Cutaneous Metastasis after Surgery, Injury, Lymphadenopathy, and Peritonitis: Possible Mechanisms

Cutaneous metastases from internal malignancies are uncommon. Umbilical metastasis, also known as Sister Joseph nodule (SJN), develops in patients with carcinomatous peritonitis or superficial lymphadenopathy, while non-SJN skin metastases develop after surgery, injury, and lymphadenopathy. In this review, the possible mechanisms of skin metastases are discussed. SJNs develop by the contiguous or lymphatic spread of tumor cells. After surgery and injury, tumor cells spread by direct implantation or hematogenous metastasis, and after lymphadenopathy, they spread by extranodal extension. The inflammatory response occurring during wound healing is exploited by tumor cells and facilitates tumor growth. Macrophages are crucial drivers of tumor-promoting inflammation, which is a source of survival, growth and angiogenic factors. Angiogenesis is promoted by the vascular endothelial growth factor (VEGF), which also mediates tumor-associated immunodeficiency. In the subcutaneous tissues that surround metastatic lymph nodes, adipocytes promote tumor growth. In the elderly, age-associated immunosuppression may facilitate hematogenous metastasis. Anti-VEGF therapy affects recurrence patterns but at the same time, may increase the risk of skin metastases. Immune suppression associated with inflammation may play a key role in skin metastasis development. Thus, immune therapies, including immune checkpoint inhibitors reactivating cytotoxic T-cell function and inhibiting tumor-associated macrophage function, appear promising.