Sentinel lymph node biopsy has become standard procedure for staging the regional lymph nodes in primary cutaneous melanoma and for identifying those patients that might benefit from a CLND.2, 4, 20, 21
The technique, originally described by Morton22
and colleagues in 1992, was initially adopted by surgeons working mostly in high volume melanoma centers but, as the technique became refined and data demonstrated its reliability, the popularity and acceptance of SLNB increased world wide. The primary reasons for this are that the technique has proven both highly reliable and reproducible in correctly locating the sentinel node(s) with an acceptably low false-negative rate and a negligible incidence of “skip” metastases.1, 3,4
In addition, associated surgical morbidity is quite low with very few related major long-term complications. 4, 23
Local complications do occur, however, at a rate consistent with other elective, clean operations. For example, Morton el al reported a 10% total wound complication rate in 937 patients that underwent SLNB in conjunction with WLE for malignant melanoma but reported only a 1% rate of either regional or systemic complication in this same group of patients.4
The management of clinically negative nodal basins in patients with primary cutaneous melanoma had been a matter of controversy long before the development and widespread use of selective lymphatic mapping and localization.5, 6
Prior to the initiation of several large, prospective, randomized studies, a number of smaller retrospective reports had provided conflicting data on the survival benefit of elective lymph node dissection (ELND).24–26
Initial randomized studies from the World Health Organization (WHO) and others addressed the benefit question in patients with early stage melanoma and failed to demonstrate any survival advantage for immediate ELND in comparison to observational management (delayed lymph node dissection).27–29
Criticisms regarding the inability of these studies to identify potential survival benefit in specific patient subsets, as well as conflicting results from several other studies, led to the initiation of the Intergroup Melanoma Trial. In this multi-institutional study, 740 patients with clinically localized, intermediate thickness (1–4 mm) melanoma were randomized to either ELND or nodal observation.5
Initial results were reported in 1996 and follow-up results reported in 2000 that demonstrated significant survival benefit for ELND in patients under the age of 60 with early, non-ulcerated primary lesions 1–2 mm in depth.5, 6
This study also confirmed the importance of both tumor depth and ulceration as predictors of occult nodal involvement and of nodal status as the best single predictor of patient outcome.6
As the SLNB era arrived, these reports and others formed the foundation for guidelines regarding the indications for SLNB in patients presenting with primary cutaneous melanoma. Proposed cutoffs took shape that paralleled the American Joint Committee on Cancer (AJCC) recommendations regarding tumor thickness (T) staging; tumor depth ≤ 1.0 mm thick, in the absence of other significant factors, was a relative contraindication for SLNB given the low yield of tumor-positive nodes and the expected outstanding survival of these patients.14
The incidence of melanoma, however, is increasing worldwide and up to 70% of new cases are thin lesions.30, 31
Although these patients continue to do well overall, good outcomes are far from assured.7, 8
Multiple studies have demonstrated that 5% to 10% of these patients harbor occult nodal metastasis that will often result in recurrent disease. For example, Karakousis et al, examined their experience with 472 patients diagnosed with thin cutaneous melanoma in the pre-SLNB era.11
Patients were included in the study if they were found to have no clinical evidence of nodal disease at the time of WLE and if they had been followed reliably for a minimum of 10 years. A total of 67 patients developed recurrent disease and roughly half of those recurrences, or 7% of the total, were in a regional nodal basin. The strongest predictor of a disease-specific death was nodal recurrence (RNM). In the past, both the cost and significant morbidity of ELND balanced against a theoretical benefit, argued for a largely observational approach in patients with thin primary lesions. The emergence of selective lymphatic sampling as a safe and reliable technique to identify patients that might potentially benefit from CLND, however, has led clinicians to challenge conventional indications for nodal sampling and staging.2, 32
In an attempt to better identify those thin melanoma patients that might best benefit from SLNB, some investigators have studied thin melanoma patients who experienced a poor outcome and attempted to identify adverse prognostic factors that might better predict patients suitable for more aggressive staging and management. Kalady et al, reviewed their 30-year experience comprising 1,158 patients with thin melanomas. 8
The incidence of clinically evident nodal recurrence was 8%. Neither Clark’s level nor ulceration correlated with recurrence or survival. Gimotty et al, studied outcomes in 884 patients with thin melanoma and developed a risk factor classification scheme based primarily upon mitotic rate, growth phase and gender.33
Male patients with a mitotic rate > zero and a vertical growth phase had a 31% chance of developing metastatic disease over 10 years.
Other authors have reported their institutional results for SLNB in thin melanoma patients and attempted to identify factors associated with occult nodal metastasis.10, 13, 17, 34–38
Patient age and gender, as well as the mitotic rate, ulceration status, thickness, Clark’s level, and vertical growth phase have been implicated as risk factors for occult nodal metastasis () but there is no consensus among studies. Our results reflect this as well. We found that SN status correlated with age, gender (female) and Clark’s level but not with ulceration or even tumor thickness as the percentage of patients with tumor-positive nodes was roughly equivalent at all stratified tumor depths ≤1 mm (). Although the reason for the differences between our study and some others is not clear, the discrepancies are not particularly surprising in view of the frequent inconsistencies that exist amongst these other reports. As already mentioned, disparity exists for virtually all of these data points from one study to the next and this highlights the difficulty of properly selecting those thin melanoma patients that are most likely to benefit from SLNB.
Reported results of Sentinel Lymph Node Biopsy in patients with thin (≤1.0 mm) primary cutaneous melanoma and factors correlated with a tumor-positive Sentinel Node.
What appears to be more consistently represented amongst earlier smaller studies and in our results as well (the largest study we know of to date) is that the status of the sentinel node in patients with thin cutaneous melanoma reveals important prognostic information. In the few studies previously mentioned where prognostic impact of nodal status was assessed, occult nodal metastasis detected by SLNB at the time of WLE had a significant impact on patient outcome. 16, 17, 34
Furthermore, in observational studies of large numbers of thin melanoma patients treated only with WLE, recurrence in the regional nodal basins has been the strongest predictor of poor outcome.7,8, 11
In our series, DFS was markedly reduced by the finding of a tumor-positive sentinel node and that reduction not only held up but actually increased over time (). Correspondingly, recurrence rates were much higher in node positive patients (42%) than node negative patients (3%). Recurrent disease clearly translated into patient deaths as results for MSS paralleled DFS with significant differences seen at both 5 and 10 years of patient follow-up ().
Additional prognostic information may be conveyed, not only by tumor status of the sentinel node, but also by quantification of tumor burden within the tumor-positive node. For instance, 21% of the patients with ITC developed recurrent disease compared to 59% of those with micrometastasis and macrometastasis combined. In addition, although our data did not demonstrate significant MSS differences between the 3 nodal burden groups, this was likely due to sample size as 86% of those with ITC were alive at 10 years compared to 77% of those with microscopic disease, representing a possible trend of decreasing survival with increasing nodal tumor burden.
There is strong evidence that nodal status provides extremely relevant prognostic information for patients with thin melanoma. Perhaps the more pertinent issue when weighing the cost and morbidity of SLNB against the admittedly low yield (5% in our series) of the procedure in these patients is whether or not minimizing nodal recurrence through SLNB and appropriate completion dissection improves outcome in terms of DFS and/or OS in this patient group – ie, what are the consequences of nodal recurrence in patients with thin cutaneous melanoma that do not undergo selective nodal staging at the time of original diagnosis and surgical treatment? The Multicenter Selective Lymphadenectomy Trial (MSLT) Group addressed this question in a prospective, randomized study of patients with intermediate thickness
primary cutaneous melanoma. 1
The findings from this trial included results and outcomes for 1, 269 eligible patients that either underwent WLE plus SLNB with immediate CLND if indicated or WLE alone followed by nodal observation with delayed LND if indicated. Results demonstrated both disease progression relative to the involved nodal basin in the delayed management patients as well as a decrease in 5-year survival and increase in melanoma specific death in the patients randomized to nodal observation. Although this study involved a group of patients with a higher incidence of nodal involvement than thin primary cutaneous melanoma patients (16% compared to 5%), given that the prognostic impact of nodal metastasis seems as significant in thin primary patients as other groups, it seems likely that the impact of delayed nodal management and disease progression in the setting of nodal metastasis will likely be significant as well, albeit in a smaller group of patients.
While it is clear from our report and others that the majority of patients with a newly diagnosed, thin primary cutaneous melanoma will not derive any benefit from SLNB as part of their initial surgical management, it seems equally clear that for the small number of patients with occult nodal metastasis at the time of their initial diagnosis, correct identification provides critical prognostic information that can only be obtained with SLNB. In addition, patients with tumor-negative SN(s) can be reassured that their risk of recurrence and melanoma-related death is extremely low. Because no parameters currently exist that allow clinicians to reliably select node-positive thin melanoma patients, or exclude node-negative ones, all patients with invasive thin primary melanoma should be counseled regarding the implications of occult nodal metastasis and the ability of SLNB to reliably identify patients with this more advanced disease. Patients of younger age with deeper lesions that possess other adverse prognostic factors such as ulceration, elevated mitotic rate and evidence of a vertical growth phase should be made aware of available evidence suggesting they have a greater chance of already having occult nodal metastasis at the time of initial diagnosis and, therefore, might be more likely to benefit from SLNB. Patients should further be informed, however, that the correlation of these different variables with SN status from one study to the next has been poor. Future studies should focus on the development of a more reliable system of risk stratification that will more readily assist clinicians in identifying the relatively few patients with thin primary cutaneous melanoma that could benefit from SLNB.