Lymph node metastasis is an important prognostic factor in patients with colorectal cancer, and many studies have indicated that the location and number of metastatic nodes affect prognosis [5, 10–12]. Many studies have described the risk factors of lymph node metastases [1, 2, 13], but information regarding the mechanism or process of the metastatic spread of tumor cells to distant regional lymph nodes in patients with colorectal carcinoma is sparse at present. The key observations made in this study can be summarized as follows: In our cases with resected colorectal cancer with metastatic lymph nodes, the presence of ECI at positive lymph nodes at the N1 site was significantly associated with lymph node metastasis at the N2 site. This finding suggests that ECI may be a key process following distant lymph node metastasis.
Previous studies have demonstrated and confirmed that the presence of ECI at metastatic lymph nodes is significantly related to prognosis in not only colorectal carcinoma but also in various other types of carcinoma [4–7, 14–17]. The ability of metastatic nodes to recruit degradation factors that permit cancer cells to break through the lymph node capsule is indicative of a very aggressive cancer. These studies imply that ECI is a biologic marker of aggressive nodal disease. We previously demonstrated that ECI at metastatic sentinel nodes in breast cancer was strongly associated with non-sentinel nodes metastasis . These findings essentially support our findings; the presence of ECI of positive lymph nodes is significantly related to the nodal spread of the tumor cells in colorectal cancer patients. Tumor cells invade the lymphatic vessels, which enables the tumor cells to penetrate into the lymphatic system. Furthermore, in the group negative for metastasis at the N2 site there were 9 patients with ECI (Table 1), and the presence of ECI may be a clear sign of more aggressive disease, as those 9 patients had a greater total number of positive lymph nodes than did the patients without ECI (P < 0.05).
It is clear that the successful clinical application of sentinel lymph node biopsy used in cases of breast cancer and melanoma cannot simply be transferred into colorectal cancer treatment [18, 19]. Sentinel lymph node biopsy in cases with colorectal cancer is a controversial issue, and we have sometimes experienced cases of colorectal cancer with skipping lymph node metastasis, in which distant nodes were positive but those closer to the tumor were negative. Skipping nodal metastases in colorectal carcinoma suggested the possibility of a bypass flow that has not been generally recognized . In our series, skipping nodal metastasis was observed in 9 cases among the 46 cases with positive lymph nodes. Therefore, the presence of ECI at a positive lymph node might explain in part the mechanism or process to disseminate to distant regional lymph nodes, and there thought to be other mechanism, including skipping nodal metastasis.
This study has potential limitations. The major limitation of our study is that we used retrospective methods of data collection. In addition, the number of cases in our study was relatively small. However, the clinical implications of this data are very important, and these findings serve to emphasize that ECI at metastatic lymph nodes is one of the processes or mechanisms of distant lymph node dissemination and is a biologic marker of aggressive nodal disease. Additional research is needed to explore other patterns or mechanisms of lymph node spreading.