Angiotropic melanoma and extravascular migratory metastasis: a review

How metastases develop is poorly understood. The concept of intravascular dissemination of cancer cells has been widely accepted as a central paradigm. In addition to this explanation, however, other mechanisms may be operable. Ultrastructural studies have identified in malignant melanoma an angio-tumoral complex, in which tumor cells are linked to endothelium by a matrix containing laminin without evidence of intravasation. This observation has suggested that melanoma cells may migrate along the external surface of vessels and other anatomic structures, a mechanism termed "extravascular migratory metastasis" (EVMM). Angiotropism (melanoma cells cuffing the external surface of vessels) is the histopathologic counterpart of the angio-tumoral complex. The authors have recently drawn attention to the importance of angiotropism as a biologic phenomenom and prognostic factor in melanoma and as a likely correlate of EVMM. In addition, recent experimental studies strongly suggest a correlation of angiotropism of melanoma cells with EVMM. These studies, including cocultures of melanoma cells with capillarylike structures in vitro and the growth of green fluorescent protein-labeled melanoma cells in the shell-less chick chorioallantoic membrane model, have demonstrated the migration of angiotropic melanoma cells along the vascular channels, supporting the concept of EVMM. The new field of EVMM reviewed in this paper may prove useful in elucidating the molecular interactions involved in melanoma metastasis.