Nonsentinel Node Metastases in Melanoma: Do They Reflect the Biology of the Tumor, the Lymph Node or the Surgeon?

Two decades ago, elective lymph node dissection was essentially abandoned as a surgical strategy for melanoma patients for clinically negative (cN0) regional lymph nodes, based on three key facts: (1) less than 20% of patients with cN0 intermediate-thickness melanomas have histopathologic evidence of nodal involvement (pN1), (2) an effective salvage strategy—therapeutic lymph node dissection at the time of nodal relapse—was felt to exist for pN1 patients upon nodal relapse, and (3) there was no compelling evidence that elective node dissection conveyed outcome advantages for pN1 patients (in particular, improved survival, better regional disease control or decreased surgical morbidity) of sufficient magnitude to offset the inescapable drawback that 80% or more of the patients subjected to the procedure were incurring morbidity without any expectation of oncologic benefit. Elective node dissection has now been replaced by sentinel node biopsy, and we find ourselves today in an eerily parallel situation regarding completion node dissection for our sentinel node-positive patients. Specifically, (1) less than 20% of patients with a positive sentinel node have histopathologic evidence of involvement of nonsentinel nodes (usually arbitrarily defined as those regional nodes not removed at sentinel node biopsy for whatever reason), (2) an effective salvage strategy—therapeutic lymph node dissection at the time of nodal relapse—may exist for sentinel node-positive patients upon nodal relapse, and (3) there is as yet no compelling evidence that completion node dissection conveys outcome advantages for sentinel node-positive patients (in particular, improved survival) of sufficient magnitude to offset the drawback that all sentinel node positive patients are incurring morbidity including some as yet undefined percentage who would never relapse in the remaining regional nodes.1–3 However, it is well to introduce the caution that these two situations—elective node dissection in the absence of any clinical evidence of nodal involvement, and completion node dissection in the presence of histopathologic proof of sentinel node involvement—are not entirely analogous. The sentinel node biopsy experience has taught us that some regional lymph node metastases undetected on routine histologic evaluation of a bisected lymph node submitted as part of a node dissection are readily apparent—and unequivocally clinically significant—when the node is serially sectioned and evaluated with immunohistochemical stains for melanocyte antigens. Since “nonsentinel nodes” are almost never examined using serial sectioning and immunohistochemistry, we must assume that the frequency of involvement of nonsentinel nodes is greater than currently recognized—and the yield (if not necessarily the benefit) of completion node dissection is almost surely underestimated. Nonetheless, understanding the clinicopathologic factors that predict nonsentinel node involvement would surely inform the decision of whether or not to pursue completion dissection in all cases of positive sentinel nodes. So what have we learned about the biology of melanoma metastasis as it relates to the nonsentinel node?