MELANOMA METASTASES THROUGH THE LYMPHATIC SYSTEM

Many patients with cancer, including those with cutaneous malignant melanoma, can be treated to cure if their tumor is surgically excised early in its evolution, at which point the tumor is confined to its site of origin. Management becomes more difficult as tumor cells detach from the primary tumor mass and metastasize to sites in the body that are remote from their point of origin. All forms of metastasis increase the problems of patient management and the likelihood that a patient will die from the effects of their cancer. There is, however, an important hierarchy of risk associated with cancer spread by different routes and to different organs. 31 Because the problems associated with spread through the circulatory system to visceral sites remain so intractable, most research has focused on determining the mechanisms of this type of metastatic extension. Less attention has been paid to spread from the primary tumor through the lymphatics to the regional lymph nodes. Some investigators regard the regional nodes as merely way stations en route to the blood stream and the vital organs, and consider that treatment of the nodes is unlikely to influence the final outcome. Others regard this view as negative and believe that timely and complete removal of tumor metastases, especially in the early phase of nodal metastasis to the regional nodes, can interrupt the sequence of events that eventually leads to visceral metastases and death. Involvement of the regional nodes by metastatic melanoma certainly is a serious event, and approximately 50% of patients in whom this occurs die of melanoma within 5 years. On the other hand, most patients who remain tumor-free 5 years after lymphadenectomy achieve long-term tumor-free survival. 2 This contrasts sharply with the fate of patients who develop visceral metastases, most of whom die from disseminated melanomatosis within months or a few years. The difference in outcome between these two groups indicates that they represent different stages in disease evolution or variants of melanoma pathobiology. There is a clear incentive to do whatever is possible to prevent the evolution of melanoma to or beyond the stage of nodal involvement. The need to reappraise the significance of the lymph nodes' regional role in cancer is suggested by recent data from a variety of sources. Increased understanding of lymph node function and pathobiology has come from studies showing that each lymph node functions as a separate organ. 10 It has also been shown that the lymph node(s) located closest to a primary tumor, on the direct lymphatic pathway from primary to regional nodal group, the sentinel node(s), often are reliably and exclusively the site of earliest metastases. 9,24 The author and others have demonstrated that the regional lymph nodes located nearest to a primary tumor are dysfunctional. 8,16,23 Tumor-proximate lymph nodes show profound alterations in the distribution and phenotype of lymphoid and other cells, especially in the T-dependent paracortical areas. 6,8,12 These modifications of lymph node structure and function are most likely caused by mediators released by the tumor. 10 Recent studies focusing on the sentinel nodes from melanoma and breast cancer patients have shown that the nodes most exposed to tumor influence are significantly more modulated than adjacent, non-sentinel nodes. 7,17 The relationship of tumor-induced suppression of lymph node function and an environment in the sentinel nodes that is conducive to the survival and expansion of metastatic tumor cells probably is critical to tumor progression. This may represent the last stage of tumor evolution that is susceptible to therapeutic intervention to prevent or reverse the progress of tumor cells toward dissemination. Although present intervention is primarily surgical, an understanding of the mechanisms of nodal dysfunction may lead to medical therapies to reverse the process and reduce nodal susceptibility to tumor spread.