Factors affecting number of lymph nodes harvested and the impact of examining a minimum of 12 lymph nodes in stage I-III colorectal cancer patients: a retrospective single institution cohort study of 1167 consecutive patients

In the 7th edition of the AJCC Cancer Staging Handbook published by the American Joint Committee on Cancer (AJCC) and the International Union Against Cancer (UICC), the recommendation for the number of lymph nodes (LNs) that need to be removed is 10–14 [1]. As the detection of positive LNs is critical for the prediction of patient outcomes, an adequate number of LNs must be examined. In a commentary on TNM classification, Compton and Green indicated that at least 12 LNs need to be removed [2]. In addition, the “College of American Pathologists Consensus Statement” [3] and the clinical practice guidelines from the National Comprehensive Cancer Network [4] also recommend that at least 12 LNs be removed.

Despite emerging data on the prognostic utility of molecular profiling, pathologic assessment of resected specimens remains the strongest predictor of survival in patients with CRC. Goldstein et al. [5] used mathematical models to show a direct linear relationship between LN yield and the probability of finding a positive node. Moreover, LN harvest has been shown to impact clinical outcomes in patients with stage II and stage III disease, such that more negative LNs confer a survival advantage [6‐8]. In addition, Sarli et al. reported that the factors influencing nodal harvest are multifactorial [9]. Three key variables are thought to impact LN yield, including patient-dependent factors, surgeon-dependent factors, and the pathologic assessment of specimens.

Data from large series of cases from single institutions are rare. The aims of this retrospective study were to address this issue by identifying the factors affecting the harvest of LNs and by examining the associations between the 12-LN measure and clinical outcomes to analyze the impact of the pathological examination of 12 regional LNs on overall survival (OS) and disease-free survival (DFS) in patients with stage I-III CRC following radical resection.

The novel aspects and findings of the present study were as follows: (1) there appeared to be only one independent factor affecting the harvest of lymph nodes for stage I–III rectal cancer patients; (2) we found that an adequate number of retrieved LNs was most significantly associated with the DFS of stage I-III CRC patients and the OS of stage II and III CRC patients; and (3) this is the first comprehensive report identifying significant factors predicting the retrieval of lymph nodes in colon cancer and rectal cancer respectively.

Previous researchers have demonstrated a relationship between the number of histologically examined lymph nodes and prognosis: the more LNs examined, the better the prognosis [13‐16]. Numerous observational studies have also shown that CRC patients for whom an adequate number of LNs have been examined have a considerably lower rate of mortality [17, 18]. The 12 lymph node benchmark for LN retrieval and examination arose in recent years from the observed relationship between higher numbers of LNs and improved patient survival [19]. Moreover, the results of this study support previous findings that there are many factors influencing the harvest of regional lymph nodes [9].

Our results are similar to the finding of previous studies that the number of LNs harvested is inversely associated with the age of colon cancer patients [20, 21]. Inflammation and its contributing process have been known to cause LNs to become enlarged, making them easier to identify than normal nodes among both surgeons and pathologists [22]. Tekkis et al. [23] reported that older individuals could have reduced immunologic and inflammatory reactions to cancers that would lead to decreased numbers of LNs being harvested. It is also possible that LNs may undergo a process of involution with increasing age.

One interesting finding of the current study is that larger tumors are more likely to result in a higher nodal harvest regardless of whether the given patient has colon cancer or rectal cancer, a result which is consistent with the observations of Chen et al. [24]. A biological explanation for this finding is not yet known, but it is possible that larger tumors may lead to more profound inflammatory responses in the mesentery basin, resulting in a greater number of LNs (though not necessarily positive LNs) in the resected mesentery being harvested for pathological examination. In addition, it is noteworthy that our data indicated that T-descriptor, which refers to the depth of wall penetration in the colon was directly correlated with the number of LNs retrieved. A deeper penetration of the bowel wall found in patients with T3 or T4 tumors may result in a greater antigenic immune and inflammatory response within the regional LNs, making them more apparent to pathologic examination [20]. In a population-based study of 2281 CRC patients, Kelder et al. [25] also demonstrated that T stage was independently associated with the number of examined LNs. In that study, the number of LNs recovered increased with advanced TNM stage, and we found the controversial results in our study.

In this study, the mean examined number of LNs was 15.73 ± 9.29. Our enrolled patients with LNs examination are adherent to the LN quality measure, of which the 12 LNs goal is nearly 70 %. Three population-based studies have confirmed the impact of a high number of examined LNs (≧12) on long-term survival in patients with stage II CRC [26, 27]. However, some reports on stage III CRC are contradictory. Vather et al. reported that the 5-year survival rate was increased with increased nodal harvests, with the greatest difference occurring at the < 12 and ≧12 LNs cut-off [27]. Conversely, Kelder et al. reported no significant difference in survival in three subsets of nodal harvests (<6, 6–11, and ≧12) in 738 stage III patients [25]. We found that stage I-III CRC patients with a higher number of examined LNs (≧12) had better overall survival rates than those with a lower number of examined LNs (<12). In terms of DFS, the same observations applied except for among the stage I CRC patients. This may have been due to the relatively low rate of recurrence for the stage I CRC patients. Herein, we propose three possible mechanisms for the detrimental impact of low LN harvests on survival: (1) surgeon-related factors, with worse survival being associated with less complete resections, which also lead to less nodes being removed [28]; (2) pathologist-related factors, with worse survival occurring due to the phenomenon of stage migration [29]; (3) a mechanism reflecting interactions between the tumor and the host that may also be associated with prognosis [30].

The limitations of this study were as follows: (1) it consisted of a retrospective cohort study involving only a single institute; (2) it involved many surgeons, and surgeon-dependent factors might be among the most important factors affecting the harvest of lymph nodes; and (3) we did not categorize the surgeries by the anatomic type of resection (e.g. right-hemicolectomy, left-hemicolectomy, sigmoidectomy, extended, lower anterior resection etc.), which may have resulted in a statistical bias. More accurate identification of patients with an adequate retrieval of lymph nodes and appropriate intensive treatment/follow-up, especially systematic chemotherapy, may improve the efficacy of various treatments and overall survival. However, it will be necessary to analyze clinical data from multiple institutions in order to develop simpler, more sensitive, and specific criteria for detecting patients with a high prediction of sufficient lymph-node retrieval and, in turn, to improve clinical outcomes.

This study further confirmed that a total of 12 or more examined LNs is associated with increased long-term survival in stage I-III CRC patients. Furthermore, a minimum of 12 LNs examined is not only the standard of care, and thus important in predicting outcomes and directing treatment goals, but is also associated with a reduction in mortality.