Lymph node metastases: the importance of the microenvironment

Although, to the authors' knowledge, no prospective randomized clinical trial has demonstrated improvement in survival following the radical dissection of lymph nodes in the treatment of cancer patients, lymphadenectomy is still routinely performed for curative purposes. For many years, regional lymph nodes (RLNs) in tumor-bearing hosts have been considered anatomic barriers to the systematic dissemination of tumor cells. More recently, the belief has been held that lymph nodes play a completely passive role, by virtue of the observations that many lymphatic and lymphaticovenous shunts bypass RLNs and allow both lymphatic and hematogenous dissemination of malignant cells at an early stage in the vast majority of cancers. Furthermore, surgical removal of RLNs apparently has no effect, deleterious or beneficial, on the well-being of the host.

A comprehensive and critical review of the scientific literature was conducted to evaluate, from a biologic point of view, the role played by RLNs during the interactions between the tumor and the host's immune system.

Recent advances in our understanding of the molecular events of antigen recognition by T cells and T-cell activation have provided strong experimental evidence to demonstrate that these secondary lymphoid organs constitute the primary sites where the specific recognition of tumor antigens and the proper activation of the immune system take place. Indeed, the notion that naive T cells are induced or silenced by tumor cells in the periphery may today be questioned, because effective induction can only occur in these secondary lymphoid organs where cell-to-cell interactions are properly guided and cells can meet in an appropriate cytokine-enriched microenvironment.

Promising results obtained in the human setting with the use of dendritic cells as novel immunotherapeutic tools have recently renewed interest in active immunotherapy for the treatment of solid tumors. However, for accomplishing this goal, the maintenance of the integrity of the immune system remains a crucial issue. Studies showing that radical tumor-draining RLN dissections exert a markedly negative influence on the efficacy of postoperative immunotherapy protocols in mice as well as in humans seem to support adoption of a more conservative approach regarding uninvolved RLNs in the treatment of cancer patients.