Progression from atypical/dysplastic intraepidermal proliferations and carcinoma in situ to invasive tumors: a pathway based on current knowledge.

Oncology research efforts in recent years have begun to elucidate the role of the peritumoral stroma in the development of dysplasia and subsequent invasive malignancy. In the skin, the stroma surrounding keratinocytic and melanocytic tumors reacts to the dysplastic epidermis in a similar fashion to the wound healing response. Once epidermal genetic mutations and aberrant molecular signaling have occurred, the stroma responds through a 3-phase process-extracellular matrix degradation is produced by matrix metalloproteinases; angiogenesis is induced by vascular endothelial growth factor and mast cell mediators; and the inflammatory response is elicited by cytokines and cyclin D1 overexpression balanced by the immunosuppression of mast cell mediators such as tumor necrosis factor alpha, histamine, and transforming growth factor beta. By reacting like injured dermis, the actions of various stromal mediators directly allow for, and even encourage, the progression of in situ atypia/dysplasia to invasive malignancy. The intent of this article is to review the multistep biological and chemical stromal processes, which are involved in the progression of atypical/dysplastic intraepidermal proliferations to invasive malignancy.