Departments of 1Surgery and 2Pathology, Tokyo Metropolitan Komagome Hospital, Tokyo, Japan
Background: 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. There have been few reports of this condition and its clinical characteristics have not been clarified. This study was conducted to clarify the status of skipping lymph node metastasis and its clinicopathological characteristics in colorectal cancer. Methods: We analyzed 452 patients with colorectal cancer and nodal metastases (270 with colon cancer and 182 with rectal cancer). All the resected nodes were examined using histological procedures with a microscope and were classified by their location according to the General Rules for Clinical and Pathological Studies on Cancer of the Colon, Rectum and Anus. We studied the status of skipping nodal status and the correlation between the nodal status and clinicopathological findings, including the disease-free survival, depth of tumor, histological type, staging and recurrence. Results: Twenty-eight (10.4%) of the colon cancer patients and 20 (11.0%) of the rectal cancer patients were found to have skipping nodal metastases. In rectal cancer patients with n2 (nodal metastases at the N2 site) in the direction of the main node, patients with skipping lymph node metastases had a significantly better prognosis than those without (p = 0.026). In all colon cancer patients and rectal cancer patients with lateral n3 (nodal metastases at the lateral N3 site), there were a tendency for those with skipping nodal metastases to have better disease-free survival rates (p = 0.1). Also, the mean number of positive nodes in skipping cases was significantly lower than that in non-skipping cases. In addition, skipping nodal metastases in rectal cancer suggested a possibility of bypass flow which was not generally recognized. Conclusion: These findings in colorectal cancer suggest the presence of previously unknown lymphatic tracts and that the cancers concerned have a better prognosis than those without skipping nodal metastases.
Many authors have evaluated a wide variety of clinicopathological parameters in order to assess the prognosis of patients with colorectal cancer and several prognostic factors have already been identified. One of the most important factors is the presence of lymph node metastasis and this prognostic factor is used in many staging systems (1-4), including Dukes' classification (5), for colorectal cancer. Subclassification of Dukes C patients has been attempted in order to divide postoperative patients into those requiring limited or more intensive therapy. Many authors have described significant differences in disease-free survival rates between patients with one to four positive nodes and those with five or more positive nodes (6-9). They concluded that the number of nodal metastases may have strong predictive value and this subclassification of nodal status is used in the TNM classification (2). On the other hand, some authors have reported that the location of lymph node metastases, rather than the number, is the most important prognostic factor in colorectal cancer patients (10). In general, when tumor cells begin to metastasize to lymph nodes, they usually metastasize toward the node of origin of the tumor feeding artery and the location of nodes with metastasis is a marker of staging in colorectal cancer. In Japan, the `General Rules for Clinical and Pathological Studies on Cancer of the Colon, Rectum and Anus' were devised on the basis of this subclassification of nodal metastasis (11). Sometimes we have experienced cases with skipping lymph node metastases. However, there have been few reports of skipping nodal metastases, in which distant nodes were positive but those closer to the tumor were negative, in colorectal cancer (10) and their clinical characteristics are not known. Therefore, the purpose of this study was to investigate the status of skipping nodal metastasis and its clinical characteristics.
Table1. Lymph node classification according to the Japanese General Rules.
Table2. Skipping nodal metastasis in colorectal cancer patients.
Between January 1988 and December 1994, 1022 primary colorectal adenocarcinomas were resected at Tokyo Metropolitan Komagome Hospital. In 452 of these cases, lymph node metastases were detected by histological examination. Of the patients, 270 had colon cancer and 182 had rectal cancer. Patients with multiple advanced cancer and familial polyposis coli were excluded from this study. Histological examination of lymph nodes was made after extraction from freshly resected specimens, fixed in 15% buffered formalin solution and embedded in paraffin. All the removed nodes were classified by their location according to the Japanese General Rules (11) and were examined using histological techniques after maximum cross-sections of the nodes had been stained with hematoxylin and eosin. When we examined nodal metastases by microscopy, we excluded nodules without traces of lymph node from nodal metastases. Histological examination of the resected nodes was performed twice by pathologists.
Figure1. Disease-free survival rates of skip+ and skip- patients with more than n2 colon cancer. There was a tendency, without significance, that skip+ had a better prognosis than skip- (log-rank test, p = 0.1).
Figure2. Disease-free survival rates of n1, n2 skip+ and n2 skip- patients with colon cancer. The survival curves show a similar prognosis between n2 skip+ and n1.
In colon cancer, nodal metastases spread in two directions: the direction of the bowel axis (paracolic nodes) and the origin of the major named vessel supplying the tumor (main nodes). In rectal cancer, metastases spread in three directions: the pararectal nodes, main nodes and lateral nodes which are along the internal, external and common iliac arteries. Briefly, the nodal classification is shown in Table 1. N1, N2, N3 and N4 indicate the locations of nodes and n1, n2, n3 and n4 indicate the most distant metastasis detected by histological examination. A skipping nodal metastasis was defined as a case in which distant nodes were positive but those closer to the tumor were negative, e.g. in an n2 patient without metastasis in N1 nodes. In addition, we decided that cases in which a lateral node was positive without metastasis in the direction of the main node and paracolic node were also cases of skipping nodal metastases in rectal cancer below the peritoneal reflection.
Table3. Skipping nodal metastasis and clinicopathological backgrounds
Table4. Skipping nodal metastasis and number of metastatic nodes.
We studied the status of skipping nodal metastases in colorectal cancer and the correlation between the nodal status and clinicopathological findings. These included the disease-free survival period, patient age and gender, depth of tumor, histological type, lymphatic invasion, vessel permeation, staging, recurrence site and recurrence rate. For statistical analysis, the chi-squared test and unpaired t-test were used for analysis of two unpaired samples. Disease-free survival rates after resection were calculated by the Kaplan-Meier method and differences in survival curves were assessed by the log-rank test.
In 28 (10.4%) of the 270 colon cancer patients with nodal metastases, skipping lymph node metastases had been detected. Among the 28 instances of skipping metastases, 26 were in the direction of the main node and two were in the paracolic nodes (Table 2). There were 134 patients with colon cancer showing more than n2 nodal metastases, of whom 28 had skipping metastases (skip+) and 106 did not (skip-). There was a tendency that, without significance, skip+ had a better prognosis than skip- in all patients with colorectal cancer (Fig. 1, p = 0.1). In n2 and n1 patients, n2 skip+ had a similar 5 year disease-free survival rate to n1 (Fig. 2). The mean numbers of positive nodes in the n2 skip+ and n2 skip- groups and n1 were 1.5, 5.9 and 2.0, respectively. A significant difference was demonstrated between n2 skip+ and n2 skip- in the number of positive nodes (p = 0.009). The n2 skip+ group also had a similar mean number of positive nodes to n1 (Table 4). There were no significant differences between skip+ and skip- in other clinicopathological parameters (Table 3). Although the number of cases was small, there was no significant difference between skip+ and skip- in n3. These two subgroups showed a similar pattern of their survival curves (data not shown). In the direction of the main node, an n4 case with skipping nodal metastasis involved N4 metastases which derived from multiple hepatic metastases.
Figure3. Disease-free survival rates of n2 skip+ and n2 skip- patients with colon cancer in the direction of the main node. There was a significant difference in the 5 year survival rate between these two groups (log-rank test, p = 0.026).
Figure4. Disease-free survival rates of skip+ and skip- patients with lateral node metastasis in rectal cancer. In the n2 group, there was no significant difference in the 3 year survival rate between these two groups. Hence, in the n3 group, the survival curves showed a tendency, but with no significance, that skip+ had a better prognosis than skip- (log-rank test, p = 0.09).
Twenty (11.0%) of 182 rectal cancer patients with nodal metastases were recognized to have skipping nodal metastases. Among 20 skip+ cases, six were in the direction of the main node and 14 were in the lateral lymph nodes. Among 14 skip+ cases with lateral node metastases, seven were lateral node positive without nodal metastases in the direction of the main node and seven were lateral n3 cases without metastases to the lateral N2 node but with metastases with the main route (Table 2). In all rectal cancer patients, no significant differences in clinicopathological findings (Table 3) and disease-free survival rate (data not shown) were observed between skip+ and skip- cases. In cases of n2 in the direction of the main node, all four skip+ patients were alive at the time of the writing and the 5 year disease-free survival of skip- patients was 52.1%. Although the total number is still small, there was a significant difference between these two groups in 5 year disease-free survival rate (Fig. 3, p = 0.026). In the lateral node, no significant difference was evident between these two groups in 3 year disease-free survival for n2 patients. However, there was a tendency for skip+ to have a better prognosis than skip- (Fig. 4, p = 0.09). A significant difference in the number of positive nodes was observed between these two groups (p = 0.01). In particular, the mean numbers of positive lateral nodes in skip+ and skip- cases were 1.4 and 12.7, respectively (Table 4, p = 0.006).
The lymph node classification in the Japanese General Rules in accordance with the node locations were defined by the position of the feeding artery to the tumor, the lymphatic tract which exists along the artery and the distance from the tumor. Although some different lymphatic pathways may exist, the lymph node classification reflects the lymphatic drainage pathway from an anatomical standpoint. In general, when tumor cells begin to metastasize to lymph nodes, they continuously metastasize nodes toward the drainage lymphatic tract. However, we occasionally detected non-continuous nodal metastasis toward the drainage lymphatic tract. Skipping nodal metastases were defined as a case in which distant nodes were positive but those closer to the tumor were negative. Up to now, there have been few reports on skipping nodal metastases. Shida et al. (10) reported that 12 of 38 n2 patients with colon cancer had skipping nodal metastases and that there was no significant difference between skip+ and skip- in 5 year disease-free survival. In this study, we showed that 10.4% of colon cancer patients and 11.0% of rectal cancer patients with nodal metastases had skipping nodal metastases. When detecting patients with skipping nodal metastases, some technical errors may occur for the following reasons: (1) erroneous identification of the location of lymph nodes when these are removed from resected specimens; (2) histological misdiagnosis due to the use of only one cross-section of the resected lymph nodes; and (3) pathologists' oversight of metastatic tumor cells in resected lymph nodes. However, we identified the location of lymph nodes again and pathologists examined the resected lymph nodes again by microscopy. The examination of lymph node metastases was acceptable. Skipping nodal metastases could really occur in colorectal cancer. In the direction of the main node of n2 colon cancer patients and in lateral nodes of n3 rectal cancer patients, we found a tendency for skip+ cases to have a better prognosis than skip- cases and skip+ cases had significantly fewer metastatic nodes than skip- cases. A small amount of nodal metastases may contribute to a better prognosis in cases with skipping nodal metastases. With regard to other background factors, there were no significant differences between these two groups. In seven cases of rectal cancer, skipping nodal metastases were main N2 and/or N3 node positive and lateral N3 node positive without lateral N2 node metastases. The major anatomical characteristic of lymphatic flow in the direction of the main node in the rectum is mesenteric lymphatic flow along the inferior mesenteric artery and superior rectal artery in the rectal proper fascia. However, there is a possibility of bypass lymphatic flow which is not generally recognized and it penetrates the adherent fascia and reaches nodes directly along the internal iliac artery and aortic bifurcation. These seven cases proved the existence of this type of bypass flow.
Recently, laparoscopic resection of the colon for colonic malignancies has been attempted. However, it is not possible to resect mesenteric lymph nodes completely from the origin of the tumor-feeding artery using this technique. If this procedure is used for colon resection, it is necessary to consider the possibility of skipping nodal metastases.
In conclusion, skipping nodal metastases were detected in colorectal cancer. These tumors with skipping nodal metastases may have a better prognosis than tumors without them. In addition, these tumors may indicate the presence of a previously unknown lymphatic pathway.
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