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EDITORIAL |
From the Memorial Sloan-Kettering Cancer Center, New York, New York.
Correspondence: Address correspondence to: Daniel G. Coit, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021; Fax: 212-717-3400; E-mail: coitd{at}mskcc.org
In a 1992 landmark publication, Morton et al.* reintroduced the concept of an orderly pattern of spread of melanoma to regional lymph nodes.1 In that paper, Dr. Morton defined the biologic phenomenon of sentinel nodes as "the nodes most likely to contain metastatic melanoma." His operational definition of the sentinel lymph node described that node whose hilus was stained blue by a vital blue dye that drained to it through afferent lymphatics from the primary site. Although all patients in this study who had ambiguous lymphatic drainage underwent cutaneous lymphoscintigraphy, those with "predictable" lymphatic drainage based on anatomic grounds were studied with blue dye alone. The authors reported a high rate of success in identifying blue-stained sentinel nodes. All patients underwent planned elective lymph node dissection; Morton was thus able to immediately define a low false-negative rate (i.e., the absence of positive non-sentinel nodes in the setting of a negative sentinel node). This initial support did not contain long-term follow-up to describe the incidence of nodal failure in a basin with a negative sentinel node.
Three years later, Krag et al.2 published a report of lymphatic mapping in melanoma patients using a radioactive tracer, locating the sentinel nodes primarily by handheld gamma counter. In this multicenter study, only 44 of 121 patients (36%) had concurrent injection of blue dye to assist in the visual identification of the sentinel node. These authors arbitrarily defined the sentinel node as the node or nodes containing at least 15 counts per 10 seconds, and a ratio of counts 3 times that of the background. Their paper states that "counts were obtained of the bed of the resected lymph nodes to verify that all radioactive lymph nodes had been removed"; however, they did not describe the minimal residual radioactivity allowed to ensure removal of all relevant nodes. Although the authors stated that they were able to identify "a radiolabeled sentinel lymph node" in 118 of 121 patients (98%), none of these patients underwent completion lymph node dissection to ascertain that positive lymph nodes were not left behind. With a relatively short follow-up of 220 days, only one patient had suffered a regional nodal recurrence at the site of a prior negative sentinel node biopsy. More importantly, however, the authors stressed that cutaneous lymphoscintigraphy identified sentinel lymph nodes outside the typically named nodal groups in four patients, nodes that would not have been detected using blue dye alone. Reintgen et al.,3 Uren et al.,4 and others have stated the importance of routine cutaneous lymphoscintigraphy to identify unsuspected extra-anatomic locations of draining lymph nodes, even in patients with extremity melanoma.
Albertini et al.5 from the Moffitt Cancer Center have described the complementary roles of blue dye and radioisotope guided sentinel lymph node biopsy. In their series, 139 of 200 sentinel nodes (69.5%) demonstrated blue dye staining, whereas 167 of 200 sentinel nodes (83.5%) were "hot" according to radioisotope localization. Using both techniques, sentinel lymph nodes were identified in 124 of 129 basins sampled (96%). For 72 patients who had sentinel lymph nodes harvested, they observed a mean ex vivo ratio of SLN-to-non-SLN radioactivity of 135.6 to 1. Albertini’s operational definition of the sentinel node included all blue-stained lymph nodes, all hot nodes, and all lymph nodes with > 150% of background. As in the Krag et al.2 study, no patient underwent completion lymph node dissection in this series and, consequently, the false-negative rate of this approach was not reported.
Gershenwald et al.6 described the pattern of failure in 243 patients following a negative sentinel lymph node biopsy. With a median follow-up of 35 months, the authors described recurrence after negative SLN biopsy in 27 of 243 patients (11%). Of those 27 patients, 10 (4.1%) experienced regional nodal basin failure, either solely or as a component of initial site of recurrence. On further pathologic review, eight of those patients were found to have had micrometastatic melanoma in the sentinel lymph node that was originally thought to be negative. Using the combined isotope and blue dye technique in most patients, this paper described the sentinel node broadly as "one that localized blue dye and/or concentrated radiolabeled colloid within a regional nodal basin." Importantly, however, they also emphasized that a thorough pathologic evaluation is an essential component of the operational definition of the sentinel node.
With increasing reported experience with this technique, the concept of the initial orderly spread of melanoma to regional lymph nodes seems valid, although this process also seems to be more complex than originally stated. There may be one or more "sentinel nodes" in every patient with melanoma. A single melanoma may have separate parallel draining afferent lymphatics to more than one lymph node, occasionally in different lymph node basins. Furthermore, aberrant lymphatic drainage patterns cannot always be predicted on the bases of the initial anatomic criteria of Sappey.7
The technique of lymphatic mapping and sentinel lymphadenectomy is quite robust. Various authors have reported using different types of blue dye (Isosulfan blue, Patent blue V), different types and doses of radioisotope (99mTc sulfur colloid [both filtered and unfiltered]), 99mTc-labeled albumin, antimony sulfur colloid), and variations in the timing of isotope injection relative to lymphatic mapping (same day versus the preoperative day). In general, and in large part due to a large excess of radioactivity in relevant nodes compared with background, radioactive nodes can be readily identified. When histologically positive sentinel nodes are found, they are usually, but not always, the hottest node, and usually, but not always, the bluest node. In the context of this experience, a number of operational definitions of the sentinel nodes have evolved over time to help the surgeon decide exactly which node(s) should be removed in order to maximize the likelihood of locating the true biologic sentinel node while minimizing the superfluous removal of multiple non-sentinel nodes. Ultimately, however, the true definition of the sentinel node is a biologic one (i.e., the regional lymph node or nodes to which a melanoma would first metastasize).
In the current issue of the Annals of Surgical Oncology, McMasters et al.8 have described another serious attempt to provide a meaningful, operational definition of the sentinel node. This has been made possible by the meticulous record keeping required in the Sunbelt Melanoma Trial. Every node harvested has been described both in terms of its radioactive counts, as well as its blue dye status. Using this extensive database, the authors have described at least three acceptable operational definitions that could be used to minimize the possibility of missing a relevant sentinel node. These definitions are: (a) the hottest node and all blue nodes, (b) the first or second SLN identified, and (c) all blue nodes and all nodes containing radioactive counts 
10% that of the hottest nodes removed. Although not statistically significantly different, the third of these three definitions was associated with the lowest "false-negative rate." The threshold of 10% is arbitrary, and may in fact be too low. It would be quite interesting to see what the false-negative rate would be if the authors looked at other thresholds, such as 20% or 30% of the hottest node. By establishing a higher threshold and also applying the stated blue dye staining criteria, it is entirely possible that fewer negative nodes would be harvested, while all relevant positive nodes could still be identified. The Sunbelt Trial database presents a unique opportunity to establish an "optimal" threshold, rather than to describe an arbitrary one.
In the context of the Sunbelt Trial, in which patients with a negative sentinel node do not undergo completion elective node dissection, the authors acknowledge that the true "false-negative" rate of their operational definition will only be determined by long-term follow-up for nodal recurrence in basins found to have negative sentinel nodes. The acknowledged limitation of the current manuscript is the fact that such long-term follow-up is missing. With short-term follow-up, the authors have already noted seven "false-negative results."
Although this article represents an enormously important contribution to our understanding of the operational definition of a sentinel lymph node, only with longer follow-up will we be certain that their definition is an adequate reflection of the biologic phenomenon of the sentinel lymph node.
If, as expected, their conclusions hold up over time, the authors will confirm that the sentinel lymph node is best defined and identified using the combination of both blue dye and radioisotope. Meticulous and consistent criteria must be used by surgeons who use this technique to stage patients with melanoma. Every node removed should be carefully characterized by terms of radioactivity and blue dye status. This is imperative if we are to understand why patients develop nodal failure in basins with negative sentinel nodes. Finally, surgeons must maintain accurate data with regards to patterns of failure in these patients, including complete reporting of all nodal recurrences, before any definitive statements can be made as to the validity of an optimal operational definition of this biologic phenomenon.
Footnotes
*A review of the Science Citation Index reveals that, to date, subsequent authors have referenced that publication at least 530 times.
Received for publication December 12, 2000. Accepted for publication December 15, 2000.
REFERENCES
This article has been cited by other articles:
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  R. Riber-Hansen, P. Sjoegren, S. J. Hamilton-Dutoit, and T. Steiniche Extensive Pathological Analysis of Selected Melanoma Sentinel Lymph Nodes: High Metastasis Detection Rates at Reduced Workload Ann. Surg. Oncol., May 1, 2008; 15(5): 1492 - 1501. [Abstract] [Full Text] [PDF]
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O. E. Nieweg and S. H. Estourgie What is a Sentinel Node and What is a False-Negative Sentinel Node? Ann. Surg. Oncol., March 1, 2004; 11(3_suppl): 169S - 173S. [Abstract] [Full Text] [PDF]
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 D. Lardinois, T. Brack, A. Gaspert, T. Spahr, D. Schneiter, H.C. Steinert, and W. Weder Bronchoscopic radioisotope injection for sentinel lymph-node mapping in potentially resectable non-small-cell lung cancer Eur. J. Cardiothorac. Surg., May 1, 2003; 23(5): 824 - 827. [Abstract] [Full Text] [PDF]
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