When a new primary tumor first arises, it is usually not vascularized. In this prevascular state, tumor volume is less than a few cubic millimeters. External in situ carcinomas of the skin, cervix, and oral mucous membranes, which can be observed directly, are usually thin and flat because their expansion is limited by the diffusion of nutrients and oxygen from normal vessels that lie beneath the epithelial layer. Thus, a new melanoma is separated from capillary vessels in the dermis, which are already occupied by normal cells. The prevascular stage of an internal tumor, such as carcinoma in situ of the breast, can usually be seen only with microscopic examination (Fig. 32-1). These tumor cells are also usually separated from host microvessels by a basement membrane. From experimental studies, we know that these prevascular lesions exist in a steady state of tumor cell proliferation balanced by cell death.1 Externally located prevascular tumors may remain in this state for months to years, but we do not know about internal lesions. The onset of neovascularization, however, can be relatively sudden and is called the angiogenic switch.2,3

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