Clinical Significance of Tumor Microenvironment in Acral Melanoma: A Large Single-Institution Study of Caucasians

Abstract

Background: The presence of tumor-infiltrating lymphocytes (TILs) in many studies is associated with a better prognosis in melanoma patients. Programmed death-ligand 1 (PD-L1) expression has a significant value in predicting several cancers, but its role in melanoma remains ambiguous. The study aims to report a comprehensive analysis of TILs characteristics and their impact on survival in primary acral melanoma (AM). Methods: Clinical and pathological features and survival outcomes were investigated in 70 patients with AM. Immunohistochemical quantitative analysis of TILs, including expression of CD4, CD8, FOXP3, PD-1, and PD-L1, on melanoma cells was performed. Results: Kaplan-Meier analysis showed significant differences in overall survival (OS) for CD4+ (p = 0.021), CD8+ (p = 0.037), FOXP3+ (p = 0.007), and TILs density (p = 0.043). In univariate analysis of immunohistochemical features, FOXP3, CD4, CD8, PD-1, and Melanoma Institute of Australia (MIA) grading TILs (grade, density, and distribution) were correlated with survival. The higher density of FOXP3-positive cells was an independent factor associated with better survival. Conclusions: High TILs content (classed as brisk Clark scale and marked/diffuse TILs MIA grade) regardless of its immunophenotype was associated with better survival outcomes in AM. PD-L1 expression on tumor cells did not influence OS and was independent of clinical and pathological characteristics. We demonstrated that TILs are significant biomarkers in sentinel lymph node status prediction.

Impact of clinical and histopathological characteristics on the disease‐free survival of stage I‐II acral melanoma patients

“…Among AM tumors, higher TIL levels were related to better OS. 27,38,39 Curiously, lower TIL levels were shown to be associated with longer progression-free survival, 27 indicating a better DFS, which is consistent with our results.…”

“…In studies comparing acral and non‐acral cutaneous melanoma, lower presence of TILs was shown in the former, 27,42 suggesting that low TIL levels could explain the poor prognosis of AM. Among AM tumors, higher TIL levels were related to better OS 27,38,39 . Curiously, lower TIL levels were shown to be associated with longer progression‐free survival, 27 indicating a better DFS, which is consistent with our results.…”

“…The role of TIL 27,38,39 and perineural invasion 40,41 in AM has been explored in only a few studies. In our study, while the presence of TIL did not differ in univariate and multivariate analyses, we found that it significantly decreased the 5-year DFS compared with patients with tumors without lymphocyte infiltration.…”

Clinical features, molecular pathology, and immune microenvironmental characteristics of acral melanoma

“…For example, it has been suggested that TILs, particularly cytotoxic CD8 + T cells, are a prognostic factor for the OS in melanoma patients and are also associated with the response to immune checkpoint inhibitors (ICIs) [71]. For example, a study with AM patients demonstrated that high TILs can be associated with a good survival prognosis [75], similar to Castaneda et al [76,77]. Moreover, AM has a lower response rate to ICIs compared to CM [78,79].…”