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Patients with thin melanoma are not typically offered sentinel lymph node biopsy (SLNB) because of the low incidence of nodal metastasis and perception that nodal status has little impact on outcome.
We hypothesized that status of the SN confers important prognostic information for thin melanoma patients.
Tertiary Care Cancer Institute
We queried our melanoma database to identify patients undergoing SLNB for thin (≤ 1.0 mm) cutaneous melanoma. Slides of tumor-positive sentinel nodes (SNs) were reviewed by a melanoma pathologist to confirm nodal status and intranodal tumor burden, defined as isolated tumor cells (ITC), micrometastasis or macrometastasis (≤0.2, 0.21 – 2.0, or >2.0 mm, respectively). Nodal status correlated with patient age and primary tumor depth (≤0.25, 0.26 – 0.50, 0.51 – 0.75, or 0.76 – 1.0 mm). Survival was determined by log-rank test.
Disease-Free (DFS) and Melanoma-Specific Survival (MSS)
Of 1,592 patients that underwent SLNB from 1991–2004, 631 (40%) had thin melanomas and 31 of 631 (5%) had a tumor-positive SN. At a median follow-up of 57 months, 10-year rates of DFS and MSS for SN - versus SN + patients were 96±1.1% versus 54±9.6% (p<0.0001) and 98±0.9% versus 83±7.7% (p<0.0001), respectively. Tumor-positive SNs were more common in patients ≤ 50 years old (p<0.05). SN status maintained importance on multivariate analysis for both DFS (p<0.0001) and MSS (p<0.0001).
Status of the SN is significantly linked to survival in thin melanoma patients and, therefore, SLNB should be considered to obtain complete prognostic information.
Sentinel lymph node biopsy (SLNB) is a well established method of staging the draining nodal basin in patients with malignant melanoma.1, 2 The technique has most often been applied to patients with primary cutaneous melanoma that have a moderate to high risk of nodal metastasis. These primary lesions are typically greater than 1 mm in depth or have other characteristics associated with a poor prognosis. In this setting, correctly performed SLNB can accurately identify patients with occult nodal metastasis and expectedly poorer outcome that might therefore benefit from a completion nodal dissection (CLND) and evaluation for systemic adjuvant therapies.1, 3, 4
Prior to the widespread use and acceptance of SLNB in the management of patients with primary melanoma, indications for elective nodal staging and dissection had long been a matter of controversy.5 Prospective, randomized multicenter studies demonstrated an equivocal survival benefit associated with elective lymph node dissection (ELND) in selected patients with primary melanoma 1–4 mm in thickness, but there was no consensus regarding its use in patients with thinner lesions.5,6 In recent years, data from phase II and phase III trials have confirmed the adverse prognostic impact of nodal recurrence in patients with intermediate-depth primary cutaneous melanoma.1 The clinical relevance of occult metastasis in the sentinel node, and the established safety and reliability of the sentinel node technique, have led investigators to reassess the role of nodal staging in a broader group of melanoma patients.
Although patients with thin primary lesions and no clinical evidence of nodal metastasis have done well with wide local excision (WLE) alone, nodal recurrence can occur and worsen patient outcome.7, 8 Five years ago, we reported our experience with SLNB for patients with primary melanoma ≤ 1.5 mm in thickness.9 Our early results indicated the value of SLNB for lesions between 1.0 and 1.5 mm, and possibly for thinner melanomas. Since then, several groups have advocated SLNB in patients with American Joint Committee on Cancer (AJCC) T1 (≤ 1 mm) primary cutaneous lesions, either routinely or in selected cases with adverse prognostic factors. 10–15 Few reports, however, have documented the results of SLNB in this patient group, particularly as relates to the impact of nodal status on long-term outcome.16, 17 To better determine the value of SLNB for primary cutaneous melanoma ≤ 1 mm in thickness, and to test our hypothesis that the status of the sentinel node (SN) confers important prognostic survival information for these patients, we reviewed our experience for this specific subgroup.
Our tertiary cancer center has prospectively maintained a comprehensive melanoma database dating back over 30 years. We conducted a review of that database to identify all patients that underwent SLNB for thin (≤ 1 mm), primary cutaneous melanoma since standardization of the technique in 1991. Demographics and tumor information gathered for each patient included age, gender, primary tumor characteristics (anatomic site, Clark’s level, Breslow depth, and presence or absence of ulceration) and tumor status of the SLNB specimen. Mitotic rate, vertical growth phase and regression were not available for analysis in this study. Metastatic tumor burden in the SN was categorized by a maximal dimension of largest tumor deposit as follows: ≤ 0.2 mm, isolated tumor cells (ITC); 0.21 mm - 2.0 mm, micrometastasis and > 2.0 mm, macrometastasis.
Survival was determined by the Kaplan-Maier method and comparisons were made using the log-rank test. In addition, both univariate and multivariate Cox-regression analyses were performed to determine the prognostic importance of SN status relative to other variables, and Fisher’s exact test was used to test the correlation between patient characteristics and occult nodal metastasis (tumor-positive SN). Primary outcome measures were disease free survival (DFS), defined as the period of time from the initial primary diagnosis until first melanoma recurrence and melanoma specific survival (MSS), defined as period of time from the initial primary diagnosis until occurrence of melanoma-specific death. In those cases where a tumor-positive SN was confirmed, the original pathology report of the primary tumor was reviewed to determine method of biopsy. Method of biopsy was not determined for the remaining thin melanoma patients (N=600) with a tumor-negative SN, as this information was not available in our database. Of note, no changes in tumor depth or classification were made based on retrospective chart review. Rather, the original tumor depth as determined by the examining melanoma pathologist at the time of the individual case was assumed to be correct. This study was approved by our institutional review board (IRB).
At our institution, all patients with a newly diagnosed primary cutaneous melanoma > 1 mm in depth are offered SLNB as part of their surgical management in the absence of clinically evident nodal disease or known distant metastasis. Those with thin primary lesions are offered SLNB on a more select basis. These patients are not selected for SLNB according to a specific protocol or institutional criteria, however. Rather, the options and rationale for SLNB are discussed individually between each patient and their respective dedicated melanoma surgeon. A large number of factors contribute to specific recommendations regarding SLNB, including patient age, tumor location and depth, presence or absence of ulceration, and other variables thought to affect nodal status. Also of great importance are the patient’s concerns regarding nodal status and desire to undergo SLNB despite a relatively low risk of occult nodal metastasis.
Our technique for SLNB in melanoma has been described in detail.18 In brief, patients undergo same-day lymphatic mapping with technetium-99 filtered sulfur colloid injected intra-dermally around the primary site. Skin markers are then placed to identify SN sites and the patient is transported to the operating room. Ten minutes prior to the skin incision, up to 1 cc of Lymphazurin (Tyco International, Norwalk, CT) is injected intradermally followed by brief dermal massage. SNs are identified by levels of radioactivity measured with a hand-held gamma probe and by visualization of blue dye.
Pathologic handling of the SNs utilized paraffin sections at two levels (prior to the year 2000, the sections were separated by 40um but in subsequent years by 200um) of each paraffin block stained with hematoxylin and eosin (H&E) and immunohistochemical stains for protein S-100, HMB-45 and Melan-A (Melan-A added in 2002). All cases deemed positive were re-evaluated by a single melanoma pathologist (RRT) to confirm nodal status and assess nodal tumor burden. Known ocular field diameter was used to measure metastatic deposits in greatest dimension which were characterized as ITC, micrometastasis or macrometastasis according to AJCC 6th edition guidelines for breast carcinoma and previously described histologic criteria.14, 19 CLND was recommended for all patients found to have tumor-positive SNs.
We identified 1,592 patients with complete information regarding tumor depth in our database that underwent SLNB in conjunction with WLE for primary cutaneous melanoma. Six hundred thirty-one (40%) of those patients had primary lesions classified as thin melanoma (≤1.0 mm) and 31 (5%) of those had a tumor-positive SN. Three-hundred and thirty-eight of the patients (54%) were male and 10 (3%) of those had a tumor-positive SN. Of the 293 (46%) female patients, 21 (7%) had a tumor-positive SN. Median patient age was 44 years in the tumor-positive group compared to 52 years in the tumor-negative group (p=0.015). Patients aged 50 and younger were more likely to have positive SNs than their older counter parts (p=0.038). Demographics and tumor specific variables of both tumor-negative and tumor-positive patients are shown in Table 1. Univariate analysis confirmed the negative impact of tumor-positive SN(s) on MSS (p<0.001). This adverse effect was also significant on multivariate analysis (p<0.0001) as was the presence of primary tumor ulceration (p<0.01) and head/neck as the primary tumor site (p<0.0001)
Pathologic examination of the SN(s) demonstrated ITC in 14 patients, micrometastasis in 15 patients and macrometastasis in 2 patients. Of the 631 patients that underwent SLNB, 453 (72%) had a primary tumor thicker than 0.50mm, but the ratio of tumor-negative to tumor-positive SNs was similar across tumor depth as demonstrated in Table 2. Melanoma recurrence occurred more frequently in node-positive patients (42%) than node-negative patients (3%) and the patterns of recurrence for each group are shown in Table 3. Twenty-six of the 31 patients with nodal metastasis detected on SLNB underwent CLND. Reasons for failure to undergo CLND were based largely on patient decisions after discussion of SLNB results. Of the 5 patients that did not undergo CLND, 4 had micrometastasis and 1 had ITC in the SN; 1 of the 5 patients developed distant recurrence. Twenty-eight patients had a single positive node, 1 patient had 2 positive nodes, 1 patient had 3 positive nodes and a final patient had 4 positive nodes for a nodal average of 1.2 tumor-positive nodes per case.
At a median follow-up of 57 months, 10-year DFS for patients with a tumor-positive SN was 54 ± 9.7% compared to 96±1.1% for patients with a tumor-negative SN (p<0.0001) (Figure 1). In addition, 10-year MSS for patients with a tumor-positive SN was 83±7.7% compared to 98±0.9% for patients with a tumor-negative SN (p<0.0001) (Figure 2). Five-year DFS according to intranodal tumor burden was 73±14%, 43±13% and 0% for ITC, micrometastasis and macrometastasis, respectively (p=0.026) (Figure 3). Patients with micrometastasis in the tumor-positive SN trended towards decreased 10-year MSS when compared to patients with only ITC in the tumor-positive node (77±12% and 86±13%, respectively; p=0.64). Neither of the 2 patients with macrometastasis in the tumor-positive SN has suffered a melanoma-related death.
Of the 31 patients who had tumor-positive SNs, 15 (48%) underwent shave biopsy, 4 (13%) underwent excisional biopsy, and 12 (39%) underwent an unspecified biopsy procedure. Despite the frequent use of shave biopsy, the deep margin was in question after initial biopsy in only 4/31 (13%) cases. In 2 of those 4 cases, residual melanoma was identified following WLE of the primary site with adjustment of tumor thickness from 0.7 mm to 0.9 mm in a single patient.
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 (Table 4) 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 (Table 2). 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.
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 (Figure 1). 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 (Figure 2).
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.
Research supported in part by National Cancer Institute grant CA29605; the Wayne and Gladys Valley Foundation (Oakland, CA); the Harold J. McAllister Charitable Foundation (Los Angeles, CA); the Family of Robert Novick (Los Angeles, CA); the Weil Family Fund (Los Angeles, CA); the Wrather Family Foundation (Los Alamos, CA); the Carolyn Dirks Foundation (Los Angeles, CA)
Presented at the 79th Annual Meeting of the Pacific Coast Surgical Association, Coronado Island, California, February 15–18, 2008