Invited Brief Commentary: Sentinel Lymph Node Status is a Main Prognostic Parameter Needful for the Correct Staging of Patients with Melanoma Thicker than 4 mm: Single Institutional Experience and Literature Meta-analysis

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Sentinel Lymph Node Status is a Main Prognostic Parameter Needful for the Correct Staging of Patients with Melanoma Thicker than 4 mm: Single-Institution Experience and Literature Meta-Analysis

This issue of the Journal of Investigative Surgery contains a report from the Tuscan Regional Melanoma Referral Center in Florence, Italy on the efficacy of sentinel lymph node biopsy (SLNB) in thick (>4 mm Breslow thickness; T4) melanoma. The authors report not only their own experience with 147 such cases, but also a meta-analysis of 18 previously published reports on the subject.¹ The issue of SLNB for T4 melanomas is important for a number of reasons.

First, the lingering concept that clinical stage T4NO lesions have such a high risk of distant metastases that nodal staging is not important continues to permeate the thinking of many providers. This concept persists despite the fact that thick melanomas are a heterogeneous group, with some subgroups doing quite well. For example, non-ulcerated thick melanomas that can be pathologically proven to be SLN negative (SLN−; i.e., stage pT4aN0, IIB) have a 70% 5 year overall survival (OS).² Another example of heterogeneity in thick lesions if the very definition of “thick” melanoma; it is well known that some melanomas are clinically exophytic (papillomatous and nevoid melanomas) and therefore present as thicker lesions, yet can have non-aggressive clinical courses usually associated with thinner lesions.³

Unfortunately, the Multicenter Sentinel Lymph Node Trial-1 (MSLT-1) was underpowered to show if the improvement in OS afforded by SLN biopsy (SLNB) to intermediate thickness (T2, T3) lesions extended to T4 lesions,⁴ although it did show an improvement in disease free survival (DFS) of 10% (p = 0.03). Accordingly, much of the supportive evidence for SLNB in thick melanoma has fallen to single institution reports such as ours,⁵ the current study,¹ and the other reports summarized in the author's meta-analysis.

Similar to the other papers, the authors looked at outcomes in T4 melanoma, comparing SLN positive (SLN+) to SLN- patients. Overall they found that 42% of such lesions are SLN+, similar to the 36% reported by our group.⁵ Also similar to our study, SLN− patients had significantly better DFS and OS compared to SLN+ patients. To bolster this finding, the authors performed a meta-analysis of studies confined to T4 lesions staged with SLNB that reported 5 year OS rates. OS was significantly worse for SLN+ patients compared to SLN− patients in 16 of the 18 studies that met their criteria (Table 4), resulting in an overall significant difference in OS by SLN status, as shown in the Forrest plot (Figure 2).

Importantly, thick melanoma patients who were SLN+ in the present study had a 38% chance of harboring additional tumor in the other (“non-sentinel”) nodes removed by subsequent completion lymph node dissection (CLND), much higher than the 11% rate reported in the Multicenter Sentinel Lymph Node Trial-2 (MSLT-2). It is therefore possible that a randomized trial confined only to thick melanoma would show both OS and DFS improvement for CLND in this group; the MSLT-2 showed only improved DFS for CLND, but excluded T4 patients.⁶

Regardless of these potential survival benefits, there is no argument that SLNB in patients with T4 melanomas separates them into two distinct clinical stage groups (IIB or IIC vs. IIIA or IIIB) with different prognoses, risks, and therapeutic options. Specifically, high risk node negative patients should be offered clinical trials looking at adjuvant options (vaccines, kinase inhibitors, and check point inhibitors), such as the upcoming East Coast Oncology Group (ECOG 6161) trial, which will randomize thicker, often ulcerated, but pathologically node negative patients to receive or not receive Pembrolizamab. In contrast, high-risk node positive patients are already candidates for newer therapies, approved by the FDA.

One of the values of the current study is the stress the authors put on the heterogeneity of T4 patients-this is a truly diverse group of melanoma patients, and SLN biopsy is an important tool to help the clinician better risk-stratify a given individual. As mentioned above, patients with T4 melanomas who are SLN− can have a fairly good prognosis. This conclusion was consistent across the present study,¹ our study,⁵ and the meta-analysis.¹ In the current era of personalized medicine, it is incumbent on the provider to deliver to the patient the clearest and most inclusive available picture of the risk presented by their melanoma, to aid the patient and provider in making shared decisions regarding not just treatment, but also follow-up. The National Comprehensive Cancer Network (NCCN) recommends follow-up for melanoma patients based on their individual risk.⁷ Beside SLN status, other available risk determination tools include the on-line American Joint Committee on Cancer (AJCC) Melanoma Risk-Prediction Tool (which uses a combination of histologic and demographic factors),⁸ cross-sectional imaging,⁹ and genetic expression profile testing.^10,11 Taken together, all of these items give the patient and provider a much clearer picture of the potential outcome of a given melanoma, far beyond the mere fact that the tumor is greater than 4 mm in Breslow depth.

Declaration of Interest

The author reports no conflict of interest. The author alone is responsible for the content and writing of this article.