(i) Basal cells in the interfollicular epidermis and hair follicles sustain mutations (light blue cells) due to exposure to UV radiation, chemical carcinogens, viruses, and other pathogens; however, without epigenetic intervention, most of these mutations will lay dormant. (ii) Repeated skin irritation or wounding can heighten inflammatory chemokine levels over that which can be sustained through interception by the D6 receptor (expressed by lymphatic endothelial cells [LECs] in the dermis), resulting in the exacerbated levels of mast cells and T lymphocytes critical for stimulating benign papilloma formation. (iii) In the chronic situation, high levels of immune cells are maintained in the skin and enhance malignant conversion and metastasis of neoplastic epidermal cells (dark blue).