Lack of functioning lymphatics and accumulation of tissue fluid/lymph in interstitial "lakes" in colon cancer tissue

Abstract

There is controversy as to whether intratumoral or peritumoral lymphatics play a dominant role in the metastatic process. The knowledge of how and where exactly tumor cells enter lymphatics is important for therapeutic targeting either the tumor core or peritumoral tissue with drugs or radiation. The basic questions remain: what is the morphological structure of intra- and peritumoral interstitium and lymphatics; what is their hydraulic conductivity?; and do these local physical conditions allow detached tumor cells to migrate to lymphatics? Identification of lymphatics has been based on immunohistochemical staining of lymphatic endothelial cells. This method does not, however, show the tissue fluid filled interstitial space and the shape of minute lymphatic vessels in tumors. We visualized the interstitial space and lymphatics in the central and peripheral regions of tumors using our original method of color stereoscopic lymphography in translucent tissue fragments and simultaneously with immunohistochemical staining of lymphatic and blood endothelial cells. The density of open and compressed lymphatic and blood vessels was measured in the intratumoral "hot spots" and at tumor edge. Moreover, the intratumoral tissue hydraulic conductivity was measured to define force necessary for propelling tissue fluid to peritumoral lymphatics. We found very few rudimentary minor blind lymphatics in the tumor core and numerous minor fluid "lakes" in the interstitium with no visible connection to the peritumoral lymphatics. Lining of "lakes" did not express molecular markers specific for lymphatic endothelial cells. Ninety-five percent of structures of what looked like lymphatics had compressed lumen and the hydraulic conductivity was 3 powers of magnitude lower than in the adjacent non-tumoral tissue. It can be concluded that lack of functioning lymphatics in tumor foci manifested by accumulation of tissue fluid in "lakes," low fluid conductivity and compression of lymphatics by tumor cells, and proliferating connective tissue may hamper escape of tumor cells. The most favorable site of entry of tumor cells to lymphatics seems to be the interface of the tumor and surrounding tissue with open lymphatics.