Colon adenocarcinoma was ranked as one of the most frequent malignant tumors worldwide (1). The tumor node metastasis (TNM) cancer staging system proposed by the American Joint Committee on Cancer (AJCC) has been widely used to guide treatment plans and evaluate prognosis of colon cancer patients. Based on this staging system, the most obvious difference between stage II and stage III colon cancer was the presence of pathological lymph node metastasis.

Recommended by the American College of Pathologists (ACP) and the American Joint Committee on Cancer (AJCC), the pathological examination of lymph nodes should be at least 12 in the surgical specimen, which has become the general consensus to ensure accurate nodal staging in colon cancer patients (2, 3). It was reported by researchers that the least number of lymph nodes examined was 13 to identify more than 90% local lymph node metastasis (4). In spite of that, inadequate number of lymph nodes examined was not uncommon. Inadequate number of lymph nodes examined might lead to inaccurate assessment for lymph node involvement, which would misguide clinical treatment decisions and adversely affect patient outcomes (5, 6).

It was previously reported in a big retrospective study that the number of lymph nodes examined ranged between 5.5 and 21.3 lymph nodes, and the average lymph node harvest was 11.7, which was less than the recommended minimum lymph nodes examined (7). In the present study, using the data from a big cancer database with long‐term follow-up, we aimed to evaluate the prognostic value of inadequate number of lymph nodes examined in stage II colon cancer.

The high and increasing incidence of colon cancer around the world made the related studies a hot topic in recent years (8–11). In this study, we aimed to evaluate the clinical role of inadequate number of lymph nodes examined in stage II colon cancer, with comparison of node positivity in stage III colon cancer.

With a median follow-up time of 75 months, 80,296 colon cancer patients were enrolled in the whole cohort. Therefore, this was a large retrospective study with long-term follow-up, and it has added more credibility to our main findings. The median number of lymph nodes examined in total was 16, which exceeded the recommended number of lymph nodes examined according to the clinical recommendations of AJCC and ACP. Our results have revealed that up to 26.8% of all the colon cancer patients did not have adequate retrieval of the recommended number of lymph nodes. However, adequate lymphadenectomy has been suggested for colon cancer, and recent studies showed that increased number of lymph nodes examined for pathological identification would contribute to improved OS in colon cancer, indicating the necessity of finding ways to increase the number of lymph nodes examined (12–15).

To the best of our knowledge, the present population-based study was the largest one that has addressed the clinical role of inadequate lymph node examined in stage II colon cancer. It was found that white race, younger age, later tumor stage, advanced tumor grade, female, mucinous/signet ring cell histology, and later year of diagnosis were prone to being associated with enough (≥12) lymph nodes removed. Previous studies also reported that the length of the bowel resection and the location of ligation of the blood vessels (such as a higher ligation in a complete excision) could affect the number of lymph nodes retrieved (16). Apart from that, several other factors such as the extent and the technique of surgical dissection, physiological factors, and the pathologist’s work experience and technical level were also found to exert an effect on the lymph nodes examined (17–19).

Using Kaplan–Meier method, our initial analysis indicated that N0 stage with <4 lymph nodes examined would present with worse OS compared with N1 stage (46.2% vs. 57.1%, p < 0.001). Moreover, N0 stage with less than eight but more than four lymph nodes examined (5-year OS rate = 54.1%) also presented with worse OS compared with N1 stage (p < 0.001). In addition, multivariate analyses were conducted based on the Cox proportional hazards model with the recognized prognostic factors included; the results showed that the OS of N1 stage had 9.1% decreased risk of overall mortality compared with less than four lymph nodes in node-negative patients after adjusting for other recognized factors.

Therefore, we have combined less than four lymph nodes with more than four but less than eight lymph nodes examined together in node-negative patients. The Kaplan–Meier survival analyses indicated that N0 stage with <8 lymph nodes examined would present with worse OS compared to stage N1 (5-year OS rates, 51.6% vs. 57.1%, p < 0.001). Other recognized prognostic characteristics were then taken account into multivariate analyses, which indicated that the OS of N0 stage with <8 lymph nodes examined was similar to that of N1 stage.

In our analyses, the result that survival of N0 stage with less than eight lymph nodes examined was comparable to that of N1 stage was parallel to previous findings (3, 14, 20). As early as 2002, it was reported by Cianchi and his colleagues (20) that the 5-year survival rate of the Dukes B patients with <8 retrieved lymph nodes was similar to that of the Dukes C patients. Then, in 2005, Sarli et al. (14) recruited 745 stage II and 493 stage III colorectal cancer patients in Italy and found that patients with stage III tumor with only one to three positive lymph nodes had a similar 5-year survival rate (52.6%) compared with that of patients with stage II colon cancer with less than nine lymph nodes examined in total (51.3%).

Similarly in 2009, one British study showed that the survival of Duke’s B (stage II) colorectal cancer patients with less than nine lymph nodes examined in total was not better than that of Duke’s C (stage III) disease patients (3). In spite of that, it was noteworthy that the abovementioned three studies did not enroll enough cases to evaluate the prognostic value of inadequate number of lymph nodes examined in stage II colon cancer. Moreover, in the present study, with 80,296 patients recruited from a big cancer database, we concluded that N0 stage with less than eight lymph nodes examined in stage II colon cancer presented with similar OS compared to that of N1 stage. Stage II colon cancer with less than eight lymph nodes examined needed to be given greater emphasis in clinical practice.

As suggested by the clinical recommendations of European Society for Medical Oncology, some clinical factors such as pT4 stage, bowel obstruction or tumor perforation, lymph nodes sampling <12, lymphatic or vascular or peripheral invasion, and poorly differentiated tumor were listed as risk characteristics in stage II disease (21). Recently, some researchers have questioned the efficacy of chemotherapy in high-risk stage II colon cancer patients (22–24). In 2018, it was also reported by some American researchers that adjuvant chemotherapy was not associated with improved survival if less than 12 lymph nodes was deemed as the sole high-risk factor (25). The number of enrolled patients in the current study was sufficiently large to give us confidence that the results were high in reliability to evaluate the clinical role of inadequate number of lymph nodes examined in stage II colon cancer. The results of our analyses, together with what have been discussed above, made us believe that stage II colon cancer with less than eight lymph nodes examined needed to be given greater emphasis in clinical practice. However, it should be recognized that preoperative chemotherapy and postoperative chemotherapy were mixed up as chemotherapy and thus analyzing whether neoadjuvant treatment would have effect on the number of lymph nodes examined because of the limitation of this cancer database. Improvements in technology and research in oncology have greatly improved the prognosis of colon cancer patients in the past decade, which may have an influence on the findings of our study. Moreover, the selection bias would also exist in a study with retrospective design. Therefore, it would be interesting to carry out a prospective study to further explore the clinical role of less than eight lymph nodes examined in offering adjuvant therapy in stage II colon cancer.

Our study showed that OS of N0 stage with less than eight lymph nodes examined was comparable to that of N1 stage in stage II colon cancer. Therefore, stage II colon cancer with less than 8 lymph nodes examined needed to be given greater emphasis in clinical practice. It would be interesting to carry out a prospective study to further explore the clinical role of less than eight lymph nodes examined in offering adjuvant therapy in stage II colon cancer.

The raw data are available from the corresponding author upon reasonable request.

DZ and YW conceived and designed the study. QW and ZZ contributed to the acquisition of data. QW, YC, JC, and YJ interpreted the data. QW wrote the first draft of the manuscript. DZ and YW reviewed and edited the manuscript. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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