| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
ORIGINAL ARTICLES |
From the Department of Surgery, Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, Florida.
Correspondence: Address correspondence and reprint requests to: Douglas Reintgen, MD, Cancer Center Director, Lakeland Regional Cancer Center, 300 Parkview Place, P.O. Box 95448, Lakeland, FL 33805; Fax: 863-413-5997; E-mail: doug.reintgen{at}lrmc.com
 |
ABSTRACT |
|---|
 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAPPENDIX 1REFERENCES |
|---|
Methods: Lymphatic mapping techniques involving the combined use of blue dye and radiocolloid were taught to participating surgeons through a formal 2-day training course at the Moffitt Cancer Center. In protocol 1, surgeons performed their first 20 to 25 cases of breast mapping with SLN biopsy followed by complete axillary lymph node dissection. In protocol 2, after the learning phase, surgeons did not perform axillary lymph node dissection unless a SLN was positive for metastatic disease.
Results: Forty-two institutions, including 12 university-based research centers, participated in the trial. From July 1, 1997, through January 31, 1999, a total of 965 patients were accrued. Lymphoscintigraphy identified drainage to an axillary SLN 64% of the time, but by using sensitive handheld gamma probes at the time of the operation, an axillary SLN could be identified 86% of the time. The rate of success for finding an axillary SLN was 92.8% for cases performed at the Moffitt Cancer Center. For other university centers, the rate of success of identifying an axillary SLN was 91.4%, and for other community/regional hospitals in the study, it was 85.2%. For cases in which protocol 1 was followed, the rate of false-negative SLN biopsy was 4%. There was no axillary nodal recurrence after a negative SLN in protocol 2 when a negative SLN biopsy was followed by observation. The median follow-up for the patients on protocol 2 was 16 months.
Conclusions: These data show a high rate of success for finding an axillary SLN and a low rate of skip metastasis in a national multicenter study of lymphatic mapping for breast cancer. This study suggests that SLN biopsy for breast cancer can be performed successfully in community/regional hospitals, as well as in major university-based centers.
Key Words: Lymphatic mapping • Sentinel lymph node biopsy • Nodal staging • Lymphoscintigraphy
|
INTRODUCTION |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAPPENDIX 1REFERENCES |
|---|
Preoperative lymphoscintigraphy was also studied in the protocol. This nuclear medicine test is an integral part of the lymphatic mapping procedure in patients with melanoma, the tumor system in which the concept of radioguided surgery was initially established. For melanoma, lymphoscintigraphy identifies the basin at risk for metastases, in-transit nodes (in 5% of patients), the number of SLNs that has to be collected to accurately stage the patient, and the relationship of the location of the SLNs to other neighboring non-SLNs in the basin. The role of lymphoscintigraphy in the breast lymphatic mapping procedure is poorly defined and was also investigated in this national trial.
The national trial had three funded-specific aims. The first was to determine the rate of successful localization of SLNs in breast cancer patients. We hypothesized that the success rate for identification of one or more SLNs in breast cancer patients from multiple institutions would be similar to that from MCC and other published trials and would be high enough to make lymphatic mapping a viable procedure across surgical practices. The second aim was to determine the incidence of skip metastasis in breast cancer patients. We hypothesized that the incidence of skip metastases in the axillary basin of patients with invasive breast cancer would be <5%, which is low enough to make selective sentinel node biopsy clinically useful in these patients. The first two aims determine the viability of the technique across surgical practices. The third aim was to determine the utility of preoperative lymphoscintigraphy in patients with breast cancer. We hypothesized that this preoperative study could be used to identify a subset of women who have no axillary drainage and can be spared any further type of axillary staging procedure. In addition, whether lymphoscintigraphy could identify women with breast cancer who have multidirectional drainage from their primary tumor sites was also investigated.
|
MATERIALS AND METHODS |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAPPENDIX 1REFERENCES |
|---|
From July 1, 1997, through January 31, 1999, a total of 965 patients were accrued, including 192 patients from the home institution. The mean age was 59 years (range, 27–89 years). Infiltrating ductal carcinoma predominated the histological type of the cancers, accounting for 77% of the tumors. Ten percent of the cancers were infiltrating lobular, with the remaining 13% of the cancers being divided among nine other histopathologic types. Most of the tumors were either T1 or T2, with 96% of the women being in the early stages of their breast cancer. Lumpectomies and breast preservation were performed in 75% of the women.
The study was approved by the University of South Florida institutional review board (IRB) and by each of the participating institutions’ IRBs and met the guidelines of the DoD. This IRB-approved study excluded patients who were pregnant or had clinically positive lymph nodes.
Technique of Preoperative Lymphoscintigraphy
On the day of the operation, patients were brought to the nuclear medicine suite for their preoperative lymphoscintigraphy study. Women with palpable tumors were injected with six injections around the periphery of the tumor at the depth of the mass. No attempt was made to inject above or below the tumor. This was a breast parenchymal injection, as opposed to the skin and subareolar plexus injections favored by some groups.1,2 Women who had had an excisional biopsy to diagnose their breast cancer were injected around the rim of the biopsy cavity, making sure that the injection was outside the cavity by use of either palpation or ultrasound examination. For patients with mammographic abnormalities, the mapping agents (radiocolloid or vital blue dye) were injected around the previously placed localization wire with either mammographic or ultrasound guidance. The injection was outside the cancer diffusely around the circumference and was not injected down the localization wire.
Of the 965 women on the study, 617 (64%) underwent preoperative lymphoscintigraphy with approximately 450 µMi of a .22-µm filtered 99mTc sulfur colloid. The patients were then imaged in a dynamic fashion starting at 15 minutes after the injection. Breast massage was used in the nuclear medicine suite in the later part of the study in an attempt to increase interstitial pressure and help drive the mapping agents into the lymphatics. The breast massage was intermittent to allow the valves in the lymphatic channels time to open and the mapping agents to flow. An increased volume of injectate was used (6 mL) to place the mapping agent diffusely around the circumference of the tumor and to increase interstitial pressure. The patients were then imaged in a dynamic fashion starting at 15 minutes after injection. Images were acquired over 8 to 10 minutes per view to ensure high count density. A standard large-field gamma camera, a high-resolution collimator, and a 10% imaging window at the 140-keV energy peak were used for preoperative imaging. A cobalt flood source or a hot marker was used to provide an outline of the body to obtain anatomical landmarks of reference for the imaged SLNs.
The patient was positioned with the arm over the head to optimize axillary exposure and distance between the primary site and the regional basins. Lateral and anterior-posterior views of the chest were obtained. The lateral view has previously been found to be important in unmasking the axillary SLN from the star artifact of the primary site injection. Internal mammary and supraclavicular lymph nodes were noted and marked in the anterior projection, whereas the axillary SLNs were tattooed with the patient in the lateral position with the arm held above the head.
Technique of Intraoperative Lymphatic Mapping and SLN Biopsy
The patients were then taken to the operating room to undergo an SLN biopsy procedure. Briefly, the patients were placed in the supine position and given general anesthesia. The breast was then prepared and draped in the usual fashion. Five milliliters of a vital blue dye (Lymphazurin, 1% isosulfan blue; USSC, Norwalk, CT) was injected into the breast parenchyma sterilely around the palpable tumor, the excisional biopsy scar, or the mammographic abnormality. The Lymphazurin injection was performed in a similar fashion at all the institutions—that is, if the tumor was intact, then the blue dye was injected into the breast parenchyma around the tumor. If the tumor had been removed with an excisional biopsy, the blue dye was injected into the breast parenchyma around the excisional biopsy cavity. Five minutes of massage was performed, and the axillary incision was made, to collect the SLN. The SLN was defined as a blue-stained node, a node with a blue-stained afferent lymphatic entering it (to cover the situation of a node completely replaced by tumor that may not take up much of the dye), or a node with radioactivity counts with a 10:1 ratio, with the denominator being activity in a neighboring non-SLN.
Most of the patients were entered onto protocol 1 as the surgeons went through their learning curve. In this phase of the study, the SLN collection was followed immediately by a CLND of the axilla. This was a level I and II node dissection. In this way, the false-negative SLN biopsy rate (or skip metastasis rate) was apparent immediately. In those patients who had a negative SLN biopsy and were observed (protocol 2), the false-negative rate was determined by the number of women whose disease recurred in the nodal basin on long-term follow-up. Per protocol, if no SLN was found (no vital blue dye or radiocolloid appeared in the basin), then a standard level I and II node dissection was performed. Whether to resect extra-axillary sites of documented lymphatic drainage by preoperative lymphoscintigraphy was left up to the discretion of the operating surgeon.
Histological Examination of the SLN
The SLN was collected initially and submitted separately to the pathologist. All SLNs were examined by bivalving the node and placing all the submitted tissue in a block. More than one block was necessary on the larger nodes. SLNs with a measurement of 5 mm or less in maximal diameter were bivalved, and nodes >5 mm in diameter were serially sectioned at 2- to 3-mm intervals to maximize the examined surface area. The routine stain was hematoxylin and eosin (H&E). Cytokeratin immunohistochemical stains were performed at selected centers. Cytokeratin staining was performed in the following fashion if routine histology with H&E stains was negative. More sections were cut off the SLN block and stained with cytokeratin-19 immunostain. Cytokeratin-positive cells may have been identified, but for the purposes of the study they were always confirmed to be malignant with a cytological examination of the next section stained with H&E. Thus, to call an SLN positive, the node would have to be positive with both cytokeratin and H&E. The disease may initially have been found with the cytokeratin stain in the SLN, but the cells were always confirmed to be malignant with H&E. The nodes from the CLND were examined in the routine fashion by making one or two sections of the central cross-section of the node and staining with H&E.
National Breast Lymphatic Mapping Database
A national network of university medical centers, regional community hospitals, and physician groups has been organized; these physicians were trained to use standardized lymphatic mapping techniques for breast cancer. The registered surgeons participated in a national research protocol while they gained the necessary experience to eventually be able to perform SLN biopsy without CALND. In addition, a National Breast Lymphatic Mapping Database was established with the capability for electronic submission of data forms with automatic transfer into the database (by fax, the Internet, or both) so that investigators could enter data at the point of service and compare their breast-mapping data with those from other hospitals around the country. The quality assurance protocol include a review of approximately 10% of the data forms. Many of the surgeons and institutions who participated in the DoD-sponsored trial have continued to enter cases into the database to help monitor success and skip metastasis rates as well as for credentialing purposes (Fig. 1).
|
|
RESULTS |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAPPENDIX 1REFERENCES |
|---|
|
|
|
No axillary SLNs were imaged or found intraoperatively in 14% of the cases. In these patients, a routine level I and II node dissection was performed, and metastatic disease was found in 46% of the dissections.
Intraoperative Breast Lymphatic Mapping
The rate of success of finding an axillary SLN at MCC, where the surgeons are experienced with breast lymphatic mapping, was 92.8%. For university centers outside the home institution, the rate of success of axillary SLN identification was 91.4%, whereas community/regional hospitals had a 85.2% rate. The success rate of just being able to find an axillary SLN was uniform among all locations of the primary tumor. The success rate was slightly higher when mapping after a fine-needle aspiration with the tumor intact than after an excisional biopsy or stereotactic core (Table 2). The average number of SLNs collected was comparable between MCC and the outside institutions (Table 3) and averaged 2.25 and 2.04 SLNs per axilla, respectively. For the total trial, 2.13 SLNs per axilla were collected.
|
|
|
|
DISCUSSION |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAPPENDIX 1REFERENCES |
|---|
It is clear that data from breast lymphatic mapping studies will profoundly change the staging system for breast cancer. At this time the finding of occult metastases in the SLN of the axilla qualifies as stage II disease (American Joint Committee of Cancer), the finding of micrometastatic disease in the SLN from the internal mammary nodal chain is stage III disease, and micrometastatic disease in the supraclavicular fossa is stage IV breast cancer. However, direct drainage from primary sites in the breast has been documented at all three sites, and micrometastatic disease in any of the three sites probably represents the same biological phenomena. It is reasonable to envision that patients with regional nodal micrometastatic disease should be staged similarly.
It does not seem possible by the data from this study to use preoperative lymphoscintigraphy to identify a subgroup of women with breast cancers that do not drain at all to the axilla and do not need any axillary procedure for staging. The sensitivity of the cameras in nuclear medicine is not at a level that would allow this to occur. Axillary SLNs are imaged 64% of the time but are found 86% of the time with the more sensitive gamma detector probes used during surgery. In addition, some of these SLNs that are not imaged but are found during surgery have metastases in them; this is documented as a false-negative lymphoscintigraphy procedure. This reinforces the finding that the handheld gamma detectors used during surgery at the level of the lymph nodes after the axilla is open are much more sensitive than the imaging cameras used in nuclear medicine. If surgeons are concerned only about mapping to the axilla, then preoperative imaging may be abandoned. The patient would still need to be injected with radiocolloid to perform the radioguided surgery, but the imaging of the patient would not be necessary.
The other line of evidence that addresses the lack of sensitivity of the preoperative lymphoscintigraphy study is the fact that in those patients who have negative imaging and in whom on exploration none of the mapping agents migrates to the axilla, when a level I and II node dissection is performed, 48% of the patients have tumor discovered in the basin. This suggests that metastases did occur to the axillary nodes despite no documented drainage, and this may be because SLNs full of tumor may not take up much vital blue dye or radiocolloid. Although imaging axillary SLNs with scintigraphy effectively ensures successful SLN identification, negative imaging should not be the sole indicator of mapping failure or success. SLNs are still identified in the majority of image-negative patients (an axillary SLN was imaged in 64% of the lymphoscintigraphy studies but was found during surgery 86% of the time). In addition, patients who have negative imaging and no blue dye or radiocolloid in the axilla still need a level I and II node dissection because 46% will have metastatic disease.
It is encouraging that in protocol 2, the part of the study during which patients were observed after a negative SLN biopsy and in which a CLND was not performed, at a mean follow-up of 16 months, no patient’s disease had recurred in the axilla. These patients will continue to be observed to obtain a more meaningful figure for the false-negative SLN biopsy rate.
The study examined benchmarks for axillary nodal mapping for determining the viability of the lymphatic mapping procedure in the community/regional hospital. Extra-axillary sites of SLNs were not uniformly dissected, even if identified before surgery with the lymphoscintigraphy study, because the importance of these extra-axillary lymphatic drainage sites has not been established and would add morbidity to the procedure. In addition, the community/regional hospital physician at this time is concerned with performing accurate mapping to the axilla. Extra-axillary SLN sites are being collected as part of the National Surgical Adjuvant Breast and Bowel Project Breast Lymphatic Mapping Trial, and the results of this important national trial may determine whether all draining basins of the primary breast cancer should be dissected.
The trial did document a reasonable success rate of finding an axillary SLN in the smaller community/regional hospital and a low enough false-negative rate to make breast lymphatic mapping a viable procedure in these local hospitals. The American Society of Breast Surgeons established benchmarks for a successful mapping program to include a success rate of SLN identification of 85% and a skip metastasis rate <5%. These benchmarks were adopted for this study. The SLN identification rate on the DoD study is better than what has been previously reported,5 and this may be because all teams of surgeons, nuclear medicine physicians, and surgeons attended a formal 2-day training course at the home institution; learning curve guidelines were followed that involved more patients than in other trials; and a combination mapping technique with a vital blue dye and radiocolloid was used in the trial. The 85.2% success rate of identifying an axillary SLN for community/regional hospitals on the DoD trial meets one of the necessary criteria established by the American Society of Breast Surgeons to eliminate a CLND in those women who have a negative SLN biopsy. This figure also meets the requirements established by the American College of Surgeons for participation in their breast lymphatic mapping national trial. Lymphatic mapping has the potential for changing the standard of surgical care in the breast cancer population and should be applicable in the community/regional hospital, where most breast cancer care occurs in this country.
|
APPENDIX 1 |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAPPENDIX 1REFERENCES |
|---|
|
|
Acknowledgments |
|---|
|
Footnotes |
|---|
Received for publication March 16, 2001. Accepted for publication November 14, 2001.
|
REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAPPENDIX 1REFERENCES |
|---|
This article has been cited by other articles:
 |
|
 |
|
  C. Cox, L. White, N. Allred, M. Meyers, D. Dickson, E. Dupont, A. Cantor, Q. Ly, S. Dessureault, J. King, et al. Survival Outcomes in Node-Negative Breast Cancer Patients Evaluated With Complete Axillary Node Dissection Versus Sentinel Lymph Node Biopsy Ann. Surg. Oncol., May 1, 2006; 13(5): 708 - 711. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. G. Wilke, L. M. McCall, K. E. Posther, P. W. Whitworth, D. S. Reintgen, A. M. Leitch, S. G. A. Gabram, A. Lucci, C. E. Cox, K. K. Hunt, et al. Surgical Complications Associated With Sentinel Lymph Node Biopsy: Results From a Prospective International Cooperative Group Trial Ann. Surg. Oncol., April 1, 2006; 13(4): 491 - 500. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. B. Edge, J. C. Niland, M. A. Bookman, R. L. Theriault, R. Ottesen, E. Lepisto, and J. C. Weeks Emergence of Sentinel Node Biopsy in Breast Cancer as Standard-of-Care in Academic Comprehensive Cancer Centers J Natl Cancer Inst, October 15, 2003; 95(20): 1514 - 1521. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. A. Litvak and A. E. Giuliano The Results of the Department of Defense's Breast Lymphatic Mapping Study Ann. Surg. Oncol., June 1, 2002; 9(5): 428 - 429. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
