheless, the exact axillary status is necessary, and there is no alternative, effective method to ALND to assess whether the cancer has spread to the axillary region. One-day, prognostic parameters of the primary tumor, now under consideration, might supplant the need for histopathologic evaluation of axillary lymph nodes (6,7). Sentinel lymph node biopsy (816), guided by a radioactive probe after lymphoscintigraphy, has been investigated as a way to modulate ALND by histologically examining only the sentinel lymph node, but this approach has technical and conceptual limits (17). Positron emission tomography (PET) coupled with 2-[18F]fluoro-2-deoxy-D-glucose (FDG) is an alternative noninvasive approach (18,19). We have previously reported (20) data on this issue from 68 patients with operable breast cancer, who are also included in this study. In that study, we showed that PET can detect axillary metastases with a good overall diagnostic accuracy of 86%, which rose to 95% in patients with palpable but clinically uninvolved axillary lymph nodes (N1a). A PET evaluation might also contribute to the prognostic characterization of breast cancer; recently, the relationship between PET and other biologic or pathologic prognostic parameters of the primary tumor has been investigated (21).

In this study, our goal was to use FDG–PET prospectively to investigate whether PET could be used to identify involved axillary lymph nodes and thus to identify patients who might avoid ALND.


    PATIENTS AND METHODS
 Top
 Notes
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Patients and Surgical Treatment

We studied 167 consecutive patients with T1 (<=20 mm) or T2 (21–50 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 = 28–84 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 = 5–50 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 1–7 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 45–60 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 T1a–b (<=10 mm), T1c (11–20 mm), or T2 (21–50 mm). Lymph nodes isolated from axillary fat tissue were formalin fixed, paraffin embedded, and stained with hematoxylin–eosin. 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 FDG–PET 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.


    RESULTS
 Top
 Notes
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 
On average, 23 lymph nodes per patient were surgically removed (range = 9–49). From the histopathologic examination, metastases were found in 72 (43%) of the 167 patients. As expected, the percentage of metastases increased progressively with tumor size from 15% (seven of 48 patients) in T1a–b tumors, to 32% (16 of 50 patients) in T1c tumors, and to 71% (49 of 69 patients) in T2 tumors.

Table 1Go 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 FDG–PET scan; 95% CI = 74.2% to 90.5%) and 95.3% (82 patients with histologically negative lymph nodes of 86 patients with a negative FDG–PET 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.


View this table:
[in this window]
[in a new window]
 
Table 1. Overall results for positron emission tomography with 2-[18F]fluoro-2-deoxy-D-glucose (FDG–PET) in the detection of axillary metastases*
 
Table 2Go summarizes the histopathologic findings from the four patients with false-negative PET results in our study. In these patients, the extent of metastatic involvement was minimal: five lymph nodes with metastases (two with partial involvement and three with microscopic involvement) in a total of 78 lymph nodes removed from these patients.


View this table:
[in this window]
[in a new window]
 
Table 2. Type of metastatic involvement in false-negative positron emission tomography*
 
Data from patients were then grouped according to tumor size (T1a–b, T1c, and T2; Table 3Go) and reanalyzed. The diagnostic accuracy of PET was quite similar (86.0%–94.2%) in all groups, with the highest sensitivity in T2 tumors (98.0%) and the highest specificity in T1a–b tumors (87.8%). Negative-predictive values of PET ranged from 93.5% to 97.3%, and positive-predictive values ranged from 54.5% to 94.1%.


View this table:
[in this window]
[in a new window]
 
Table 3. Positron emission tomography (PET) results in the detection of axillary metastases according to tumor size*
 
Fig. 1Go shows examples of transaxial PET images of axillary lymph nodes with metastases; lymph node status was later confirmed histopathologically. In some patients, abnormal FDG uptake in the retrosternal region was detected. Even in the absence of histologic confirmation, these PET findings were highly suggestive of metastases in the internal mammary lymph nodes, and these findings emphasize the potential of PET to evaluate the entire lymph node basin in breast cancer. No abnormal uptake of FDG in the supraclavicular region was detected in any patient studied.



View larger version (51K):
[in this window]
[in a new window]
 
Fig. 1. A) Transaxial slice of the axillary region showing a single area of high 2-[18F]fluoro-2-deoxy-D-glucose (FDG) uptake on the right (arrow) (one partial axillary metastasis at histologic examination). B) Transaxial slice of the axillary regions showing two areas of high FDG uptake on the left (arrows) (two microembolic nodal involvements at histologic examination). Ant = anterior.

 

    DISCUSSION
 Top
 Notes
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 
The Halstedian concept of extended surgery to cure breast cancer and to improve overall survival has changed progressively during the last 25 years. Conservative surgery, radiotherapy, and medical treatments have had dramatic results, and new conceptual perspectives have arisen. Breast cancer has been regarded as a predominantly systemic disease, and variations in effective locoregional treatment are unlikely to affect survival substantially (25). Recently, it has been suggested (26) that prophylactic ANLD may play a role in breast cancer survival, although the confidence levels of Bayesian meta-analysis of clinical trials performed in the 1960s and the 1970s are debatable. Experience with adjuvant treatments, with the substantial reduction in the annual probability of death and absolute improvement in survival, has further changed the thinking of physicians (27). Consequently, ANLD has been accepted as a staging rather than as a therapeutic option, and determination of complete and accurate clearance of the axilla has become therapeutically important only for those patients with clinically involved axillary lymph nodes. However, because 80% or more of patients with T1 breast cancer are axillary lymph node negative by histologic examination, the challenge is to devise methods that identify patients who can safely be spared axillary surgery.

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 FDG–PET 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 FDG–PET scan; 95% CI = 84.7% to 99.9%) for patients with T1a–b 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 FDG–PET 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 FDG–PET was confirmed by the results from patients with T2 breast carcinoma. For these patients, FDG–PET had a negative-predictive value of 94.4% (17 of 18 patients with negative FDG–PET 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 FDG–PET studies are conducted, patients should fast, and their blood glucose concentration should be taken into account when the FDG–PET results are evaluated (39). Thus, potential pitfalls associated with diabetic patients must be considered, and, in general, diabetics should be excluded from FDG–PET 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 {gamma}-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 FDG–PET 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 T1a–b 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 T1a–b 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 FDG–PET 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.


    NOTES
 
Supported in part by the Progetto Finalizzato Ministero Sanità and the Associazione Italiana Ricerca sul Cancro.

We are deeply indebted to Dr. Marco Sandri (Center for Scientific Calcolus, University of Verona, Italy) for mathematical help.


    REFERENCES
 Top
 Notes
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

1 Copeland EM. Is axillary dissection necessary for T1 carcinoma of the breast? [editorial]. J Am Coll Surg 1997;184:341–5.[Medline]

2 Haffty BG, Ward B, Pathare P, Salem R, McKhann C, Beinfield M, et al. Reappraisal of the role of the axillary lymph node dissection in the conservative treatment of breast cancer. J Clin Oncol 1997;15:691–700.[Abstract]

3 Silverstein MJ, Gierson ED, Waisman JR, Senofsky GM, Coldburn WJ, Gamagami P. Axillary lymph node dissection for T1a breast carcinoma. Is it indicated? Cancer 1994;73:664–7.

4 Dees EC, Shulman LN, Souba WW, Smith BL. Does information from axillary dissection change treatment in clinically node-negative patients with breast cancer? An algorithm for assessment of impact of axillary dissection. Ann Surg 1997;226:279–86.[Medline]

5 Cabanes PA, Salmon RJ, Vilcoq JR, Durand JC, Fourquet A, Gautier C, et al. Value of axillary dissection in addition to lumpectomy and radiotherapy in early breast cancer. The Breast Carcinoma Collaborative Group of the Institut Curie. Lancet 1992;339:1245–8.[Medline]

6 Menard S, Bufalino R, Rilke F, Cascinelli N, Veronesi U, Colnaghi MI. Prognosis based on primary breast carcinoma instead of pathological nodal status. Br J Cancer 1994;70:709–12.[Medline]

7 Greco M, Agresti R, Cascinelli N, Casalini P, Giovanazzi R, Maucione A, et al. Breast cancer patients treated without axillary surgery: clinical implication and biologic analysis. Ann Surg 2000;232:1–7.[Medline]

8 Keshtgar MR, Ell PJ. Sentinel lymph node detection and imaging. Eur J Nucl Med 1999;26:57–67.[Medline]

9 Nieweg OE, Jansen L, Valdes Olmos RA, Rutgers EJ, Peterse JL, Hoefnagel KA, et al. Lymphatic mapping and sentinel node biopsy in breast cancer. Eur J Nucl Med 1999;26(4 Suppl):S11–6.[Medline]

10 Giuliano AE, Kirgan DM, Guenther JM, Morton DL. Lymphatic mapping and sentinel lymphadenectomy for breast cancer. Ann Surg 1994;220:391–8; discussion 398–401.[Medline]

11 Veronesi U, Paganelli G, Viale G, Galimberti V, Luini A, Zurrida S, et al. Sentinel lymph node biopsy and axillary dissection in breast cancer: results in a large series. J Natl Cancer Inst 1999;91:368–73.[Abstract/Free Full Text]

12 Krag D, Weaver D, Ashikaga T, Moffat F, Klimberg VS, Shriver C, et al. The sentinel node in breast cancer—a multicenter validation study. N Engl J Med 1998;339:941–6.[Abstract/Free Full Text]

13 Cox CE, Pendas S, Cox JM, Joseph E, Shons AR, Yeatman T, et al. Guidelines for sentinel node biopsy and lymphatic mapping of patients with breast cancer. Ann Surg 1998;227:645–51; discussion 651–3.[Medline]

14 Borgstein PJ, Pijpers R, Comans EF, van Diest PJ, Boom RP, Meijer S. Sentinel lymph node biopsy in breast cancer: guidelines and pitfalls of lymphoscintigraphy and gamma probe detection. J Am Coll Surg 1998;186:275–83.[Medline]

15 Snider H, Dowlatshahi K, Fan M, Bridger WM, Rayudu G, Oleske D. Sentinel node biopsy in the staging of breast cancer. Am J Surg 1998;176:305–10.[Medline]

16 O'Hea BJ, Hill AD, El-Shirbiny AM, Yeh SD, Rosen PP, Coit DG, et al. Sentinel lymph node biopsy in breast cancer: initial experience at Memorial Sloan-Kettering Cancer Center. J Am Coll Surg 1998;186:423–7.[Medline]

17 McMasters KM, Giuliano AE, Ross MI, Reintgen DS, Hunt KK, Byrd DR, et al. Sentinel-lymph-node biopsy for breast cancer—not yet the standard of care. N Engl J Med 1998;339:990–5.[Free Full Text]

18 Wagner HN. A brief history of positron emission tomography (PET). Semin Nucl Med 1998;28:213–20.[Medline]

19 Flanagan FL, Dehdashti F, Siegel BA. PET in breast cancer. Semin Nucl Med 1998;28:290–302.[Medline]

20 Crippa F, Agresti R, Seregni E, Greco M, Pascali C, Bogni A, et al. Prospective evaluation of fluorine-18-FDG PET in presurgical staging of the axilla in breast cancer. J Nucl Med 1998;39:4–8.[Abstract]

21 Crippa F, Seregni E, Agresti R, Chiesa C, Pascali C, Bogni A, et al. Association between [18F]fluorodeoxyglucose uptake and postoperative histopathology, hormone receptor status, thymidine labelling index and p53 in primary breast cancer: a preliminary observation. Eur J Nucl Med 1998;25:1429–34.[Medline]

22 Agresti A, Coull B. Approximate is better than exact for interval estimation of binomial proportions. Am Statistician 1998;52:119–26.

23 Newcombe R. Two-sided confidence intervals for the single proportion: comparison of seven methods. Stat Med 1998;17:857–72.[Medline]

24 Gleason JR. Sg119. Improved confidence interval for binomial proportions. Stata Technical Bulletin 1999;52:16–8.

25 Fisher B. Laboratory and clinical research in breast cancer—a personal adventure: the David A. Karnovsky memorial lecture. Cancer Res 1980;40:3863–74.[Medline]

26 Orr RK. The impact of prophylactic axillary node dissection on breast cancer survival— a Bayesian meta-analysis. Ann Surg Oncol 1999;6:109–16.[Abstract/Free Full Text]

27 Early Breast Cancer Trialists' Collaborative Group. Polychemotherapy for early breast cancer: an overview of the randomised trials. Lancet 1998;352:930–42.[Medline]

28 Tse NY, Hoh CK, Hawkins RA, Zinner MJ, Dahlbom M, Choi Y, et al. The application of positron emission tomographic imaging with fluorodeoxyglucose to the evaluation of breast disease. Ann Surg 1992;216:27–34.[Medline]

29 Hoh CK, Hawkins RA, Glaspy JA, Dahlbom M, Tse NY, Hoffman EJ, et al. Cancer detection with whole-body PET using 2-[18F]fluoro-2-deoxy-D-glucose. J Comput Assist Tomogr 1993;17:582–9.[Medline]

30 Wahl RL, Cody RL, Hutchins GD, Mudgett EE. Primary and metastatic breast carcinoma: initial clinical evaluation with PET with the radiolabeled glucose analogue 2-[F-18]-fluoro-2-deoxy-D-glucose. Radiology 1991;179:765–70.[Abstract]

31 Nieweg OE, Kim EE, Wong WH, Broussard WF, Singletary SE, Hortobagyi GN, et al. Positron emission tomography with fluorine-18-deoxyglucose in the detection and staging of breast cancer. Cancer 1993;71:3920–5.[Medline]

32 Adler LP, Faulhaber PF, Schnur KC, Al-Kasi NL, Shenk RR. Axillary lymph node metastases: screening with [F-18]2-deoxy-2-fluoro-D-glucose (FDG) PET. Radiology 1997;203:323–7.[Abstract]

33 Smith IC, Ogston KN, Whitford P, Smith FW, Sharp P, Norton M, 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.[Medline]

34 Avril N, Dose J, Janicke F, Ziegler S, Romer W, Weber W, et al. Assessment of axillary lymph node involvement in breast cancer patients with positron emission tomography using radiolabeled 2-(fluorine-18)-fluoro-2-deoxy-D-glucose. J Natl Cancer Inst 1996;88:1204–9.[Abstract/Free Full Text]

35 Budinger TF. PET instrumentation: what are the limits? Semin Nucl Med 1998;28:247–67.[Medline]

36 Noh DY, Yun IJ, Kim JS, Kang HS, Lee DS, Chung JK, et al. Diagnostic value of positron emission tomography for detecting breast cancer. World J Surg 1998;22:223–7; discussion 227–8.[Medline]

37 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]

38 Wahl RL, Henry CA, Ethier SP. Serum glucose: effects on tumor and normal tissue accumulation of 2-[F-18]-fluoro-2-deoxy-D-glucose in rodents with mammary carcinoma. Radiology 1992;183:643–7. [Abstract]

39 Crippa F, Gavazzi C, Bozzetti F, Chiesa C, Pascali C, Bogni A, et al. The influence of blood glucose levels on [18F]fluorodeoxyglucose (FDG) uptake in cancer: a PET study in liver metastases from colorectal carcinomas. Tumori 1997;83:748–52.[Medline]

40 van der Wall E. The sentinel node in breast cancer: implication for adjuvant treatment? Eur J Nucl Med 1999;26(4 Suppl):S17–9.[Medline]

41 Oshida M, Uno K, Suzuki M, Nagashima T, Hashimoto H, Yagata H, et al. Predicting the prognoses of breast carcinoma patients with positron emission tomography using 2-deoxy-2-fluoro[18F]-D-glucose. Cancer 1998;82:2227–34.[Medline]

Manuscript received July 12, 2000; revised January 30, 2001; accepted February 7, 2001.


This article has been cited by other articles in HighWire Press-hosted journals:


             
Copyright © 2001 Oxford University Press (unless otherwise stated)
Oxford University Press Privacy Policy and Legal Statement