ABSTRACT
Although tumor-infiltrating lymphocytes (TILs) of primary cutaneous melanoma (PCM) include cytolytic T cells able to exert anti-PCM immunity, progression of PCM most frequently occurs, raising the hypothesis that the PCM microenvironment may also exert suppressive forces, for example, possibly developed by regulatory T (T(REG)) lymphocytes. The aim of this study was to investigate whether TILs of PCMs include lymphocytes bearing the transcription factor forkhead box protein P3 (FOXP3), which is the T(REG) lineage specification molecule in mice, and is debated to have a similar role in humans. Fourteen patients with PCM were selected, of which four had radial growth phase (RGP) stage I melanoma, five had vertical growth phase (VGP) stage I melanoma, and five had VGP stage III-IV melanoma. Formalin-fixed, paraffin-embedded sections were utilized for immunohistochemical single and double stainings. TILs of PCMs included FOXP3-bearing lymphocytes, which predominantly were CD20- and CD8-negative, but CD3-, CD4-, and CD25-positive, thus consistent with the standard immunophenotypical characteristics of "natural" T(REG) cells. Further, the proportions of FOXP3-bearing lymphocytes were higher in vertical than in RGP (P=0.001), as well as in late than in early melanoma stages (P<0.001). Should these FOXP3-bearing lymphocytes actually exert regulatory capabilities within the PCM microenvironment, they may suppress "in vivo" the local anti-PCM immune response, thus favoring melanoma progression.
Subject(s)
Forkhead Transcription Factors/metabolism , Melanoma/pathology , Neoplasm Staging/methods , Skin Neoplasms/pathology , T-Lymphocyte Subsets/pathology , Biomarkers/metabolism , Cell Lineage/immunology , Disease Progression , Humans , Immunophenotyping , Melanoma/immunology , Melanoma/metabolism , Skin Neoplasms/immunology , Skin Neoplasms/metabolism , T-Lymphocyte Subsets/immunology , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/pathologyABSTRACT
BACKGROUND: Some dermatopathological parameters are recognized as dominant indicators of high metastatic potential in melanoma, especially Breslow thickness, ulceration, Clark's level of invasion and mitotic rate. Because NM23 protein is the product of a melanoma metastasis suppressor gene, the aim of this study was to compare such dermatopathological indicators of melanoma prognosis with NM23 protein expression in primary cutaneous melanoma. METHODS: The immunohistochemical NM23 expression was semiquantitatively assessed in 30 primary cutaneous melanomas. Ten dermatopathological parameters were evaluated and compared with NM23 expression. RESULTS: A significant inverse correlation was found for NM23 expression in comparison with Breslow thickness (p < 0.01), ulceration (p < 0.05), Clark's level (p < 0.01), mitotic rate (p < 0.05), and vertical growth phase (p < 0.05). By contrast, no significant correlation was found for NM23 expression in comparison with cell morphology, presence of adjacent nevus, pigmentation, tumor-infiltrating lymphocytes, and regression was impossible to evaluate. CONCLUSIONS: The expression of NM23 protein in primary cutaneous melanoma is significantly inversely correlated with dermatopathological parameters currently recognized as powerful indicators of melanoma prognosis. NM23 may be therefore considered in the dermatopathological evaluation of primary cutaneous melanoma.
