Importance of Sentinel Lymph Node Biopsy in Patients With Thin Melanoma

Hypothesis  The status of the sentinel node (SN) confers important prognostic information for patients with thin melanoma.

Design, Setting, and Patients  We queried our melanoma database to identify patients undergoing sentinel lymph node biopsy for thin (≤1.00-mm) cutaneous melanoma at a tertiary care cancer institute. Slides of tumor-positive SNs were reviewed by a melanoma pathologist to confirm nodal status and intranodal tumor burden, defined as isolated tumor cells, micrometastasis, or macrometastasis (≤0.20, 0.21-2.00, or >2.00 mm, respectively). Nodal status was correlated with patient age and primary tumor depth (≤ 0.25, 0.26-0.50, 0.51-0.75, or 0.76-1.00 mm). Survival was determined by log-rank test.

Main Outcome Measures  Disease-free and melanoma-specific survival.

Results  Of 1592 patients who underwent sentinel lymph node biopsy from 1991 to 2004, 631 (40%) had thin melanomas; 31 of the 631 patients (5%) had a tumor-positive SN. At a median follow-up of 57 months for the 631 patients, the mean (SD) 10-year rate of disease-free survival was 96% (1%) vs 54% (10%) for patients with tumor-negative vs tumor-positive SNs, respectively (P < .001); the mean (SD) 10-year rate of melanoma-specific survival was 98% (1%) vs 83% (8%), respectively (P < .001). Tumor-positive SNs were more common in patients aged 50 years and younger (P = .04). The SN status maintained importance on multivariate analysis for both disease-free survival (P < .001) and melanoma-specific survival (P < .001).

Conclusions  The status of the SN is significantly linked to survival in patients with thin melanoma. Therefore, sentinel lymph node biopsy 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 who 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 complete lymph node 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 to 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 2 and phase 3 trials have confirmed the adverse prognostic effect of nodal recurrence in patients with intermediate-depth primary cutaneous melanoma.¹ The clinical relevance of occult metastasis in the sentinel node (SN) and the established safety and reliability of the SN technique have led investigators to reassess the role of nodal staging in a broader group of patients with melanoma.

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 In 2003, we described our experience with SLNB for patients with primary melanoma having a thickness of 1.5 mm or less.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 T1 (≤1-mm) primary cutaneous lesions, either routinely or in selected cases with adverse prognostic factors.^10-15 Few articles, however, have documented the results of SLNB in this patient group, particularly the effect of nodal status on long-term outcome.^16,17 To better determine the value of SLNB for primary cutaneous melanoma with a thickness of 1.00 mm or less and to test our hypothesis that the status of the 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 more than 30 years. We conducted a review of that database to identify all of the patients who underwent SLNB for thin (≤1.00-mm) primary cutaneous melanoma since standardization of the technique in 1991. Demographics and tumor information gathered for each patient included age, sex, primary tumor characteristics (anatomical site, Clark 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 the largest tumor deposit as follows: 0.20 mm or less, isolated tumor cells (ITCs); 0.21 to 2.00 mm, micrometastasis; and more than 2.00 mm, macrometastasis.

Survival was determined by the Kaplan-Meier 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 the Fisher 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 from the initial primary diagnosis until the first melanoma recurrence, and melanoma-specific survival (MSS), defined as the period 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 the method of biopsy. The method of biopsy was not determined for the remaining patients with thin melanoma with a tumor-negative SN (n = 600) as this information was not available in our database. Of note, no changes in tumor depth or classification were made based on retrospective record 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. Microscopic slides for the initial biopsy specimen of the primary tumor as well as the WLE specimen were reviewed by our pathologists for essentially all patients. This study was approved by our institutional review board.

At our institution, all patients with a newly diagnosed primary cutaneous melanoma greater than 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 his or her 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 Tc 99m filtered sulfur colloid injected intradermally 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 mL of Lymphazurin (Tyco International, Norwalk, Connecticut) is injected intradermally followed by brief dermal massage. The SNs are identified by levels of radioactivity measured with a handheld gamma probe and by visualization of blue dye.

Pathologic handling of the SNs used paraffin sections at 2 levels (the sections were separated by 40 μm prior to 2000 but by 200 μm in subsequent years) of each paraffin block. Sections were stained with hematoxylin-eosin and with immunohistochemical stains for S-100 protein, HMB-45, and Melan-A (Melan-A was added in 2002). All cases deemed positive were reevaluated by a single melanoma pathologist (R.R.T.) to confirm nodal status and assess nodal tumor burden. Known ocular field diameter was used to measure metastatic deposits in the greatest dimension, which were characterized as ITCs, micrometastasis, or macrometastasis according to American Joint Committee on Cancer, 6th edition guidelines for breast carcinoma and previously described histologic criteria.^14,19 For all patients found to have tumor-positive SNs, CLND was recommended.

We identified 1592 patients with complete information regarding tumor depth in our database who 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 (≤1.00 mm), and 31 of those 631 patients (5%) had a tumor-positive SN. Three hundred thirty-eight of the 631 patients (54%) were male, and 10 of those 338 patients (3%) had a tumor-positive SN. Two hundred ninety-three of the 631 patients (46%) were female, and 21 of those 293 patients (7%) had a tumor-positive SN. The median patient age was 44 years in the tumor-positive group compared with 52 years in the tumor-negative group (P = .02). Patients aged 50 years and younger were more likely to have tumor-positive SNs than their older counterparts (P = .04). Demographics and tumor-specific variables of both tumor-negative and tumor-positive patients are shown in Table 1. Univariate analysis confirmed the negative effect of tumor-positive SN(s) on MSS (P < .001). This adverse effect was also significant on multivariate analysis (P < .001) as was the presence of primary tumor ulceration (P = .003) and head or neck as the primary tumor site (P < .001).

Pathologic examination of the SN(s) demonstrated ITCs in 14 patients, micrometastasis in 15 patients, and macrometastasis in 2 patients. Of the 631 patients who underwent SLNB, 453 (72%) had a primary tumor thicker than 0.50 mm, but the ratio of tumor-negative to tumor-positive SNs was similar across tumor depth as shown in Table 2. Melanoma recurrence occurred more frequently in patients with tumor-positive nodes (42%) than patients with tumor-negative nodes (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 who did not undergo CLND, 4 had micrometastasis and 1 had ITCs in the SN; 1 of the 5 patients developed distant recurrence. Twenty-eight patients had a single tumor-positive node, 1 patient had 2 tumor-positive nodes, 1 patient had 3 tumor-positive nodes, and 1 patient had 4 tumor-positive nodes, for a nodal average of 1.2 tumor-positive nodes per case.

At a median follow-up of 57 months, the mean (SD) 10-year DFS rate was 54% (10%) for patients with a tumor-positive SN compared with 96% (1%) for patients with a tumor-negative SN (P < .001) (Figure 1). In addition, the mean (SD) 10-year MSS rate was 83%(8%) for patients with a tumor-positive SN compared with 98% (1%) for patients with a tumor-negative SN (P < .001) (Figure 2). The mean (SD) 5-year DFS rate according to intranodal tumor burden was 73% (14%), 43% (13%), and 0% for ITCs, micrometastasis, and macrometastasis, respectively (P = .03) (Figure 3). Patients with micrometastasis in the tumor-positive SN trended toward decreased 10-year MSS when compared with patients with only ITCs in the tumor-positive node (mean [SD], 77% [12%] and 86% [13%], respectively; P = .64). Neither of the 2 patients with macrometastasis in the tumor-positive SN has had 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 the initial biopsy in only 4 of 31 cases (13%). 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 who might benefit from a CLND.^2,4,20,21 The technique, originally described by Morton et al²² in 1992, was initially adopted by surgeons working mostly in high-volume melanoma centers. As the technique became refined and data demonstrated its reliability, the popularity and acceptance of SLNB increased worldwide. The primary reason is that the technique has proven both highly reliable and reproducible in correctly locating the SN(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 and colleagues reported a 10% total wound complication rate in 937 patients who underwent SLNB in conjunction with WLE for malignant melanoma but only a 1% rate of either regional or systemic complications in this same group of patients.⁴

The management of clinically tumor-negative nodal basins in patients with primary cutaneous melanoma had been a matter of controversy long before the development and widespread use of SLNB.^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 ELND.^24-26 Initial randomized studies from the World Health Organization and others addressed the benefit question in patients with early-stage melanoma and failed to demonstrate any survival advantage for immediate ELND in comparison with 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- to 4-mm) melanoma were randomized to either ELND or nodal observation.⁵ Initial results⁵ reported in 1996 and follow-up results⁶ reported in 2000 demonstrated a significant survival benefit for ELND in patients younger than 60 years with early, nonulcerated primary lesions 1 to 2 mm in depth. The study also confirmed the importance of both tumor depth and ulceration as predictors of occult nodal involvement and the importance 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 paralleling the American Joint Committee on Cancer recommendations regarding tumor thickness staging (T stage) took shape; tumor depth of 1.0 mm or less 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 Although these patients continue to do well overall, good outcomes are far from ensured.^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 al¹¹ examined their experience with 472 patients diagnosed with thin cutaneous melanoma in the pre-SLNB era. 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 up 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. 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 who might benefit from CLND, however, has led clinicians to challenge conventional indications for nodal sampling and staging.^2,31

In an attempt to better identify those patients with thin melanoma who might best benefit from SLNB, some investigators have studied patients with thin melanoma who experienced a poor outcome. They attempted to identify adverse prognostic factors that might better predict patients suitable for more aggressive staging and management. Kalady et al⁸ reviewed their 30-year experience comprising 1158 patients with thin melanoma. The incidence of clinically evident nodal recurrence was 8%. Neither the Clark level nor ulceration correlated with recurrence or survival. Gimotty et al³² studied outcomes in 884 patients with thin melanoma and developed a risk factor classification scheme based primarily on mitotic rate, growth phase, and sex. Male patients with a mitotic rate more than 0 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 patients with thin melanoma and have attempted to identify factors associated with occult nodal metastasis.^{10,13,17,33-37} Patient age and sex as well as the mitotic rate, ulceration status, thickness, Clark 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, sex (female), and Clark 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 of 1.00 mm or less (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 among these other reports. As already mentioned, disparity exists for virtually all of these data points from one study to the next, highlighting the difficulty of properly selecting those patients with thin melanoma who are most likely to benefit from SLNB.

What appears to be more consistently represented among earlier, smaller studies and in our results (to our knowledge the largest study to date) is that the status of the SN in patients with thin cutaneous melanoma reveals important prognostic information. In the few studies previously mentioned where the prognostic effect of nodal status was assessed, occult nodal metastasis detected by SLNB at the time of WLE had a significant effect on patient outcome.^16,17,33 Furthermore, in observational studies of large numbers of patients with thin melanoma treated with only 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 SN, and that reduction not only held up but actually increased over time (Figure 1). Correspondingly, recurrence rates were much higher in patients with a tumor-positive node (42%) than in patients with a tumor-negative node (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 SN but also by quantification of tumor burden within the tumor-positive node. For instance, 21% of the patients with ITCs developed recurrent disease compared with 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 ITCs were alive at 10 years compared with 77% of those with microscopic disease. This represents 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 minimizing nodal recurrence through SLNB and appropriate CLND improves outcome in terms of DFS and/or overall survival in this patient group (ie, what are the consequences of nodal recurrence in patients with thin cutaneous melanoma who do not undergo selective nodal staging at the time of original diagnosis and surgical treatment?). The Multicenter Selective Lymphadenectomy Trial 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 1269 eligible patients who underwent either WLE plus SLNB with immediate CLND if indicated or WLE alone followed by nodal observation with delayed CLND if indicated. In the patients randomized to nodal observation, results for those with nodal metastases demonstrated disease progression relative to the involved nodal basin as well as a decrease in 5-year survival and an increase in melanoma-specific death. Although patients in the Multicenter Selective Lymphadenectomy Trial had a higher incidence of nodal involvement than did our patients with thin primary cutaneous melanoma (16% vs 5%, respectively), given that the prognostic effect of nodal metastasis seems as significant in patients with thin primary melanoma as in other groups, it seems likely that the effect of delayed nodal management and disease progression in the setting of nodal metastasis will be significant as well, albeit in a smaller group of patients.

While it is clear from our study and others that most 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 be obtained only with SLNB. In addition, patients with tumor-negative SNs can be reassured that their risk of recurrence and melanoma-related death is extremely low. As yet there is no reliable noninvasive technique to determine which thin primary melanomas are likely to have metastasized to the regional lymphatic basin. Therefore, 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. Younger patients with deeper lesions characterized by 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 that they have a greater risk of 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 who could benefit from SLNB.

Correspondence: Donald L. Morton, MD, Department of Surgical Oncology, John Wayne Cancer Institute, 2200 Santa Monica Blvd, Santa Monica, CA 90404 (mortond@jwci.org).

Accepted for Publication: April 6, 2008.

Author Contributions:Study concept and design: Wright, Essner, and Morton. Acquisition of data: Wright, Scheri, Faries, Turner, and Essner. Analysis and interpretation of data: Wright, Ye, Faries, and Morton. Drafting of the manuscript: Wright, Scheri, Ye, Turner, Essner, and Morton. Critical revision of the manuscript for important intellectual content: Wright, Faries, and Morton. Statistical analysis: Ye and Faries. Administrative, technical, and material support: Wright, Turner, Essner, and Morton. Study supervision: Wright, Scheri, Essner, and Morton.

Financial Disclosure: None reported.

Funding/Support: This work was supported in part by grant CA29605 from the National Cancer Institute; the Wayne and Gladys Valley Foundation, Oakland, California; the Harold J. McAllister Charitable Foundation, Los Angeles, California; the Family of Robert Novick, Los Angeles; the Weil Family Fund, Los Angeles; the Wrather Family Foundation, Los Alamos, California; and the Carolyn Dirks Foundation, Los Angeles.

Previous Presentation: This paper was presented at the 79th Annual Meeting of the Pacific Coast Surgical Association; February 18, 2008; San Diego, California; and is published after peer review and revision. The discussions that follow this article are based on the originally submitted manuscript and not the revised manuscript.

Financial Disclosure: None reported.