In our study of 3445 patients, 16.3% had one or more positive SLNs. Reported rates of sentinel node positivity have ranged from 12.66
The rate noted in this report is consistent with several other large series including those from the Italian Multicenter Study (16.9%),24
the Sydney Melanoma Unit (16.8%),20
and the M. D. Anderson Cancer Center (16.9%).13
In this large multicenter SLNWG dataset increasing Breslow thickness, younger age, trunk tumor location, the presence of LVI or ulceration, and the absence of regression were found to be independent predictors of a positive SLN in multivariate analysis. The findings of Breslow thickness, ulceration, age, and LVI are consistent with previous published reports.1,6–8,11–20,22,23,27
The prognostic significance of regression, particularly in patients with thin melanomas, has been debated for decades. Some studies have found the presence of regression to be a poor prognostic indicator,30,35–37
while other studies have found regression to have no effect on the risk of recurrence or survival.38–40
On the supposition that the primary tumor was at one time more deeply invasive, the presence of regression in a thin melanoma has been used as justification for SLN biopsy.41
Although Cook et al. and others have suggested that regression may be required for thin melanomas to metastasize,30
other host immune responses, including vitiligo, have been previously shown either to be beneficial on their own or to correlate with a response to systemic therapy.42–45
Thus, regression or vitiligo may indicate an autoimmune response to the primary tumor and therefore may be a beneficial prognostic indicator. In accordance with this theory, the presence of regression has been previously found to be statistically significantly associated with a decreased risk of SLN metastases in univariate analysis in several studies.7,11,28,29
One recent large study by Testori et al. confirmed the protective effect of regression on the risk of SLN metastases in a multivariate analysis.24
In the Testori study, the presence of regression was a significant predictor of negative lymph nodes when stratified by Breslow thickness, which contrasts a report from Morris et al. that found regression lost its prediction significance when stratified by Breslow thickness.29
Our current report demonstrating an odds ratio of 2.4 (95% confidence interval 1.3–4.4) further supports the findings of Testori et al.24
on the significance of regression. Together, these large studies lend further credence to the theory that a significant immunologic response in melanoma is suggestive of an improved outcome. Regression in the thin melanoma population was not specifically examined in this report; further study is warranted to elucidate the role of this potential criterion in determining indications for SLN biopsy in patients with thin melanomas.
In our data set, absence of regression and presence of LVI are statistically significant independent predictors of SLN status. In contrast to our results, multiple reports from the Sunbelt Melanoma Trial have found regression carries no significance for predicting SLN metastases.1,8,22
With regard to LVI, an early report from the Sunbelt Melanoma Trial found this factor to be statistically significant in univariate analysis but nonsignificant in multivariate analysis.8
However, in a subsequent report, LVI was found to be significant in multivariate analysis.22
graphically demonstrates the importance of LVI across Breslow depth and in both ulcerated and nonulcerated tumors. LVI was not investigated as a predictive factor in the recent multi-institutional report from Testori et al.24
Two additional variables that have shown promise in predicting SLN status are the TMR6,7,11,14,16,17
and absence of TIL.6,15
Although neither of these factors reached statistical significance in this report, high TMR and the absence of TIL both trended toward predicting a positive SLN. It is possible that the lack of clear significance was related to the relative paucity of data for these factors in this data set; 65% of patients had no data for TMR, and 76% had no data reported for TIL. The reporting of TIL is not required by the College of American Pathologists guidelines,46
and the routine use of mitotic rate began in January 2010 with the adoption of the 7th edition of the American Joint Committee on Cancer Cancer Staging Manual
We have updated the current SLNWG database to include these parameters, which will be analyzed in future reports. Given the potential prognostic significance as evidenced by the trends in our report and the significance reported by others,6,7,11,14–17
we encourage pathologists to include TIL status on primary melanoma pathology reports.
Limitations of these data include those inherent to a partially retrospective, multi-institutional, multinational report. As is the nature of these types of reports, indications for performing SLN biopsy were not strictly standardized (particularly for the patients with thin lesions), nor was there a single standard procedural approach for SLN biopsy including the methods used by nuclear medicine physicians, surgeons and pathologists. In general, the investigators in this multicenter study used a combination of radioactive colloid and blue dye with preoperative lymphoscintigraphy. One pioneer group in the 1980s initially used blue dye only from November 6, 1985, to October 7, 1992, in 45 patients; thereafter, they used a combination of blue dye and radioactive colloid. For the remaining groups, the usual method was the use of radioactive colloid and blue dye. On some occasions, radioactive colloid was used alone and blue dye omitted. It has been shown that radioactive colloid is far superior in the identification of SLNs to the blue dye.47
Because most of the patients in this multicenter database had radiocolloid used as a tracer for preoperative lymphoscintigraphy and intraoperative gamma probe detection, we believe the results reported are reliable. Furthermore, to date, the absolute standard of the technique for SLN identification has not been established and agreed on by the experts in the field. Similarly, the pathology reports were not standardized. All the pathology assessment was performed by institutional pathologists; however, the conventional method to process the SLN and identify micrometastasis was similar in that multiple level sections were made and stained with hematoxylin and eosin. If negative, immunochemistry was performed. Given the varied interests of the investigators and/or their institutions, for some aspects of this report, only small cohorts were studied. Standard definitions of some variables (e.g., TMR, TIL) did not exist. No strict criteria were used in patients with T1a lesions who underwent SLN biopsy (), limiting extrapolation of this information. Despite these limitations, we believe the data we present here are representative of the broad spectrum of current practice. In the future, a central pathologist may be recruited to review the slides for these specific factors to achieve uniformity among different centers.
This large data set from the SLNWG represents 17 institutions from around the world. Our findings suggest reemphasizing the importance of pathologic factors such as LVI and regression, in addition to the well-established factors of ulceration and Breslow thickness, when selecting candidates for SLN biopsy and estimating the risk of involved lymph nodes.