The S100 family of proteins is a member of the calcium-binding EF-hand superfamily. Although the exact function of S100 proteins is not clear, they are involved in the regulation of a diverse host of cellular functions, including contraction, motility, growth, differentiation, cell cycle progression, transcription, and secretion [10
]. Certain S100 proteins are highly expressed in non–small cell lung cancer, breast cancer, gastric cancer, and lymphoma, whereas reduced levels of other members are found in breast and prostate cancer [10
]. The association of S100 proteins with neoplastic processes suggests the possibility that different isotypes may act as tumor suppressors, whereas others may act as oncogenes. S100 protein expression may also have prognostic significance in a variety of tumors [12
]. Aside from the diagnostic importance of S100 protein expression, its relationship with melanoma pathogenesis is unclear [15
S100 protein is expressed in most metastatic melanoma. In our study, S100 immunoreactivity is present in 99% of melanomas, consistent with prior reports [6
]. Detection of this antigen is best achieved using monoclonal antibodies because commercially available polyclonal antibodies are not specific [16
Our study, which follows the evolution of S100 antigenicity in a subset of melanomas, demonstrated that 82% of the cases had prior metastases that were immunoreactive for S100. This change in antigenicity may reflect dedifferentiation of tumor cells or, alternatively, clonal selection of a subpopulation with a growth advantage. Differences in specimen processing may account for loss of antigenicity; however, this is unlikely because other antigens (eg, GP100) were not affected and positive controls were included in each assay. Antigenic loss has been studied in a variety of tumor types and model systems, and is thought to be associated with escape from immune surveillance in some tumors and with dedifferentiated phenotype in others [17
]. This phenomenon has been studied in metastatic melanoma in association with escape from immunotherapy [21
S100-negative melanomas arising from ocular melanoma were disproportionately high relative to the overall proportion of ocular melanoma. These findings are consistent with a previous study that demonstrated a uniform lack of S100 immunoreactivity in a subset of spindle cell ocular melanomas [23
]. This phenotype may reflect inherent differences in uveal versus cutaneous melanocytes.
When confronted with a metastatic poorly differentiated tumor, the initial immunostains should include S100 and, where necessary, the standard panel to rule out carcinoma, sarcoma, and lymphoma. Based on this current study, immunoreactivity for GP100/MART-1 or a prior documentation of melanoma (S100 positivity or primary lesion) should confirm the diagnosis of melanoma if S100 is negative. Prior (and current) tumor specimens should be extensively sampled for S100 because most first or early metastases (82%) were immunoreactive for this antigen.