In the present study, high LN yield in the resection specimen was associated with improved disease-free survival. This was observed mainly in stage II patients, while for stage III patients only a trend toward better survival was seen in cases of high LN yield. Regarding stage II patients, we identified high-risk patients based on NCCN criteria.29
We analyzed T-stage, histologic grade, vascular invasion, and number of lymph nodes sampled of all tumor specimens. These characteristics are included in Table and Fig. . For these characteristics, no significant difference was observed between patients with low lymph node count (<10) and those with high lymph node count (≥10), as shown in Table .
Several studies strongly confirm the association between high LN yield and improved survival in colorectal cancer patients, both in stage II and III disease.10,15,18,25,30,31
The causal factors for this association are subject of debate. Stage migration has been postulated as a factor. Patients with lower numbers of nodes analyzed could be falsely designated as stage I or stage II, when the nodes examined contain no metastases, while additional node samples would have revealed tumor and thus stage III would have been assigned.
Moreover, resection of lymph nodes itself may have a therapeutic effect. For patients with positive lymph nodes, a higher number of recovered nodes has been associated with better survival.15,25,31–33
This was not strongly confirmed by the present study as stage III patients with high LN yield showed only a trend toward better disease-free survival.
Several explanations have been postulated to explain why some resection specimens of colon cancer have high lymph node yields and others do not. It has been suggested that a low number of nodes recovered in a specimen is a reflection of inadequate surgical resection or pathological examination.34–36
Guidelines recommending a certain minimum number of investigated lymph nodes are also based on the assumption that increased effort by the surgeon and pathologist will lead to higher lymph node counts. However, large studies that show inferior survival in colon cancer patients with fewer lymph nodes demonstrated that this relationship could not be explained by factors such as extent of surgical resection and pathologic processing. 30,37
Moreover, the fact that most societies nowadays recommend a minimum number of 10 to 12 lymph nodes to be investigated, and this is only achieved in about one-third to one-half of the patients, also indicates that other factors besides surgical and pathologic skills may play a role in lymph node yield.19–21
Alternatively, a low number of nodes may not necessarily represent the quality of care a patient has received and instead may be influenced by underlying biological characteristics of the tumors.
One of the underlying biological factors that have been suggested to be of influence is the microsatellite instability status of colon cancer. Microsatellite instability is 1 of 2 major distinct colorectal oncogenic pathways, the other being chromosomal instability.38–40
Microsatellite instability is observed in about 15% of sporadic colorectal cancers and is caused by a defect in the DNA mismatch repair system. Colon cancers with the MSI phenotype have been associated with a better prognosis compared with MSS tumors.38,40,41
One of the factors involved here could be the antitumor immune response, which differs between MSI and MSS colorectal cancers. In general, the immune system recognizes neoplasia poorly, but in MSI colon cancer with infiltrating lymphocytes, it has been shown that mechanisms of T-cell cytotoxicity are activated.42
Truncated peptides produced by frameshift mutations that are common in MSI cancers because of failing DNA mismatch repair may be immunogenic and contribute to the host immune response resulting in the migration of activated T-cells into the malignant epithelium of the tumor.43–50
Moreover, marked lymphocytic, so-called “Crohn’s-like” infiltrates are a hallmark of MSI colorectal cancers.51
Microscopically, hyperplastic changes are seen in lymph nodes draining colorectal tumors exhibiting prominent antitumor immune reactions, and these tumors were found to have larger and more detectable lymph nodes.52,53
These findings suggest a relation between MSI status of the primary tumor and lymph node yield in the resection specimen. This is supported by the present study, as MSI tumors were significantly associated with a high number of lymph nodes harvested (Fig. a).
The association between MSI phenotype and high lymph node yield as was observed in the present study has been reported before in 2 smaller and more heterogeneous study populations compared with the present one.54,55
One study consisted of 82 stage I (n
= 27) and II (n
= 55) both colon (n
= 52) and rectal (n
= 30) cancers, the other was based on 121 stage I–III colon cancers (12 stage I, 71 stage II, and 38 stage III patients).54,55
In the present study, rectal cancers were excluded, because in general these tumors are treated with preoperative (chemo)radiation therapy, which is known to influence lymph node retrieval of the resection specimen.56–58
In both earlier studies, heterogeneous patient populations were investigated and analysis did not include, in contrast to the present study, stratification for disease stage, possibly because the relatively small sample sizes would not allow for meaningful subgroup analysis.
The present study consisted of 185 stage II and 147 stage III colon cancer patients. This is the first study reporting a significant association between MSI tumors and high LN yield in stage III colon cancer. Interestingly, the effect of MSI on lymph node yield was highest in stage III cancer, that is, in those tumors in which metastatic spread to regional lymph has already occurred. This could be caused by an additional boost of the immune response due to more intimate exposure of lymphoid tissue to tumor cells than in stage II tumors.
In conclusion, the present study showed a strong association between MSI phenotype and high lymph node yield in colon cancer, mainly so in stage III disease. The biology of MSI colon cancers can provide explanations for this, while at the same time contributing to a better prognosis. Conversely, a less favorable outcome in patients with lower lymph node yields would then not only be attributable to understaging due to missed positive lymph nodes, but also to tumor intrinsic factors.