Correspondence to: David Krag, M.D., Department of Surgery, University of Vermont, E309 Given Bldg., Burlington, VT 05405.
In 1997, Veronesi et al. (1) reported in the Lancet on their sentinel lymph node experience in a series of 163 patients with breast cancer. The day before surgery, a small volume of colloidal human albumin labeled with technetium 99m was injected subdermally over the tumor in these patients. Gamma camera imaging was performed, and a hand-held gamma probe was used to guide the surgical resection of the sentinel nodes (SNs). The use of blue dye was not reported. In 98% of the cases, at least one SN could be identified surgically. The false-negative rate (i.e., number of cases with negative SNs but positive non-SNs x 100/total number of cases with positive nodes) was 5%. The overall accuracy was 98%. Frozen section analysis had a higher false-negative rate of 36%.
Now, this group from Milan reports in this issue of the Journal on 376 cases (i.e., the 163 cases reported in the Lancet plus 213 new cases) (2). The methods were similar to those used for the initial 163 cases. At least one SN was identified in a high percentage of cases (99%). The false-negative rate was slightly higher at 6.7% (12 of 180).
These data from Milan highlight three important issues being reported around the world: 1) SNs can be successfully removed in a very high percentage of cases; 2) the accuracy of the SNs for predicting whether axillary metastases have occurred is also very high; but 3) when cancer cells have spread to lymph nodes, the rate at which the SN misses this event is not zero. This important report (2) confirms that the development of the technical aspects of SN surgery has cleared the first hurdle on the way toward clinical utility, but it also confirms that further investigation is warranted.
The observation was made early in this century that, in human patients, lymphatic drainage of the abdominal cavity went to "glands sentinel" (3). It has been more than 20 years since the current principles of SN surgery (lymphadenectomy based on the status of the SN) were stated clearly (4). Despite the long opportunity for development, a number of technical issues needed to be resolved in order to apply SN surgery to patients with breast cancer. Blue dye alone, hand-held gamma probe-guided resection of radiolabeled SNs, or dye and tracer together achieve a success rate of axillary SN detection exceeding 90%. Thus, a number of options are available for surgical resection of axillary SNs. Successful detection of extra-axillary nodes is a different issue.
It is abundantly clear that different individuals can have lymphatic drainage of the breast that follows multiple and varied pathways (5). Even a single individual can have variable lymphatic drainage depending on positioning and local pressure. The notion that lymphatic drainage from a primary breast tumor automatically travels to a single SN in the axilla is overly simplistic.
The obvious benefit of SN surgery is that it offers the potential of a much less morbid procedure. The not so obvious potential is that it offers greater accuracy than conventional "blind" axillary lymph node resection. Will decreased morbidity and increased accuracy come with hidden costs? The technical aspects of SN surgery in patients with breast cancer have clearly made the first pass successfully. What are the important issues that now need to be addressed?
COMPREHENSIVE DETECTION OF SNS
In a recent multicenter study (6), 11% of SNs were located outside axillary level I. In 3% of all node-positive cases, the positive nodes were located exclusively outside the axilla. In these cases, conventional lymphadenectomy missed the positive nodes. The precision of locating radioactively labeled SNs allows surgical resection of SNs with a very small incision in virtually any location, including the internal mammary nodes. Further development should address improved methods of rapidly and confidently identifying all SNs draining a primary breast cancer and defining the most minimally invasive technique of removing such nodes. Despite the use of a radioactive tracer and preoperative gamma camera imaging, the Milan group did not report on extra-axillary nodes.
COMPLETE STAGING OF LYMPH NODES
It appears from the data of Veronesi et al. (2), as well as the data of others (6-9), that the status of the SNs is very accurate for determining whether regional metastases have occurred. Information regarding the status of the SN is binomial, i.e., nodal metastases have occurred or not occurred. Axillary lymphadenectomy provides quantitative information that is used as a basis for the planning of systemic treatment. How the status of the SNs will integrate as a staging tool into current conventional and experimental systemic therapy regimens (and into the TNM [tumor, node, metastasis] system) remains to be resolved.
REGIONAL CONTROL AND SURVIVAL
Axillary lymphadenectomy provides excellent long-term regional control of the axilla and may result in a limited but real survival benefit. Long-term regional control following SN surgery without a completion lymphadenectomy is unknown. Any possible survival benefit (or detriment) from surgery limited to the removal of SNs is also unknown. The National Cancer Institute has sponsored the National Surgical Adjuvant Breast and Bowel Project (NSABP) and the University of Vermont Comprehensive Cancer Center to conduct a clinical trial to address these issues. The trial, NSABP-32, began in October 1998 with the training of participating surgeons in a standardized method of SN surgery prior to patient accrual. Patients with pathologically negative SNs will be randomly assigned to SN surgery only or to completion axillary lymphadenectomy. The primary aims of the study are as follows: 1) to determine whether the rates of overall survival, disease-free survival, and regional control in patients managed with SN resection only are equivalent to the rates in patients treated with conventional axillary dissection, and 2) to document the magnitude of morbidity reduction.
INTRAOPERATIVE PATHOLOGY
The Milan group performed frozen-section analysis, and their initial report had a false-negative rate of 36% (1). The current report (2) describes an effort to improve on these results by a more intensive analysis. The described method appears to be somewhat labor intensive, but the false-negative rate decreased to 5.5%. Imprint cytology has recently been reported as a method for intraoperative analysis of SNs with a very low false-negative rate (10).
PREVIOUS EXCISIONAL BIOPSY
The Milan group excluded patients who underwent an excisional biopsy from their study. Other studies have suggested that prior excisional biopsy can lower the accuracy of SN surgery. Given that minimally invasive techniques using core or fine-needle tissue acquisition devices are universally available, it is reasonable to make efforts to obtain diagnostic tissue without an excisional biopsy if SN surgery is planned. In the United States, excisional biopsies are still commonly performed as a diagnostic method. Practice pattern changes will be required to adapt to less invasive diagnostic methods.
METHOD OF TRACER INJECTION
The Milan group injected either around the tumor or subdermally over the tumor. Groups at most other centers have injected around the tumor into the substance of the breast. Borgstein et al. (11) in Amsterdam injected radioactive tracer into the breast but blue dye into the skin over the tumor and found concordance of SN labeling. This result indicates that, at least in the majority of patients, there are common drainage pathways toward a limited set of nodes in the axilla. The Milan group did not report removing or identifying any extra-axillary SNs. Whether this was because such nodes were not sought as part of the study or whether the method of SN labeling was unable to label such nodes effectively is unclear. Since SN surgery is so minimally invasive and extra-axillary nodes are clinically important when cancer cells are present, it is an issue that should be considered in subsequent SN studies.
GAMMA CAMERA IMAGING
It is well stated by Veronesi et al. (1) that the hand-held gamma probe "guides the dissection itself, which is therefore quick and consistently successful." Gamma camera imaging is not an element of the surgical procedure but is performed preoperatively. A gamma camera provides a wide field of view and can rapidly identify extra-axillary SNs. A hand-held probe can achieve the same goal by a careful sweeping survey at the time of surgery. Extra-axillary drainage is not uncommon (5,6). How these SNs are best identified remains to be determined. Drainage to extra-axillary areas is to be expected. The Milan group does not comment on extra-axillary drainage, which, despite the outstanding results in the axilla, draws attention to the methods employed.
RADIATION EXPOSURE
The Milan group has carefully determined the magnitude of radiation exposure and has compared their findings to published recommended exposure limits for the general population. This effort demonstrates clearly that radiation exposure from SN procedures is well within accepted exposure limits (12).
The aims of the Milan study were to "clarify the role" and to "identify indications for the use of the technique." This study successfully adds to the increasing body of literature that supports the notions that SNs can be removed by minimally invasive methods and that, in the patients with clinically node-negative breast cancer, the accuracy of the SNs for determining the presence or absence of metastases is very high. From a staging perspective, this is clearly a major surgical advance. I concur with Veronesi et al. (2) that entry of patients into clinical trials to establish the safety profile of SN surgery as a sole approach for the evaluation of regional lymph nodes is highly encouraged.
NOTES
Editor's note: The author has served as a consultant to Neoprobe Corporation and to CareWise Corporation on the design of gamma probes.
REFERENCES
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