Introduction
Globally, colon cancer constitutes a major public health challenge because of its high incidence and mortality rate [
1]. By 2030, the global prevalence rate is estimated to increase by approximately 60%, and colon cancer could be a severe social burden, with more than 1.1 million deaths and 2.2 million new cases [
2].
In recent years, clinical schedules for colon cancer become standardized and streamlined. Lymph node count, as a crucial postoperative pathological data, plays an important role in the accurate estimation of patient prognosis and rational formulation of therapeutic scheme [
3‐
5]. Based on the American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) guidelines, a minimum of 12 lymph node counts is essential to ensure proper lymphadenectomy and accurate tumor stage [
6]. Although the 12-node standard has been advocated, the literature lacks consensus as to what is the minimal number of lymph nodes to accurately identify stage II cancer and therefore, the proposed standard might be unsuitable for those with node-negative disease.
Carcinoembryonic antigen (CEA) is an irreplaceable tumor marker of colon cancer. In 1965, CEA was reported firstly as a member of the immunoglobulin superfamily [
7]. Secreted by various solid tumors, CEA could be found in increased level in 90% of colorectal cancer patients [
8]. Moreover, CEA could accelerate tumor progression and support colon cancer cells to attach to the metastatic sites and was associated with unfavorable long-term survival [
9‐
12]. In 2000, the Colorectal Working Group of AJCC even recommended the serum level of CEA should be added into conventional AJCC TNM staging system of colon cancer [
6]. Therefore, more attention should be paid in CEA-elevated colon cancer patients due to their distinct characteristics.
Regarding the optimal number of lymph node examination, the level of CEA should also be taken into account. CEA-elevated colon cancer is related to a more aggressive biological property and need a more adequate lymphadenectomy to guarantee the curative resection, and therefore, the conventional 12-node standard might be insufficient for this special population. Hence, the aim of this paper was to recalculate the optimal minimum lymph node count for colon cancer patients with CEA-elevated (≥ 5 ng/ml) disease [
13], with data from the Surveillance, Epidemiology, and End Results (SEER) program and the Second Affiliated Hospital of Harbin Medical University.
Methods
Study population
Data was extracted from the Surveillance, Epidemiology, and End Results (SEER) program between January 2010 and December 2015 (user ID: 14262 - Nov2019). The National Cancer Institute’s SEER database collects cancer diagnosis, treatment, and survival data for approximately 30% of the U.S. population from 18 participating population-based cancer registries annually. In addition, data from the Second Affiliated Hospital of Harbin Medical University between January 2011 and December 2015 were also included in the current research as an External set.
Inclusion criteria included: (1) radical resection was the first course of treatment; (2) patients with CEA-elevated disease; (3) aged ≥18 years; (4) patients diagnosed as nonmetastatic colon cancer pathologically; (5) colon cancer was the only malignancy. Exclusion criteria included: (1) patients underwent neoadjuvant chemoradiotherapy; (2) patients with unknown race, grade, tumor size, histological type, number of lymph node examined and tumor stage and (3) patients without active follow-up.
In this study, cecum, ascending colon, hepatic flexure and transverse colon were considered as right colon, and splenic flexure, descending colon and sigmoid colon were considered as left colon [
14]. Based on the pathological examination of surgical specimens, all cases were uniformly re-staged according to the 8th edition of the American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) staging system.
Statistical analysis
Patients’ characteristics were demonstrated by number and percentage. For cancer-specific survival (CSS), Kaplan-Meier curves were drawn and data were analyzed using log-rank test. Based on the cancer specific survival, X-tile was used to confirm the relationship between long-term outcome and different lymph node count based on the projection of each possible cut-off point [
15]. And then, the optimal cut-off point was calculated by selecting minimum
P value with the maximum Chi-square value in all possible subdivisions of the populations.
To assess the clinical value of this revised standard, univariate and multivariate Cox regression models were conducted to examine the hazard rate (HR) and the exact 95% confidence interval (CI). ANOVA was utilized to compare the mean positive lymph node count between different subsets. All statistical analyses were performed using SPSS 22.0, and P value < 0.05 (two-sided) was considered to be statistical significance.
Discussion
CEA is a recommended prognostic marker for monitoring tumor progression in colon cancer [
16‐
19], and examining 12 nodes might be insufficient for CEA-elevated colon cancer patients who were characterized by higher risk of lymph node metastasis and poor prognosis. In this paper, we found that 18-node standard could be deemed as an alternative to the conventional 12-node standard, as a result of the accurate nodal stage and favorable prognosis.
In recent years, many scholars have reassessed the optimal lymph node yield for colon cancer patients according to different stratifications. With the consideration of anatomic factor [
20], Guan et al. revealed that at least 15 lymph nodes examined in patients with stage I-III right colon cancer could significantly improve the 5-year CSS and the rate of node-positive disease [
21]. Similarly, Cai et al. concluded that a minimum of 19 lymph nodes harvested is essential in stage II right colon cancer, with the aim of favorable survival [
18]. Regarding early-on set colon cancer cases, Guan also suggested that 22-node standard should be recommended, which required more lymph nodes than conventional guidelines [
16]. And for N0 colon cancer, Ning et al. thought that harvesting at least 18 nodes was related to better postoperative survival than the 12-node measure [
17]. However, few papers have determined the minimum optimal lymph node count for CEA-elevated patients.
Compared with above researches, the merits of current paper were twofold. On the one hand, this was the first study to explore the optimal minimum node for CEA-elevated cases, with the consideration of nodal stage and postoperative prognosis, which was consistent with the studies mentioned above. On the other hand, different from the above articles, the results in this study were also validated using an External set, which suggested the proposed standard might also apply to Chinese population, making it more convincing than others.
To our knowledge, the potential mechanisms accounting for the improved survival of patients with increased lymph node yield were multifactorial. Firstly, increased lymph node count was related to a more robust antitumor immune response, a significant indicator of favorable prognosis [
22]. Patients with less lymph nodes retrieved might have lowered resistance to metastasis and recurrence, therefore occupying decreased survival time. Secondly, lymph node count was a surrogate marker to evaluate the performance of radical surgery. According to previous studies, surgeons’ skills in lymph nodes dissection is of vital significance for patients’ survival [
23]. Patients with higher number of lymph node retrieved were more likely to accept an adequate radical cure, leading to the presence of improved survival. Thirdly, in this paper, we found the number of lymph nodes harvested was associated with nodal stage and the number of positive lymph node examined, and therefore, higher lymph node count could reduce the likelihood of false staging, making more patients benefit from adjuvant chemotherapy, which is of eminent significance for their favorable long-term survival.
Findings of the research present eminent significance in clinical work. On the one hand, since more lymph node examination is crucial for CEA-elevated patients, lymphatic tracer such as methylene blue and carbon nanoparticles suspension could be applied for this population to make the lymph node more phanerous for pathologists and surgeons [
24]. On the other hand, in the survival evaluation for CEA-elevated cancer, < 18 lymph node count might be a risk factor should be taken into consideration to better perform prognostic stratification. However, the proposed result could only provide a potential reference, but not guidance.
Still, the authors acknowledged several study limitations. Firstly, SEER database collects information about 28% of the U.S. population, leading to dramatic changes in surgical and pathological techniques used to detect lymph nodes and it could not be adjusted in this paper. Secondly, as a retrospective study, it was inevitable to have observer and confusion bias and needed to be verified by some prospective clinical studies. Thirdly, the sample size of the External set seems to be insufficient and we would like to conduct a larger scale study to further authenticate the performance of the 18-node standard in CEA-elevated colon cancer patients. Finally, some potential prognosticators such as the molecular markers and detailed information about surgical procedures are not available in the SEER database and could not be included in the survival analysis.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.