- Email: [email protected]
Criteria for establishing the adequacy of a sentinel lymphadenectomy
The American Journal of Surgery 187 (2004) 639 – 642
Scientific paper
Criteria for establishing the adequacy of a sentinel lymphadenectomy Mona Duncan, M.D., Amy Cech, M.D., Debra Wechter, M.D., Ravi Moonka, M.D.* Department of General, Vascular, and Thoracic Surgery, Virginia Mason Medical Center, C6-GSUR, PO Box 900, 1100 Ninth Ave., Seattle, WA 98111, USA Manuscript received December 11, 2003; revised manuscript January 18, 2004 Presented at the 90th Annual Meeting of the North Pacific Surgical Association, Portland, Oregon, November 14 –15, 2003
Abstract Background: Criteria are needed that could be used to terminate a sentinel lymphadenectomy for breast cancer prior to removing every sentinel lymph node, without increasing false negative rates. Methods: Quantitative information on the radioactivity and color of sentinel lymph nodes removed from 541 breast cancer patients was correlated with pathologic information to determine when a sentinel lymphadenectomy could be terminated based on characteristics of the initially removed nodes. Results: Tumor was found in the first two sentinel lymph nodes removed in 127 of 129 node-positive patients. In 65% of patients who were able to be evaluated, the most radioactive lymph node was a positive lymph node. When any axillary lymph node was blue, then the first tumor-containing sentinel lymph node was also blue. Conclusions: Removal of the most radioactive lymph node does not insure accurate assessment of the axilla. Removal of two sentinel lymph nodes accurately staged 98.4% of node-positive patients and 99.6% of the entire study population. © 2004 Excerpta Medica, Inc. All rights reserved. Keywords: Breast cancer; Sentinel lymphadenectomy; Axillary staging; Operative technique; Sentinel lymph node; Axillary dissection
Athough sentinel lymphadenectomy is a widely used tool in the staging of breast cancer, concerns over its accuracy still exist. Reported rates of false negative results were as high as 11% and 13% in the initial multicenter trials describing the procedure [1,2]. While improvements in the accuracy of the procedure are postulated to occur with increasing individual surgical experience, many studies have failed to corroborate this phenomenon [1,3]. The conscientious surgeon seeking to minimize the possibility of a false negative result naturally feels obligated to thoroughly investigate all areas of the axilla demonstrating abnormal radioactivity or color. This policy, however, provides diminishing returns as time wears on. The most impressive sentinel lymph nodes draw attention to themselves in the initial phase of the sentinel lymphadenectomy due to their avid uptake of the tracer agents, and these same lymph nodes are the most likely to bear tumor. Subsequent lymph
nodes are less likely to provide meaningful information beyond the initial lymph nodes, and become progressively more difficult to find as their activity blends with that of the axillary background. Increasing disruption of the axillary lymph channels and fat pad seems more likely to result in the morbidity of an axillary dissection, which one is seeking to avoid to begin with. Guidelines that would support the termination of a sentinel lymphadenectomy based on the character and number of lymph nodes removed early in the procedure would be helpful if the false negative rate did not rise as a result. At Virginia Mason Medical Center, each sentinel lymph node removed is assessed for intensity of color and for level of radioactivity. This detailed information was to determine when a sentinel lymphadenectomy may be confidently and safely terminated. Methods
* Corresponding author. Tel.: ⫹1-206-223-8880; fax: ⫹1-206-6257245. E-mail address: [email protected]
All patients undergoing sentinel lymph node mapping for the staging of breast cancer since its introduction for clinical
0002-9610/04/$ – see front matter © 2004 Excerpta Medica, Inc. All rights reserved. doi:10.1016/j.amjsurg.2004.01.017
640
M. Duncan et al. / The American Journal of Surgery 187 (2004) 639 – 642
use at Virginia Mason Medical Center untill June 2003 were included for evaluation. Sentinel lymph node mapping was performed on patients with invasive breast cancer, and on patients undergoing a simple mastectomy either prophylactically or for ductal carcinoma in situ. Lymphoscintigraphy was performed with 1 millicurie of technetium-99 labeled sulfur colloid injected either into the area of the tumor or biopsy cavity or into the subareolar lymphatics on the day of surgery, and all patients underwent gamma camera imaging immediately following injection. Five milliliters of isosulfan blue was injected immediately preoperatively into the same site. Lymph nodes were detected with the assistance of a handheld gamma ray counter. All lymph nodes which were blue or demonstrated radioactivity above axillary background were removed. The great majority of sentinel lymph nodes were evaluated by frozen section, with a completion axillary dissection after the finding of metastatic tumor. Axillary lymphadenectomies generally but not always were performed if tumor was found subsequent to a negative frozen section, either by hematoxylin and eosin staining or by immunoperoxidase examination. Demographic patient information was combined with pathologic information concerning both the primary tumor and all sentinel and nonsentinel lymph nodes, and surgical information regarding the site of radionuclide and dye injection, the number of lymph nodes visualized on lymphoscintigraphy, and the counts per second emitted by each harvested sentinel lymph node once it had been completely resected. Lymph nodes were also assessed for intensity of blue staining on a 3-point scale, with 0 being uncolored, 1 being dimly colored, and 2 being clearly colored.
Results Six hundred and forty-five patients underwent sentinel lymph node mapping at Virginia Mason Medical Center from March 1998 to June 2003. Twenty-eight patients having a prophylactic mastectomy, 49 patients with ductal carcinoma in situ, and 28 patients who had a failed or incomplete sentinel lymphadenectomy were excluded from analysis. Of the remaining 541 patients, 136 (25%) had three or more sentinel lymph nodes removed, with an average of 1.95 (range 1 to 8). One hundred and twenty-nine patients were found to have metastatic breast cancer within the sentinel lymphadenectomy, or 24% of the entire study population. In patients found to have a positive sentinel lymph node, a formal axillary lymph node dissection was performed in 83% (107 of 129). Of the 22 patients who did not have an axillary dissection, 77% (17 of 22) had micrometastases. The sentinel node was found to be the only site of metastasis in 64% (68 of 107) of the patients who did undergo axillary dissection. In 127 of 129 patients (98.4%) the metastasis was detected in either the first or second node removed, and in 2 patients tumor was found in the third or fourth node re-
Table 1 The number of patients in the study population and node-positive population having the designated number of sentinel lymph nodes (SLN) removed Total number of SLN removed
Study population (cumulative %)
Node-positive patients (cumulative %)
1 2 3 4 5 6 7 8
265/541 (49%) 140/541 (75%) 79/541 (89%) 29/541 (95%) 16/541 (98%) 8/541 (99%) 3/541 (99%) 1/541 (100%)
64/129 (50%) 32/129 (74%) 20/129 (90%) 4/129 (93%) 7/129 (98%) 2/129 (100%) 0/129 (100%) 0/129 (100%)
moved. Thus, in only 2 of 541 patients (0.4%) did removal of three or more sentinel nodes directly affect patient staging and treatment. Thirty-three of the 129 patients had three or more sentinel lymph nodes removed (Table 1). In examining node-positive patients in whom more than one sentinel lymph node was removed and only one lymph node revealed tumor, the lymph node with the highest level of ex vivo radioactivity was also the involved specimen in 23 of 35 patients who could be evaluated. For that same population, when any axillary lymph node contained blue dye, then tumor containing sentinel lymph node also was always blue-stained. Comments Studies seeking to establish criteria for the early termination of a sentinel lymph node mapping procedure are problematic. Even investigators with large series of breast cancer patients must ultimately draw conclusions from a relatively small number of patients, since only node-positive patients having multiple sentinel lymph nodes removed can contribute to the analysis. In addition, it is difficult to generate criteria that are not only 100% accurate but are also clinically useful. Finally, reasonable assumptions are often incorrect. For instance, the only lymph node with metastatic tumor was not necessarily the most radioactive specimen. It has been previously suggested that removing all lymph nodes whose radioactivity in counts per second equals 10% or more of the activity of the most radioactive lymph node will accurately stage nodal metastases in virtually 100% of patients [4]. While that assertion is undoubtedly true, it may be of limited practical use. Investigating levels of radioactivity that span an order of magnitude may not spare the surgeon and patient much dissection, and it is often difficult to assess the level of radioactivity of a node until it has been fully freed from the axilla and associated background activity. In other words, it may be that a lymph node cannot be deemed unnecessary to remove until it has been removed. Nonetheless, it is a potentially useful criterion when the first lymph node removed is particularly radioactive.
M. Duncan et al. / The American Journal of Surgery 187 (2004) 639 – 642
641
Table 2 Cumulative number of node-positive patients accurately staged by removal of 2, 3, or 4 sentinel lymph nodes Study
Patients
Node-positive patients
Staged in 2 nodes
Staged in 3 nodes
Staged in 4 nodes
Shrenk [5] Wong [6] McCarter [7] Zervos [8] Duncan
263 1287 1561 465 541
105 (40%) 355 (27%) 449 (29%) 128 (27%) 129 (24%)
104/105 NA NA 126/128 127/129
105/105 NA 440/449 127/128 128/129
105/105 350/355 445/449 128/128 129/129
NA ⫽ not available.
The presence of isosulfan blue in the axilla was a helpful observation. In every instance in which dye was observed in the axilla, a tumor containing sentinel lymph node also had blue dye. In other words, successful removal of all blue stained lymph nodes, if any such nodes are present in the axilla, will accurately stage these patients, regardless of the presence of residual radioactivity. Again, the practical use of this observation is limited, since it is difficult to prove that the axilla has been cleared of all isosulfan blue stain without exposing each lymph node. It does confirm, however, what many surgeons who manage patients with breast cancer have anecdotally observed. While technetium 99labeled sulphur colloid moves through the lymphatics easily and rarely fails to label a number of lymph nodes, it is less selective than isosulfan blue, which labels fewer lymph nodes but is more likely to identify true sentinel lymph nodes that have a greater relative chance of containing tumor. Technetium is sensitive, but isosulfan blue is specific. In an effort to determine criteria which could be used to terminate a sentinel lymphadenectomy for breast cancer prior to removing every sentinel lymph node, the simplest measure was also the most powerful. The first two sentinel lymph nodes accurately staged 98.4% of node-positive patients and 99.6% of the entire study population. In another way, however, the numbers are less convincing. If the analysis is limited to patients in whom three or more lymph nodes were removed, then only 94% of nodepositive patients were accurately staged by the first two sentinel nodes. In other words, in those instances in which the operating surgeon pursued three or more sentinel lymph nodes, the effort was justified by finding a third or higher lymph node as the only tumor- bearing specimen in 6% of those cases. That may be the more pertinent probability to the unfortunate but determined surgeon trying to track down the fourth or fifth sentinel lymph node, as its ephemeral signal drifts intermittently into the background range of the axilla as a whole. Nonetheless, the ability of the first two sentinel lymph nodes removed to accurately reflect the presence or absence of cancer in the axilla is a remarkable finding, which becomes only more impressive if higher order nodes are examined (Table 2). Of several thousand cumulative patients examined in the cited studies, only 9 would have been
inaccurately staged if only the initial four sentinel lymph nodes were removed. Since the false negative rate of properly performed sentinel lymph node mapping is 5% under the best of circumstances, it seems reasonable to accept the clinically imperceptible increase in that false negative rate which would result from a policy of removing a maximum of 4 lymph nodes during a sentinel lymphadenectomy . Such a policy would also be consistent with recent studies demonstrating the removal of four or five lymph nodes from the axilla, based simply on their proximity to the axillary tail or on palpation, results in false negative rates that compare quite favorably with that seen in sentinel lymph node mapping [9,10]. Ultimately, there exist circumstances in which the third, fourth, and potentially higher order sentinel lymph nodes must be found to accurately stage and properly treat patients with breast cancer. With this knowledge, many surgeons will quite understandably not terminate a sentinel lymphadenectomy after a predetermined number of nodes have been removed, but will instead investigate all areas of enhanced radioactive signal. This decision should be informed, however, by the relative improbability of higher order lymph nodes providing meaningful staging information.
References [1] Krag D, Weaver D, Ashikaga T, et al. The sentinel node in breast cancer: a multicenter validation study. N Engl J Med 1998;339: 941– 6. [2] Tafra L, Lannin DR, Swanson MS, et al. Multicenter trial of sentinel node biopsy for breast cancer using both technetium sulfur colloid and isosulfan blue. Ann Surg 2001;233:51–9. [3] Bergkvist L, Frisell J, Liljegren G, et al. Multicentre study of detection and false-negative rates in sentinel node biopsy for breast cancer. Br J Surg 2001;88:1644 – 8. [4] Martin RCG, Edwards MJ, Wong SL, et al. Practical guidelines for optimal gamma probe detection of sentinel lymph nodes in breast cancer: results of a multi-institutional study. Surgery 2000;128:139 – 44. [5] Shrenk D, Rehberger W, Shamiyeh A, Wayand W. Sentinel node biopsy for breast cancer: does the number have an impact on the accuracy of finding a positive node? J Surg Oncol 2002;80:130 – 6. [6] Wong SL, Edwards MJ, Chao C, et al. Sentinel lymph node biopsy for breast cancer: impact of the number of sentinel nodes removed on the false negative rate. J Am Coll Surg 2001;192:684 –9.
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M. Duncan et al. / The American Journal of Surgery 187 (2004) 639 – 642
[7] McCarter MD, Yeung H, Fey J, et al. The breast cancer patient with multiple sentinel nodes: when to stop? J Am Coll Surg 2001;192: 692–7. [8] Zervos EE, Badgwell BD, Abdessalam SF, et al. Selective analysis of the sentinel node in breast cancer. Am J Surg 2001;182:372– 6. [9] Macmillan RD, Barbera D, Hadjiminas DJ, et al. Sentinel node biopsy for breast cancer may have little to offer four-node samplers: results of a prospective comparison study. Eur J Cancer 2001;37: 1076 – 80. [10] Ahlgren J, Holmberg L, Bergh J, Liljegren G. Five node biopsy of the axilla: an alternative to axillary dissection of levels 1–2 in operable breast cancer. Eur J Surg Oncol 2002;28:97–102.
Commentary John T. Vetto, M.D. (Portland, OR): The authors pose a question that is important to surgeons performing sentinel node biopsy for breast cancer: when do you stop looking for nodes, particularly when the background count or blue staining in the axilla are high and diffuse? This is a particular problem with upper outer quadrant lesions and when the dose of technetium was high or delivered close to the axilla. At our institution, we have abandoned the practice of placing the radioactive tracer down the localizing needle for nonpalpable cancers in attempt to lower the risk of a diffusely “hot” axilla. Still, the problem remains. Those of us who perform this procedure on any kind of regular basis have probably had the experience (hopefully at the beginning of our learning curves) of dissecting most of the axilla because background remained high, and we were convinced that a “missed” sentinel node was lurking just a little deeper in the axilla. Plumbing their database of 541 cases, the authors conclude that removal of the hottest node is not enough for accurate assessment, but that removal of two nodes accurately identified cancer in 127 of 129 node-positive cases. Clinically, I would be hesitant to act on this information for
a number of reasons. First, as the authors correctly point out in the manuscript, the literature attempting to determine an absolute number of nodes after which one can feel safe is divided; some papers suggest two, others say three are needed. Clearly, this is a learning curve issue, and the actual number is more dependent on surgeon experience and expertise than on an arbitrary rule developed from someone else’s database. Second, if the authors had acted on their conclusion, they would have increased their false negative rate by two cases. The authors are past their learning curve and, hence, no longer perform routine completion dissections, so we do not know their false negative rate, but I would suspect it is low and that two more cases would not be insignificant. Third, at our institution, we have done a similar number of cases, yet we continue to encounter the occasional case where the hottest or bluest node is identified after two nodes have been removed—many series have confirmed this “flattening” of the learning curve. Thus, it is now our practice in diffusely hot axillae to stop when the last node—not the background— has a 10-second count of less than one-tenth that of the hottest node. Also, to avoid overstaining of the axilla, we have experienced a more crisp identification of just one or two blue-stained nodes by lowering the dose of lymphazurin blue from the originally described dose of 5 ml, which the authors use, to no more than 1 cc. The final reason I would be hesitant to act on their conclusion is that only 25% of the patients in this study actually had a third node removed, and that greatly limits the power of the study to say that two nodes is enough. I submit that their conclusion could be easily validated with a large, multicenter shared database, such as that of, for example, the National Sentinel Lymph Node Working Group, based in San Francisco.
Scientific paper
Criteria for establishing the adequacy of a sentinel lymphadenectomy Mona Duncan, M.D., Amy Cech, M.D., Debra Wechter, M.D., Ravi Moonka, M.D.* Department of General, Vascular, and Thoracic Surgery, Virginia Mason Medical Center, C6-GSUR, PO Box 900, 1100 Ninth Ave., Seattle, WA 98111, USA Manuscript received December 11, 2003; revised manuscript January 18, 2004 Presented at the 90th Annual Meeting of the North Pacific Surgical Association, Portland, Oregon, November 14 –15, 2003
Abstract Background: Criteria are needed that could be used to terminate a sentinel lymphadenectomy for breast cancer prior to removing every sentinel lymph node, without increasing false negative rates. Methods: Quantitative information on the radioactivity and color of sentinel lymph nodes removed from 541 breast cancer patients was correlated with pathologic information to determine when a sentinel lymphadenectomy could be terminated based on characteristics of the initially removed nodes. Results: Tumor was found in the first two sentinel lymph nodes removed in 127 of 129 node-positive patients. In 65% of patients who were able to be evaluated, the most radioactive lymph node was a positive lymph node. When any axillary lymph node was blue, then the first tumor-containing sentinel lymph node was also blue. Conclusions: Removal of the most radioactive lymph node does not insure accurate assessment of the axilla. Removal of two sentinel lymph nodes accurately staged 98.4% of node-positive patients and 99.6% of the entire study population. © 2004 Excerpta Medica, Inc. All rights reserved. Keywords: Breast cancer; Sentinel lymphadenectomy; Axillary staging; Operative technique; Sentinel lymph node; Axillary dissection
Athough sentinel lymphadenectomy is a widely used tool in the staging of breast cancer, concerns over its accuracy still exist. Reported rates of false negative results were as high as 11% and 13% in the initial multicenter trials describing the procedure [1,2]. While improvements in the accuracy of the procedure are postulated to occur with increasing individual surgical experience, many studies have failed to corroborate this phenomenon [1,3]. The conscientious surgeon seeking to minimize the possibility of a false negative result naturally feels obligated to thoroughly investigate all areas of the axilla demonstrating abnormal radioactivity or color. This policy, however, provides diminishing returns as time wears on. The most impressive sentinel lymph nodes draw attention to themselves in the initial phase of the sentinel lymphadenectomy due to their avid uptake of the tracer agents, and these same lymph nodes are the most likely to bear tumor. Subsequent lymph
nodes are less likely to provide meaningful information beyond the initial lymph nodes, and become progressively more difficult to find as their activity blends with that of the axillary background. Increasing disruption of the axillary lymph channels and fat pad seems more likely to result in the morbidity of an axillary dissection, which one is seeking to avoid to begin with. Guidelines that would support the termination of a sentinel lymphadenectomy based on the character and number of lymph nodes removed early in the procedure would be helpful if the false negative rate did not rise as a result. At Virginia Mason Medical Center, each sentinel lymph node removed is assessed for intensity of color and for level of radioactivity. This detailed information was to determine when a sentinel lymphadenectomy may be confidently and safely terminated. Methods
* Corresponding author. Tel.: ⫹1-206-223-8880; fax: ⫹1-206-6257245. E-mail address: [email protected]
All patients undergoing sentinel lymph node mapping for the staging of breast cancer since its introduction for clinical
0002-9610/04/$ – see front matter © 2004 Excerpta Medica, Inc. All rights reserved. doi:10.1016/j.amjsurg.2004.01.017
640
M. Duncan et al. / The American Journal of Surgery 187 (2004) 639 – 642
use at Virginia Mason Medical Center untill June 2003 were included for evaluation. Sentinel lymph node mapping was performed on patients with invasive breast cancer, and on patients undergoing a simple mastectomy either prophylactically or for ductal carcinoma in situ. Lymphoscintigraphy was performed with 1 millicurie of technetium-99 labeled sulfur colloid injected either into the area of the tumor or biopsy cavity or into the subareolar lymphatics on the day of surgery, and all patients underwent gamma camera imaging immediately following injection. Five milliliters of isosulfan blue was injected immediately preoperatively into the same site. Lymph nodes were detected with the assistance of a handheld gamma ray counter. All lymph nodes which were blue or demonstrated radioactivity above axillary background were removed. The great majority of sentinel lymph nodes were evaluated by frozen section, with a completion axillary dissection after the finding of metastatic tumor. Axillary lymphadenectomies generally but not always were performed if tumor was found subsequent to a negative frozen section, either by hematoxylin and eosin staining or by immunoperoxidase examination. Demographic patient information was combined with pathologic information concerning both the primary tumor and all sentinel and nonsentinel lymph nodes, and surgical information regarding the site of radionuclide and dye injection, the number of lymph nodes visualized on lymphoscintigraphy, and the counts per second emitted by each harvested sentinel lymph node once it had been completely resected. Lymph nodes were also assessed for intensity of blue staining on a 3-point scale, with 0 being uncolored, 1 being dimly colored, and 2 being clearly colored.
Results Six hundred and forty-five patients underwent sentinel lymph node mapping at Virginia Mason Medical Center from March 1998 to June 2003. Twenty-eight patients having a prophylactic mastectomy, 49 patients with ductal carcinoma in situ, and 28 patients who had a failed or incomplete sentinel lymphadenectomy were excluded from analysis. Of the remaining 541 patients, 136 (25%) had three or more sentinel lymph nodes removed, with an average of 1.95 (range 1 to 8). One hundred and twenty-nine patients were found to have metastatic breast cancer within the sentinel lymphadenectomy, or 24% of the entire study population. In patients found to have a positive sentinel lymph node, a formal axillary lymph node dissection was performed in 83% (107 of 129). Of the 22 patients who did not have an axillary dissection, 77% (17 of 22) had micrometastases. The sentinel node was found to be the only site of metastasis in 64% (68 of 107) of the patients who did undergo axillary dissection. In 127 of 129 patients (98.4%) the metastasis was detected in either the first or second node removed, and in 2 patients tumor was found in the third or fourth node re-
Table 1 The number of patients in the study population and node-positive population having the designated number of sentinel lymph nodes (SLN) removed Total number of SLN removed
Study population (cumulative %)
Node-positive patients (cumulative %)
1 2 3 4 5 6 7 8
265/541 (49%) 140/541 (75%) 79/541 (89%) 29/541 (95%) 16/541 (98%) 8/541 (99%) 3/541 (99%) 1/541 (100%)
64/129 (50%) 32/129 (74%) 20/129 (90%) 4/129 (93%) 7/129 (98%) 2/129 (100%) 0/129 (100%) 0/129 (100%)
moved. Thus, in only 2 of 541 patients (0.4%) did removal of three or more sentinel nodes directly affect patient staging and treatment. Thirty-three of the 129 patients had three or more sentinel lymph nodes removed (Table 1). In examining node-positive patients in whom more than one sentinel lymph node was removed and only one lymph node revealed tumor, the lymph node with the highest level of ex vivo radioactivity was also the involved specimen in 23 of 35 patients who could be evaluated. For that same population, when any axillary lymph node contained blue dye, then tumor containing sentinel lymph node also was always blue-stained. Comments Studies seeking to establish criteria for the early termination of a sentinel lymph node mapping procedure are problematic. Even investigators with large series of breast cancer patients must ultimately draw conclusions from a relatively small number of patients, since only node-positive patients having multiple sentinel lymph nodes removed can contribute to the analysis. In addition, it is difficult to generate criteria that are not only 100% accurate but are also clinically useful. Finally, reasonable assumptions are often incorrect. For instance, the only lymph node with metastatic tumor was not necessarily the most radioactive specimen. It has been previously suggested that removing all lymph nodes whose radioactivity in counts per second equals 10% or more of the activity of the most radioactive lymph node will accurately stage nodal metastases in virtually 100% of patients [4]. While that assertion is undoubtedly true, it may be of limited practical use. Investigating levels of radioactivity that span an order of magnitude may not spare the surgeon and patient much dissection, and it is often difficult to assess the level of radioactivity of a node until it has been fully freed from the axilla and associated background activity. In other words, it may be that a lymph node cannot be deemed unnecessary to remove until it has been removed. Nonetheless, it is a potentially useful criterion when the first lymph node removed is particularly radioactive.
M. Duncan et al. / The American Journal of Surgery 187 (2004) 639 – 642
641
Table 2 Cumulative number of node-positive patients accurately staged by removal of 2, 3, or 4 sentinel lymph nodes Study
Patients
Node-positive patients
Staged in 2 nodes
Staged in 3 nodes
Staged in 4 nodes
Shrenk [5] Wong [6] McCarter [7] Zervos [8] Duncan
263 1287 1561 465 541
105 (40%) 355 (27%) 449 (29%) 128 (27%) 129 (24%)
104/105 NA NA 126/128 127/129
105/105 NA 440/449 127/128 128/129
105/105 350/355 445/449 128/128 129/129
NA ⫽ not available.
The presence of isosulfan blue in the axilla was a helpful observation. In every instance in which dye was observed in the axilla, a tumor containing sentinel lymph node also had blue dye. In other words, successful removal of all blue stained lymph nodes, if any such nodes are present in the axilla, will accurately stage these patients, regardless of the presence of residual radioactivity. Again, the practical use of this observation is limited, since it is difficult to prove that the axilla has been cleared of all isosulfan blue stain without exposing each lymph node. It does confirm, however, what many surgeons who manage patients with breast cancer have anecdotally observed. While technetium 99labeled sulphur colloid moves through the lymphatics easily and rarely fails to label a number of lymph nodes, it is less selective than isosulfan blue, which labels fewer lymph nodes but is more likely to identify true sentinel lymph nodes that have a greater relative chance of containing tumor. Technetium is sensitive, but isosulfan blue is specific. In an effort to determine criteria which could be used to terminate a sentinel lymphadenectomy for breast cancer prior to removing every sentinel lymph node, the simplest measure was also the most powerful. The first two sentinel lymph nodes accurately staged 98.4% of node-positive patients and 99.6% of the entire study population. In another way, however, the numbers are less convincing. If the analysis is limited to patients in whom three or more lymph nodes were removed, then only 94% of nodepositive patients were accurately staged by the first two sentinel nodes. In other words, in those instances in which the operating surgeon pursued three or more sentinel lymph nodes, the effort was justified by finding a third or higher lymph node as the only tumor- bearing specimen in 6% of those cases. That may be the more pertinent probability to the unfortunate but determined surgeon trying to track down the fourth or fifth sentinel lymph node, as its ephemeral signal drifts intermittently into the background range of the axilla as a whole. Nonetheless, the ability of the first two sentinel lymph nodes removed to accurately reflect the presence or absence of cancer in the axilla is a remarkable finding, which becomes only more impressive if higher order nodes are examined (Table 2). Of several thousand cumulative patients examined in the cited studies, only 9 would have been
inaccurately staged if only the initial four sentinel lymph nodes were removed. Since the false negative rate of properly performed sentinel lymph node mapping is 5% under the best of circumstances, it seems reasonable to accept the clinically imperceptible increase in that false negative rate which would result from a policy of removing a maximum of 4 lymph nodes during a sentinel lymphadenectomy . Such a policy would also be consistent with recent studies demonstrating the removal of four or five lymph nodes from the axilla, based simply on their proximity to the axillary tail or on palpation, results in false negative rates that compare quite favorably with that seen in sentinel lymph node mapping [9,10]. Ultimately, there exist circumstances in which the third, fourth, and potentially higher order sentinel lymph nodes must be found to accurately stage and properly treat patients with breast cancer. With this knowledge, many surgeons will quite understandably not terminate a sentinel lymphadenectomy after a predetermined number of nodes have been removed, but will instead investigate all areas of enhanced radioactive signal. This decision should be informed, however, by the relative improbability of higher order lymph nodes providing meaningful staging information.
References [1] Krag D, Weaver D, Ashikaga T, et al. The sentinel node in breast cancer: a multicenter validation study. N Engl J Med 1998;339: 941– 6. [2] Tafra L, Lannin DR, Swanson MS, et al. Multicenter trial of sentinel node biopsy for breast cancer using both technetium sulfur colloid and isosulfan blue. Ann Surg 2001;233:51–9. [3] Bergkvist L, Frisell J, Liljegren G, et al. Multicentre study of detection and false-negative rates in sentinel node biopsy for breast cancer. Br J Surg 2001;88:1644 – 8. [4] Martin RCG, Edwards MJ, Wong SL, et al. Practical guidelines for optimal gamma probe detection of sentinel lymph nodes in breast cancer: results of a multi-institutional study. Surgery 2000;128:139 – 44. [5] Shrenk D, Rehberger W, Shamiyeh A, Wayand W. Sentinel node biopsy for breast cancer: does the number have an impact on the accuracy of finding a positive node? J Surg Oncol 2002;80:130 – 6. [6] Wong SL, Edwards MJ, Chao C, et al. Sentinel lymph node biopsy for breast cancer: impact of the number of sentinel nodes removed on the false negative rate. J Am Coll Surg 2001;192:684 –9.
642
M. Duncan et al. / The American Journal of Surgery 187 (2004) 639 – 642
[7] McCarter MD, Yeung H, Fey J, et al. The breast cancer patient with multiple sentinel nodes: when to stop? J Am Coll Surg 2001;192: 692–7. [8] Zervos EE, Badgwell BD, Abdessalam SF, et al. Selective analysis of the sentinel node in breast cancer. Am J Surg 2001;182:372– 6. [9] Macmillan RD, Barbera D, Hadjiminas DJ, et al. Sentinel node biopsy for breast cancer may have little to offer four-node samplers: results of a prospective comparison study. Eur J Cancer 2001;37: 1076 – 80. [10] Ahlgren J, Holmberg L, Bergh J, Liljegren G. Five node biopsy of the axilla: an alternative to axillary dissection of levels 1–2 in operable breast cancer. Eur J Surg Oncol 2002;28:97–102.
Commentary John T. Vetto, M.D. (Portland, OR): The authors pose a question that is important to surgeons performing sentinel node biopsy for breast cancer: when do you stop looking for nodes, particularly when the background count or blue staining in the axilla are high and diffuse? This is a particular problem with upper outer quadrant lesions and when the dose of technetium was high or delivered close to the axilla. At our institution, we have abandoned the practice of placing the radioactive tracer down the localizing needle for nonpalpable cancers in attempt to lower the risk of a diffusely “hot” axilla. Still, the problem remains. Those of us who perform this procedure on any kind of regular basis have probably had the experience (hopefully at the beginning of our learning curves) of dissecting most of the axilla because background remained high, and we were convinced that a “missed” sentinel node was lurking just a little deeper in the axilla. Plumbing their database of 541 cases, the authors conclude that removal of the hottest node is not enough for accurate assessment, but that removal of two nodes accurately identified cancer in 127 of 129 node-positive cases. Clinically, I would be hesitant to act on this information for
a number of reasons. First, as the authors correctly point out in the manuscript, the literature attempting to determine an absolute number of nodes after which one can feel safe is divided; some papers suggest two, others say three are needed. Clearly, this is a learning curve issue, and the actual number is more dependent on surgeon experience and expertise than on an arbitrary rule developed from someone else’s database. Second, if the authors had acted on their conclusion, they would have increased their false negative rate by two cases. The authors are past their learning curve and, hence, no longer perform routine completion dissections, so we do not know their false negative rate, but I would suspect it is low and that two more cases would not be insignificant. Third, at our institution, we have done a similar number of cases, yet we continue to encounter the occasional case where the hottest or bluest node is identified after two nodes have been removed—many series have confirmed this “flattening” of the learning curve. Thus, it is now our practice in diffusely hot axillae to stop when the last node—not the background— has a 10-second count of less than one-tenth that of the hottest node. Also, to avoid overstaining of the axilla, we have experienced a more crisp identification of just one or two blue-stained nodes by lowering the dose of lymphazurin blue from the originally described dose of 5 ml, which the authors use, to no more than 1 cc. The final reason I would be hesitant to act on their conclusion is that only 25% of the patients in this study actually had a third node removed, and that greatly limits the power of the study to say that two nodes is enough. I submit that their conclusion could be easily validated with a large, multicenter shared database, such as that of, for example, the National Sentinel Lymph Node Working Group, based in San Francisco.