The prognostic significance of isolated immunohistochemically positive cells in sentinel lymph nodes of melanoma patients.

To the Editor: We read with interest the recent article by Dr Satzger and colleagues describing the results of their study of sentinel lymph nodes (SLNs) from 477 patients with primary cutaneous melanomas Z1mm in thickness. The authors compared relapse-free survival and overall survival in 3 groups of patients: (1) those with negative SLNs (n=308), (2) those with micrometastases (MM) in SLNs (n=122), and (3) those with isolated immunohistochemically (HMB-45 or Melan-A) positive cells (IPC) in SLNs (n=47). They found that tumor relapse rates and melanoma-related death rates for the negative, IPC, and MM groups were 11.7%/5.5%, 12.8%/ 6.4%, and 37.7%/23.8%, respectively. The relapse-free survival and overall survival in the MM group were significantly poorer (‘‘P=0.000’’) than the negative and IPC groups, in which the rates were similar. On the basis of their results, the authors conclude that IPC in SLNs of melanoma patients are without prognostic significance. Interesting as the results are, we believe that it is important not to conclude from the results of this study with only short-term follow-up that the presence of IPC in SLNs of melanoma patients lacks clinical significance. Not only are the results of the study likely to be confounded by lead time bias, but the authors overlook the very real possibility of a potential therapeutic benefit as a result of the SLN biopsy itself and the completion lymph node dissection (CLND) in those patients with SLN metastasis. For these reasons, we urge caution in interpreting the results of this study and suggest that further data are necessary before it can reasonably be concluded that any SLN melanoma metastasis, no matter how small, is without prognostic significance. The authors concede that the follow-up period is short (mean 38.1mo, median 35.8mo, range: 0.7 to 77.2mo). It is well documented that metastasis may occur many years after diagnosis of melanoma. The short follow-up period in this study raises lead time bias as a potential confounding factor; namely that the smaller the metastatic deposit, the longer it will take for melanoma recurrence to be detected and for death to occur. We reviewed a series of patients with false-negative SLNs (ie, patients with SLNs originally reported as pathologically negative but who subsequently developed disease recurrence in the same regional node field). Subsequent more extensive pathologic analysis (deeper sections and additional immunohistochemistry) revealed very small, ‘‘submicrometastatic’’ deposits (analogous to the IPC described by Satzger et al) in the subcapsular sinus region of the SLN in some patients. Others have reported similar results. These findings are pertinent, as recently reported follow-up evidence from the first Multicenter Selective Lymphadenectomy Trial indicates that patients with a false-negative SLN biopsy had poorer survival than those with true-negative SLNs. Also, a recent study by Scheri et al reported that patients with isolated tumor cells in SLNs (measuring r0.2mm) had a significantly higher (P=0.02) melanoma-specific mortality than those with negative SLNs. The metastatic deposits were classified according to the greatest dimension of the largest cluster of cells, and therefore differ from the definition of IPC used by Satzger et al. Nevertheless, the findings of Scheri et al suggest that very small deposits of metastatic melanoma in SLNs do have prognostic significance. In addition, the patients in Satzger et al’s study may have received a therapeutic benefit as a result of the SLN biopsy itself and/or the subsequent CLND. It is conceivable, indeed highly likely, that in patients with an extremely low metastatic tumor burden (such as IPC), removal of the SLN and/or the regional nodes in the CLND (and therefore potentially all of the metastatic disease) may have a beneficial impact on disease recurrence and survival. Several studies have demonstrated the association of certain micromorphometric parameters of SLN metastases (such as centripetal thickness ie, tumor penetrative depth of the deposits, the microanatomic location of SLN tumor deposits, and the size of metastases in the SLN) with non-SLN positivity and survival. However, classifying, measuring, and assessing these parameters can be difficult. In Satzger et al’s study, univariate analysis did not reveal a statistically significant correlation between micromorphometric parameters of the SLN deposits (such as type of positive immunohistochemical antibody staining, presence of capsular involvement, number of cells, tumor penetrative depth, or presence of cytologic atypia) and prognosis in patients with IPC. However, given the very small numbers of IPC cases analyzed (6 with relapse and 41 with no relapse) and the relatively short follow-up period, the study is likely to lack the statistical power to detect subtle but clinically significant effects. It is also worth noting that the sectioning/staining protocols for pathologic analysis of SLNs may have an effect on the detection and characterization of melanoma metastases in SLNs. In our experience of reviewing many SLNs, it is not uncommon for a few dissociated cells to be present at the periphery of a larger deposit. Therefore, deeper sections cut from a SLN may reveal that a very small deposit (IPC) is in fact much larger. Whether the cases in the IPC group in Satzger et al’s study underwent additional histopathologic evaluation is not reported. Further studies are needed to determine whether or not there is a LETTERS TO THE EDITOR