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Journal of Clinical Oncology, Vol 22, No 18 (September 15), 2004: pp. 3677-3684 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.01.012 Factors Predictive of Tumor-Positive Nonsentinel Lymph Nodes After Tumor-Positive Sentinel Lymph Node Dissection for MelanomaFrom the John Wayne Cancer Institute, Santa Monica, CA Address reprint requests to Richard Essner, MD, John Wayne Cancer Institute, 2200 Santa Monica Blvd, Santa Monica, CA 90404; e-mail: essnerr{at}jwci.org
PURPOSE: Approximately 20% of sentinel node (SN) positive melanoma patients have additional non-SN (NSN) metastasis. The rationale for this study was to identify the factors associated with additional nodal disease, as a method to determine which patients may most benefit from completion lymph node dissection (CLND).
PATIENTS AND METHODS: During 1990 to 2002, 1,599 patients have undergone SN biopsy at our institute. 19.5% underwent CLND for tumor-positive SN. One hundred ninety-one of these patients had clinicopathologic information available for review. Univariate analyses used
RESULTS: Forty-six (24%) patients had tumor-positive NSN. Univariate analyses showed that primary thickness (Breslow and Clark), primary site, SN tumor size, and number of tumor-positive SNs were significantly associated with tumor-positive NSN. Multivariate analysis (167 patients), confirmed that Breslow and SN tumor size were independently predictive. Sex, histology, ulceration, mitotic index, and SN basin location were not predictive. Risk stratification by the number of prognostic factors present (Breslow CONCLUSION: Thicker primary and larger SN tumor size are factors that correlate best with tumor-positive NSN. Although none of these factors are absolutely predictive of residual nodal disease, these factors must be strongly considered if the SN contains metastasis, as they provide enhanced risk assessment for NSN tumor-positivity.
Both incidence and mortality from melanoma continue to rise in the United States. In 1992, the projected annual incidence and mortality from melanoma were 32,000 and 6,700, respectively.1 By 2003, these figures changed to 54,200 and 7,600, respectively.2 The lifetime risk of developing melanoma has risen from 1:1500 in 1935 to 1:75 in 2000.3 The mortality rate correlates with thickness of the primary lesion, presence of ulceration, and number of regional lymph node (LN) metastases. Whereas the estimated 10-year survival-rate for stage I melanoma patients is 85%, that of stage III melanoma patients is only approximately 35%.4 Among stage III patients, 5-year survival rate for patients with  4 tumor-positive lymph nodes is approximately half of that for similar patients with only a single tumor-positive LN.5
In 1892, Snow6 first proposed performing routine elective lymph node dissection (ELND) based on the concept that melanoma spreads sequentially from the primary site to the regional LN basin. Thus, by empirically removing the regional LNs early in the metastatic process, disease would not progress to distant sites. Since then, multiple nonrandomized studies have supported the efficacy of ELND.7-9 However, other studies argue that ELND offers no survival advantage and that LN dissection should be reserved for those with clinical evidence of LN metastasis.10-12 The Intergroup Melanoma Surgical Trial adds more to the uncertainty as this study demonstrated no survival advantage for patients who underwent ELND, except for a subgroup of patients who were Lymphatic mapping and sentinel lymphadenectomy (LM/SL) has now become widely accepted as a staging method for identifying tumor status of regional LN basins, essentially replacing ELND as a staging tool. By performing completion lymph node dissection (CLND) only on patients with tumor-positive sentinel nodes (SNs), we are now able to spare 75% to 80% of patients the cost and morbidity of ELND. Recent reports examining the frequency of non-SN (NSN) metastasis in SN-positive patients have shown that approximately 7% to 30% of patients with tumor-positive SN harbor additional tumor-positive LNs in the dissected LN basin.14-22 The significance of this data becomes more evident when we consider that approximately 35% of patients with tumor-positive SNs die within 10 years despite undergoing CLND and receiving adjuvant treatments (data not shown). These findings raise significant doubt about the efficacy of CLND in preventing distant metastasis or extending survival in all patients, and also question the necessity of performing CLND in all patients with tumor-positive SN. The purpose of this study was to identify clinicopathologic factors that might correlate with NSN tumor positivity in patients with tumor-positive SNs, thus helping to identify patients who would most likely benefit from CLND.
Data Acquisition The John Wayne Cancer Institute (JWCI) melanoma database was queried to identify all patients who underwent LM/SL between the years 1990 to 2002, and were found to have a tumor-positive SN. During the past 13 years, 1,599 patients have undergone LM/SL at our institute for diagnosis of clinical stage I/II melanoma. Approximately 19.5% of these patients have had a tumor-positive SN, and of those, 191 had at least one of the clinicopathologic information of interest available for analysis after undergoing CLND. The data of interest were obtained from combination of computer query and from paper chart reviews. This study was approved by the JWCI/Saint John's Health Center Joint institutional review board.
SN Biopsy Technique and CLND
Statistical Analysis
The clinicopathologic features of the 191 patients and their tumors are shown in Table 1. Of the 191 patients, four had tumor-positive NSNs identified at the time of LM/SL and 46 (24%) had tumor-positive NSNs found at the time of CLND. The youngest patient with tumor-positive NSNs was 23 years old; the thinnest lesion with NSN positivity was 0.65 mm and had Clark level of III; 1 of 3 patients who were found to have tumor-positive SNs only by IHC had tumor-positive NSNs. The univariate analyses (Table 2) show that patients with tumor-positive NSNs were significantly older (P = .025), had thicker primary lesions (Breslow P = .001; Clark P < .001), more tumor-positive SNs (P = .016), and larger SN metastasis (P < .001) with different primary site distribution than did patients with tumor-negative NSNs. The two groups were not significantly different regarding sex (P = .174), histologic subtype (P = .138), ulceration (P = .597), mitotic index (P = .102), or location of SN basin (P = .685). Figures 1 and 2 demonstrate striking correlations between the Breslow thickness and Clark level of the primary lesion and frequency of finding additional tumor-positive NSNs. Likewise, Figure 3 shows that increasing SN tumor burden correlates with the likelihood of finding tumor-positive NSNs. Additionally, as noted in Figures 4 and 5, both age at diagnosis and the number of tumor-positive SNs correlate with probability of finding additional NSN metastasis. The results of multivariate analysis are shown in Table 3. Of 167 patients included in the final model, 38 (23%) had NSN metastasis and 129 (77%) did not. Breslow thickness and SN metastasis size were noted to be significantly associated with patients having tumor-positive NSNs in our multivariate model.
The prespecified cutoff point of 3 mm for Breslow thickness comparing tumor-positive NSN group versus tumor-negative NSN group was chosen based on the studies of Haddad et al26 (2.8 mm) and Wagner et al15 (2.86 mm). The  2 test showed significant difference (P = .002) with relative risk (RR) of 2.96 (CI, 1.47 to 6.00) for NSN tumor-positivity. Similar results were noted when the data were analyzed in regards to SN tumor burden. Using 2 mm metastasis size as the cutoff point (commonly used definition of micrometastasis27), the 2 test shows a significant difference between tumor-positive and tumor-negative NSN groups (P = .003, RR = 2.93, CI, 1.42 to 6.06). Risk stratification was done using these independently significant factors that were identified in our multivariate analysis and prespecified cutoff points (Fig 6). The likelihood of NSN metastasis was 12.3% in the lowest risk group (0 factors) and 41.9% in the highest risk group (two factors).
The incidence of melanoma continues to rise, and prognosis remains poor for patients with advanced disease. The traditional treatment of early-stage disease by wide local exicision (WLE) and ELND has been a subject of debate. While many surgeons advocated ELND, others preferred observation of the regional LNs and employed therapeutic lymph node dissection (TLND) only when patients developed clinical evidence of nodal metastasis. Several retrospective studies have reported a survival advantage in patients undergoing ELND instead of observation followed by TLND.7-9 These studies suggest that ELND may be associated with improved 5- to 10-year survival in a subgroup of melanoma patients. For example, Balch et al28 reported improved survival in patients undergoing ELND, but only after 5 to 8 years of follow-up. In their subsequent study, the survival advantage was observed only in a group of patients with primary melanomas of 1.5 to 3.99 mm in thickness (for 0.76 to 1.5 mm group, mostly males benefited from ELND).29 However, the prospective randomized trials of ELND versus TLND have failed to show a survival benefit for all patients undergoing ELND, but do suggest that some subgroups may benefit from ELND. Veronesi et al30 and the WHO conducted a prospective randomized international trial and concluded that while not all patients did better after ELND, the patients with tumor-positive ELND tended to have better 10-year survival than those who underwent WLE and delayed lymph node dissection (  36% v 23%, respectively). Results from the study of Cascinelli et al,31 which compared immediate versus delayed regional lymphadenectomy, suggested that ELND mostly benefited patients with occult regional disease. Balch et al13,32 from the Melanoma Intergroup Trial found no overall survival benefit of ELND, except in a subgroup of patients (1-2 mm thick melanoma, age < 60 years, and nonulcerated primaries). This group most likely represents the patients whose regional nodal disease is limited to the SN. Since LM/SL was not done on these patients, ELND achieved complete removal of the only tumor-involved LN. Accordingly, this data also suggest that if regional LNs are involved with melanoma metastases, then earlier removal of tumor-involved LNs may be beneficial to the patient. However, although the patients in the study done by Balch et al13,32 were prospectively stratified and prerandomized, the subgroups found to have a survival benefit were not part of the original study design.13 To summarize, both retrospective and prospective studies suggest that ELND likely has therapeutic value only when LN metastases are present. This concept is further supported by a report by Gershenwald et al,33 which suggests that synchronously performing ELND on SN-negative patients does not improve survival. Lack of definitive evidence regarding the efficacy of ELND in all patients has led to the advent of LM/SL. LM/SL has become widely accepted as a minimally invasive method of staging the regional LN basin. By performing CLND only in patients with a tumor-positive SN, we are able to spare approximately 75% to 80% of the patients who would otherwise receive ELND. However, recent studies indicate that only approximately 7% to 30% (21% ± 7.8%) of patients with tumor-positive SNs have additional NSN metastasis in the same nodal basin.14-22 In our current series, approximately 24% of patients who underwent LM/SL followed by CLND for a tumor-positive SN had tumor-positive NSNs, which is well within the range of reported studies. This translates into potentially making 70% to 80% of the SN-positive patients free of nodal disease by performing LM/SL alone. The significance of this data becomes more evident when we consider the fact that approximately 35% of the patients with a tumor-positive SN die within 10 years despite undergoing CLND and receiving adjuvant treatments (data not shown). These results raise significant doubts as to the efficacy of CLND in preventing the development of distant metastases, as well as questioning the necessity of routinely performing CLND in all patients with tumor-positive SNs.
For these reasons, several investigators have examined clinical and pathologic factors that may be relevant in identifying subgroups of patients whose disease is confined to the SN and who therefore may not benefit from CLND. Whereas Joseph et al14 suggested the possibility of avoiding CLND in patients with primaries less than 1.5 mm thick, Haddad et al26 suggested that CLND can be avoided in SN-positive patients with primaries less than 2.8 mm thick. McMasters et al20 failed to find any factors that were associated with absence of NSN metastasis, thus adding to the confusion and controversy. Perhaps, the focus then should be on identifying a subset of patients who are most likely to harbor additional nodal disease after performing SN biopsy. Gershenwald et al21 reported that tumor thickness more than 2 mm and SN tumor burden more than 2 mm2 are independently predictive of NSN metastasis. Our study confirms the predictive significance of Breslow thickness and SN tumor burden. Contrary to the report of Reeves et al22 on the importance of ulceration (as a part of size/ulceration scoring system) in predicting NSN status, we were unable to confirm ulceration as an independently predictive factor (P = .597). However, even in their study, ulceration alone failed to show significance in multivariate analysis (P = .1). In our study, the frequency of NSN metastasis correlated with increases in Breslow thickness (Fig 1). More specifically, Breslow thickness It is worthy to note that factors predictive of NSN metastasis are similar to the prognostic factors for survival in melanoma patients. As mentioned earlier, in addition to Breslow thickness and the presence of LN metastasis, degree of regional lymph nodal involvement as measured by the number of tumor-positive LNs significantly influences survival.5 It is not surprising, therefore, that Breslow thickness and SN tumor burden correlate with risk of NSN metastasis. This suggests an orderly progression of loco-regional spread of melanoma from the primary site to its draining lymph nodal basin. More specifically, thicker primaries show higher likelihood of SN metastases, greater SN tumor burden correlates with additional lymph nodal involvement, and multiple tumor-positive LNs are associated with worse prognosis. Reports by Starz et al17,18 suggest that SN tumor burden (S-staging) is an independent predictive factor for development of NSN positivity, distant metastasis, and overall survival. More specifically, S3 stage (SN metastasis depth > 1 mm) has been shown to carry relative risk ratios of 8.47 and 4.69 for development of distant metastasis and melanoma related death, respectively. Furthermore, they also concluded that risk of distant metastasis is best predicted by a combination of T-staging and S-staging. Cochran et al39 report similar findings regarding prognostic utility of Breslow thickness and SN tumor burden. In their recent report, Breslow thickness, SN tumor area, and SN interdigitating dendritic cell density were all independently associated with frequency of NSN metastasis, melanoma recurrence, and melanoma-related survival. What is evident from these reports is that SN and regional lymph nodal tumor burdens correlate with risk of developing distant metastases, suggesting that regional LN basins may function as an "incubator" for melanoma, en route to eventual distant metastasis. This "incubator theory" provides compelling support for CLND as an effective therapeutic/prophylactic procedure. Conversely, the opponents of this theory may argue that given approximately 10% of stage I and 15% to 20% of stage II patients die within 5 years, subclinical distant metastasis may occur in absence of LN metastasis; in this case, regional lymph nodal dissection has minimal therapeutic role. However, this group constitutes a minority of melanoma patients. In addition, undetectable metastasis does not equate to absence of metastasis. More sensitive detection methods, such as reverse transcriptase polymerase chain reaction, are currently being evaluated in the multi-institutional Sunbelt Melanoma trial.40 As clinicians, however, we cannot ignore the significant morbidity associated with loco-regional recurrences, and limited chance for a cure in some group of patients.
Regional lymphadenectomies carry substantial amount of health care costs, patient morbidity, and most importantly lost of productivity and long-term disability. Recent prospective studies failed to show a survival advantage of performing ELND in all patients with early-stage melanoma.13,30-32 The advent of LM/SL has enabled us to spare approximately 80% of melanoma patients the morbidity associated with ELND. The question still remains however, does CLND after tumor-positive sentinel lymphadenectomy truly confer any therapeutic benefit in patients with clinically negative LNs but histologically positive SNs? If so, who would benefit most from it? Though our data do not show any single absolute predictive factor, the results suggest that patients with thicker primaries (
The authors indicated no potential conflicts of interest.
This work was supported in part by the National Institutes of Health, Bethesda, MD (grant No. CA29605), Saban Family Foundation (Los Angeles, CA), George Hoag Family Foundation (Los Angeles, CA), Harold J. McAlister Charitable Foundation (Los Angeles, CA), and funding from Nancy and Carroll O'Connor (Los Angeles, CA). This work has been presented at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003, and received the Merit Award. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
60 years of age and had nonulcerated primary melanoma of 1 to 2 mm in thickness.
