Abstract

A subset of melanoma presents with a unique pattern of metastatization, in which multiple metastases involve the skin adjacent to the site of the primary tumor. This process can go on for years before visceral metastases occur. The individual metastases often show neoplastic melanocytes colonizing the superficial aspects of the skin, including the epidermis. We have shown that activation of the WNT signaling pathway by secreted ligands from the epidermis and appendages appear to constrain the expansion of intradermal growth and shape architectural features of melanocytic neoplasms. Neoplastic melanocytes close to the sources of ligands have stronger pathway activation, resulting in a characteristic gradient of expression of factors responding to WNT activation. To determine the role of WNT signaling in epidermotropic metastases, we evaluated ?-catenin expression in 25 cutaneous metastases divided into epidermotropic (n=13) and non-epidermotropic (n=12). 8 out of 13 (62%) epidermotropic metastases showed a strong gradient of beta-catenin expression, with strongest immunoreactivity in neoplastic melanocytes near the epithelium, which decreased with the distance of cells from the epidermis. In contrast, none of the 12 (0%) non-epidermotropic cases exhibited a gradient pattern; the deeper portions of the tumors stained as intensely as the superficial portions. Our findings suggest that a subset of metastatic melanoma still responds to exogenous Wnt signaling, which may contribute to the pattern of epidermotropism. By extension, cutaneous metastases without such pattern may have become independent of extrinsic WNT by activating mutations in the pathway.

Financial Disclosure:
No current or relevant financial relationships exist.