Prognostic value of total number of lymph nodes retrieved differs between left-sided colon cancer and right-sided colon cancer in stage III patients with colon cancer

In patients with colon cancer’ survival is independently associated with the number of lymph nodes analyzed at the time of colectomy [1]. This is true in both node-positive and node-negative disease, indicating that the benefit is not solely due to upstaging and administration of adjuvant therapy [1‐3]. The American Joint Committee on Cancer recommends that a minimum of 7–14 lymph nodes be examined at colectomy to avoid understaging [4, 5]. The World Congress of Gastroenterology (1990) consensus was that at least 12 lymph nodes should be examined to ensure complete resection and adequate staging [1, 6, 7]. However, prognosis also depends on the status of regional lymph nodes, which is a major determinant of the need for adjuvant therapy.

Right-sided colon cancer and left-sided colon cancer have epidemiological, clinical, and molecular biological differences [8‐10]. Right-sided colon cancer is more likely to belong to the consensus molecular subtype 2 (CMS2) and to show high frequency of DNA somatic copy number alterations (SCNA) and microsatellite stable/weak immune activation, which makes it relatively insensitive to immunotherapy [11]. It has even been suggested that right-sided colon cancer and left-sided colon cancer may be two different entities. Thus the recommendation that a minimum of 12 lymph nodesbe evaluated may not be equally applicable in right-sided colon cancer and left-sided colon cancer though, so far, there is little biologic evidence to support this theory.

The lymph node ratio—defined as number of positive lymph nodes /the number of total lymph nodes evaluated—independently predicts prognosis in stage III colon cancer [12] and may thus act as a confounder. Wang et al. found that the significance of the total number of lymph nodes as a quality-of-care measure in stage III colon cancer disappeared after adjusting for the effect of lymph nodes ratio [13]. However, they did not take tumor location into consideration. Additionally, their sample included patients treated from 1998 to 2003. Whether their conclusion remains valid in patients treated after 2003 is not known. Especially when a previous study has reported that between 1988 and 2011 there has been marked increase (from 20% to 80%) in the number of patients having ≥12 lymph nodes excised during colectomy for colon cancer [14].

Whether the lymph node ratio has the same confounding influence in both left-sided colon cancer and right-sided colon cancer remains unknown. The aim of this study was to evaluate whether the recommended standard of ≥12 for total number of lymph nodes has the same prognostic significance in right-sided colon cancer and left-sided colon cancer after adjusting for the lymph nodes ratio in a large national cohort.

The data were obtained from the Surveillance, Epidemiology, and End Results (SEER) cancer registry. All patients receiving a first diagnosis of invasive stage III colon cancer (according to the 6th the American Joint Committee of cancer) criteria during the period from January 2004 through December 2012 were identified from the registry. The TNM stage was determined by SEER’s “extent of disease” (for T and M stage) and the “number of positive nodes” (for N stage) coding schemes. All patients had pathologically confirmed adenocarcinoma or mucinous adenocarcinoma [15], with tumor grade categorized as well differentiated, moderately differentiated, poorly differentiated, or undifferentiated. Colon cancer was evaluated as right-sided colon cancer (cecum, ascending colon, hepatic flexure, and transverse colon) or left-sided colon cancer (splenic flexure, descending colon, and sigmoid colon). The number of positive lymph node and the total number of lymph nodes evaluated were recorded, and lymph nodes ratio was calculated. Race/ethnicity was categorized as previously described. [16]

Patients were observed from 6 months after first diagnosis of colon cancer until the last follow-up, death, or end of the study, whichever occurred first.

The relationship between the total number of lymph nodes and outcome of colon cancer has been extensively studied. [1, 20‐27] Our finding of improved survival with higher lymph node yield is consistent with previous research [1, 20‐23, 25, 27‐31]. The mechanism remains unknown, but potential factors include more accurate tumor staging, improved surgical management, and superior quality of pathology service [32]. Some studies have demonstrated that a stronger host immune response [33] and the molecular/biological characteristics of the tumor are related to high total number of lymph nodes, and these too may be responsible for its effect on prognosis [32, 34]. For a long time, the presumed reason was that more extensive lymph node evaluation leads to less understaging, and thereby to better treatment and survival. However, LeVoyer et al. [1] and Prandi et al. [35] have all found that increase in the number of lymph nodes retrieved did not necessarily result in upstaging or in increased survival. [36] These authors also showed that the node positivity rate did not change despite a steep increase in total number of lymph nodes, and that it is important to consider the effect of node positivity rate on prognosis. Wong et al. [37] found that distribution of the positive lymph node frequency and the rate of receiving adjuvant chemotherapy are similar among hospital groups although the number of lymph nodes evaluated varied widely, suggesting that increasing total number of lymph nodes does not significantly upstage patients.

In our study, we found all lymph nodes ratio strata were independently predictive of overall survival. Thus, although the 12-node-minimum standard remains an important prognostic determinant, lymph nodes ratio has a separate contributory prognostic role even though the surgical benchmark and lymph nodes ratio are interrelated parameters. Importantly, our study showed no relationship between total number of lymph nodes and outcome in the left-sided colon cancer cohort when adjustment was made for lymph nodes ratio in multivariate analysis; this finding is consistent with Wang et al. [13]

The American Joint Committee on cancer TNM staging system is based on number of positive nodes, not lymph nodes ratio. In the present study, Kaplan–Meier survival analysis showed that high total number of lymph nodes is associated with significantly improved survival in the lymph nodes ratio < 0.25 subgroup. However, the difference between survival of high total number of lymph nodes and low total number of lymph nodes patients was less in the higher lymph nodes ratio strata. Furthermore, the distribution of lymph nodes ratio strata between the high total number of lymph nodes and low total number of lymph nodes groups was significantly different. This may because low lymph nodes ratio subgroups have lower metastasis risk and fewer positive lymph nodes, and so most of the lymph nodes retrieved during surgery are negative lymph nodes. The fewer number of positive nodes retrieved may cause an artificial inflation of the lymph nodes ratio—the “small-denominator effect.” Conversely, the high lymph nodes ratio subgroups have relatively higher metastasis risk and more number of positive lymph nodes. Although more lymph nodes are retrieved in the high total number of lymph nodes, the number of positive lymph nodes is also high, and the tumor burden is the leading role not the immune reaction. In this occasion, a “large-denominator” effect may be an issue as it is much easier to achieve positive nodes sampled.

A threshold total number of lymph nodes of 12 is often used as a measure of quality of surgical care. However, it may not be adequate to only use the number of lymph nodes evaluated as a quality-of-care measure; the surgeon’s technique and the pathologist’s methods must also be taken into account. Other variables, such as the patient’s immunologic response and age [38] and the location of the primary tumor, may also greatly impact the number of lymph nodes retrieved. Prandi et al. have shown that the number of lymph nodes retrieved is inversely associated with patient’s age [35]. Another study found that more lymph nodes are identified in patients with right-sided colon cancer, which led the authors to question whether the standard for regional lymph nodes evaluation should be the same in right-sided colon cancer and left-sided colon cancer [39].

Our study showed that after adjusting for the lymph nodes ratio, the association of total number of lymph nodes with survival in stage IIII colon cancer was present only in right-sided colon cancer but not in left-sided colon cancer. The biological behavior of the tumor and host parameters such as immune response may affect the number of traceable lymph nodes. Several authors have hypothesized that smaller numbers of lymph nodes found is reflection of a diminished immune response. Size and morphology of nodes are modified by immune responses, with a weak immune response leading to smaller nodes that are harder to find [21, 25, 40]. One study showed that the number of nodes found is associated with lymphocytic infiltration of the primary tumor, with more nodes being found in patients with prominent lymphocytic infiltration into the primary tumor than in patients with mild lymphocytic infiltration [41]. The differences in anatomical, physiological, and molecular characteristics between right-sided colon cancer and left-sided colon cancer may also influence the number of lymph nodes examined. [13] The benefits associated with high total number of lymph nodes might actually reflect the host lymphocytic reaction to tumor, which is associated with lymph node count [21, 41]. This phenomenon is commonly observed in lymph nodes draining the cancer. It has been postulated that the right colon mesentery contains a more complex lymphatic system, which leads to an enhanced immune response and thereby to increase in the number of lymph nodes examined in right-sided colon cancer, but there is no clear evidence in support of this theory [42]. A cadaveric study may help clarify this issue.

In summary, the study demonstrated that it may not be correct to use the threshold of total number of lymph nodes ≥12 for predicting prognosis in both left-sided colon cancer and right-sided colon cancer in stage III patients with colon cancer. Although the number of lymph nodes evaluated is a prognostic factor, this does not mean that it is also a predictive factor [43]. Presently, many undersampled patients receive unnecessary treatment, and so adequate nodal evaluation is important. There is little evidence to justify adjuvant treatment in node-negative patients when too few nodes are evaluated. Based on the results of the present study, the surgeon should take tumor location into consideration when deciding on the minimum total number of lymph nodes to be retrieved.