Reactive, usually enlarged, regional lymph nodes draining tumor areas.

Regional lymph nodes tributary to tumor-bearing organs are considered anatomic barriers to tumor spread. They are also the site where specific immune interactions between tumor antigens and responding lymphoid cells take place. According to these concepts, the primary antitumor function of lymph nodes is not merely filtration but also immunologic tumor surveillance (1,2). Tumor spread to regional lymph nodes and beyond occurs via lymphatic vessels whose proliferation is promoted by recently discovered growth factors (3,4,5). Tumor lymphangiogenesis, which contributes actively to tumor dissemination, is stimulated by a family of vascular endothelial growth factors (VEGF-C, VEGF-D), which thus are essential for lymph node metastases (3,4,5). Primary melanomas that later metastasize are characterized by increased lymphangiogenesis, which could serve as a predictor of tumor dissemination (4,6). The recently refined techniques of sentinel detection of micrometastases have shown that changes in the lymph node microenvironment involving lymphatics, dendritic cells, and particularly the responding T cells may begin even before the metastatic cancer cells have arrived in the lymph node (7,8) (Fig. 44.1).

Consequently, the regional lymph nodes are commonly enlarged as a result of reactive lymphadenopathy, tumor metastasis, or both. In response to tumor-associated antigens, the various cell populations of regional lymph nodes react in different ways, giving rise to a multitude of morphologic patterns (9). Numerous studies have been devoted to the analysis of such reactions, in an effort to understand the mechanisms of lymph node metastases. Some studies have correlated various histologic patterns of reactive lymph nodes with the dissemination of tumors (10,11,12,13,14,15,16,17,18,19), whereas others have investigated the capacity of their lymphocytes to transform in vitro when in contact with tumor antigens (20,21). Tumor-associated antigens, shed by tumor cells or released by cell death, in addition to viable tumor cells, are carried by lymph to the draining lymph nodes, providing constant nonspecific and specific stimulation. Tumor-reactive lymphocytes from sentinel lymph nodes were shown to display specific in vitro immune reaction toward primary bladder cancer (22). Thus, various defense reactions may be triggered, including phagocytosis, production of antibodies, and sensitization of lymphocytes. Such reactions were investigated in various studies by determining the amounts and types of immunoglobulins in pericancerous human lymph nodes (23) and by immunohistochemically detecting epitopes of tumor-associated glycoproteins in the draining lymph nodes. Thus, uninvolved regional lymph nodes in resected colon carcinomas were investigated immunohistochemically to detect tumor-associated antigens (24). A variety of defense mechanisms are variably activated to withstand the progress of tumors. Cytotoxic T lymphocytes and natural killer cells are mediators of immune responses against tumor cells and, as tumor infiltrating lymphocytes (TIL), are constant companions of the tumors. In the interaction between tumor cells and TILs resulting in reciprocal apoptosis, an important effective system is represented by Fas and its ligand Fas-L, expressed by both the tumor cells whether primary or metastatic and the TIL (25) (Fig. 44.2). Sinus macrophages, lymphatic endothelial cells, and especially follicular dendritic cells in the unaffected lymph nodes showed immune reactions with monoclonal antibodies against epitopes of some tumor- or colon-associated glycoproteins that were similar to their reaction to the carcinoma cells of the colonic tumor. In a study of primary and metastatic melanoma, identical T-cell responsive sequences, representing clonal expanded T-cells, were detected both in the tumor and in the draining lymph nodes, sometimes even in the absence of tumor cells (26).

In tumor-draining lymph nodes, paracortical hyperplasia and sinus histiocytosis are commonly observed. As the tumor mass increased in the lymph nodes, the density of S100+ dendritic cells and of cytotoxic T lymphocytes decreased, indicating that the immune response of the tumor-bearing host was progressively inhibited (27). A relationship between immune deficiency and tumor occurrence and aggressiveness is generally well-documented (28). The morphologic changes of lymph nodes draining tumor-bearing organs provide evidence for antitumor immune reactivity; however, after the initial studies of lymph nodes performed in the 1970s, to date, few recent reported studies have taken advantage of the new techniques.

Understanding the process of lymph node metastasis is of major theoretic importance and also of practical value. Recognition of the histologic patterns of lymph node reactivity to the presence of tumors is a common objective in the study of biopsy and surgical specimens. Not infrequently, markedly enlarged and firm lymph nodes removed as part of radical tumor excision reveal no tumor metastasis on microscopic examination. In a study of 163 patients with renal cell carcinoma, 43 patients had enlarged lymph nodes with a diameter of 1 to 2.2 cm on computed tomography (29). Of these, 18 patients (42%) had metastases of renal cell carcinoma, but 25 patients (58%) had only follicular hyperplasia or inflammatory changes, often associated with involvement of the renal vein or necrosis. The study concluded that radiologic and even gross examination findings of enlarged lymph nodes should not be interpreted as metastatic unless they are so proven by cytologic (fine needle aspiration) or histologic (biopsy) examination. The presence of lymph node metastasis constitutes an essential factor in the tumor–node–metastasis (TNM) prognostic system. Moreover, a number of studies have investigated possible correlations between patterns of lymph node reactivity and prognosis, so far without firm, conclusive results (10,12,16,30).