Cytokine expression within the different categories of tumor-infiltrating lymphocytes in primary cutaneous melanoma: an immunohistochemical study

Background: Melanoma is a highly aggressive skin malignancy with an incidence exceeding 3 per 100 000. Tumor-infiltrating lymphocytes (TILs) are often linked to better prognosis and tumor regression, reflecting an active host immune response. However, melanoma can evade immune attack, so inflammatory cells are not always effective or tumor-directed. This study evaluated tumor necrosis factor (TNF) and interferon-gamma (IFNgamma) expression in primary cutaneous melanoma across different TIL categories to determine whether these infiltrates act as active responders or passive bystanders. Methods: We performed a cross-sectional study using archival primary cutaneous melanoma tissue from the University of Pretoria (2014-2020). Skin punch biopsies, local excisions, and wide excisions were included. Immunohistochemistry for TNF and IFNgamma was performed on formalin-fixed, paraffin-embedded sections. Three pathologists independently graded TILs as negative, non-brisk, or brisk and assessed cytokine expression. Results: Sixty-six patients met inclusion criteria. TIL grades were: negative (39.4%), non-brisk (33.3%), and brisk (27.3%). Overall, 31.8% of melanomas were TNF-positive. TNF expression occurred in 16.7% of brisk TIL cases, 41% of non-brisk cases, and 15% of TIL-negative tumors. IFNgamma expression showed a clearer gradient: brisk TILs were IFNgamma-positive in 89% of cases, non-brisk in 64%, and TIL-negative in 15%. Extensively pigmented melanomas tended to show low cytokine expression, although numbers were small and firm conclusions could not be drawn. Conclusion TNF and IFNgamma expression broadly correlated with TIL grade in primary cutaneous melanoma. Brisk TILs were strongly associated with high IFNgamma expression, non-brisk TILs showed more modest cytokine levels, and TIL-negative tumors were largely cytokine-poor. These findings suggest functional heterogeneity among inflammatory infiltrates. Larger, ideally multicenter studies including more heavily pigmented melanomas and clinical outcome data are needed to clarify the prognostic and potential therapeutic implications of these cytokine patterns.