Background
Early age at onset is often considered as a poor prognostic factor for colon cancer (CC). Young-onset CC is characterized by more advanced stages, poor tumor differentiation, mucinous carcinoma, more distal location, and even a particular profile of biomarkers [
1]. Currently, CC incidence in patients younger than 50 years continue to increase, most markedly among those patients younger than 35 years by approximately 2% per year [
2]. Young CC patients are affected by the disease in the prime of their life, but the life expectancy of these patients are different from older patients. In addition, there is limited knowledge about the aetiology and pathogenesis of young CC patients, especially for patients younger than 40.
The presence or absence of lymph node metastases is pivotal to the accurate staging of CC patients, thus ensuring that appropriate decisions are made regarding adjuvant therapy [
3‐
5]. Current guidelines of the American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) advocated that a minimum of 12 lymph nodes need to be examined to establish N stage. Besides, many studies have been performed to determine the optimal number of lymph nodes that need to be examined to accurately stage CC [
5‐
7]. However, the lymph node examination could be influenced by age, cancer site, tumor stage, and many other factors [
8‐
10]. Therefore, large controversies still exist regarding optimal number of lymph nodes to be examined.
The clinical and biological characteristics of young CC patients are different from other age groups, thus request more attention. Some studies previously reported that young age associated with more lymph nodes to be examined [
11‐
13], but the result remains undefined due to distinct lack of data. To better define this issue, with data from the Surveillance, Epidemiology, and End Results (SEER) database, we attempted to discuss whether the 12 lymph nodes is the optimal minimum node count for young CC patients, and further analyzed the optimal choice for lymph node examination for patients younger than 40. Secondly, we compared the superiority between the revised 22-node measure and the standard 12-node measure based on the number of positive nodes examined. Finally, we tried to identify whether this revised node measure could be considered as an independent prognostic factor for young CC patients.
Discussion
Although patients under the age of 40 constitute a minority of all CC patients, the incidence of CC in this age group has increased over the past decades [
2,
15,
16]. Young CC patients are affected by the disease in the prime of their life, but the life expectancies of these patients are different from older patients [
17]. In addition, there is limited knowledge about the aetiology and pathogenesis of young CC patients. Thus, more attention should be paid to the diagnosis and treatment for this special group of patients.
Recently, lymph node examination has been associated with accurate staging and reasonable use of adjuvant treatment [
14]. For one thing, inadequate lymph node examination increases the risk of under staging and leads to unreasonable therapeutic decision which further influence the survival benefit of patients [
6]. For another, the number of lymph nodes examined depends on multiple factors further influence survival [
6,
11,
18‐
20]. Firstly, the skill of surgeon and pathologist, the extent of surgical field and the technique of pathology examination could influence the number of lymph nodes examined [
6,
18‐
20]. These modifiable factors serve as surrogate markers for the comprehensive strength of hospital to provide better therapeutic strategy and to benefit the prognosis of patients. In addition, patients-related factors also influence the lymph node examination. Reactive lymphadenopathies and tumor characteristics, for example, represent the immune status of patients [
18]. A worse immune status not only associates with more aggressive treatment and more nodes retrieved, but also associates with higher risk of recurrence and metastasis. However, limitation still exist since it’s hard to improve the survival by surgical resection for tumors with lots of lymph nodes metastasis. In general, adequate lymph node examination remains reasonable to improve survival of patients.
Several studies about identifying the minimum count of lymph nodes have being proposed to correctly classify patients into nodal negative or positive [
20]. Generally, although most recommendations required at least 12 lymph nodes in CC resection, lymph node harvest remained to be highly variable. Mounting evidence have confirmed that age was considered as an independent influencing factor for lymph node examination [
1,
8,
9]. Recently, young patients were noted to have more nodes retrieved in their surgical specimens than older ones [
12,
13]. Furthermore, researchers found that young patients were more likely to have a nodal yield of ≥12 nodes [
11,
21]. Compare with older patients, young-onset CC is characterized by more advanced tumor stage, more aggressive histopathologic features, higher positive rate and more extended resections, which might be the potential reasons for more nodes retrieved [
13]. Interestingly, these results were identical to our previous study [
14]. Our previous study had shown that the median number of lymph node count was decreased with increasing age, which were 25.5, 20.2, 17.8 and 16.9 for patients aged 20–39, 40–59, 60–79, and ≥ 80, respectively (
P < 0.001) [
14]. The decreased node count may result from a stronger immunological response to malignant tumor in young patients and more extended resections compare with older patients [
14]. Although the potential reasons remain undefined, these results remind us that retrieve at least 12 lymph nodes was not enough for young CC patients and 12-node measure need to be revised.
In this study, we explored the optimal cut-off value for CC patients younger than 40 based on the prediction of CSS. Firstly, we identified 22-node measure as the optimal choice for patients aged < 40. According to survival outcome, patients in stage II and stage III could obtain more survival benefit by using 22-node measure. In addition, we identified examining < 22 nodes as an independent adverse prognostic factor for young patients. Compared with the 12-node measure, 22-node measure could more effectively distinguish the prognosis of young CC patients. Finally, 22-node measure changed the migration of N stage. Accordingly, we considered that 22-node measure might be more suitable for young CC patients aged < 40. Besides, we also evaluated the time-dependent changes in lymph node yield from 2004 to 2013 to further evaluate the potential impact of improvements of surgical and pathological techniques on lymph node examination. A significant difference in lymph node yield was observed over time (Additional file
2: Figure S1).
Currently, the SEER is regarded as one of the best population-based databases, and it maintains stringent quality control measures to prevent coding errors. However, there are still defects in this cohort study. Firstly, in univariate and multivariate analysis, the type and distribution of surgery could also be influencing factors of lymph node examination since the minimal invasive operations and open laparotomies could influence the surgical approach and exploration scope. Secondly, detailed information with regard to chemotherapy and radiotherapy were not provided in SEER database, which could also influence the prognosis of CC patients. Finally, we could not avoid the selection biases since this study belonged to retrospective cohort study. Despite these limitations, SEER remains a valuable resource to analyze trends and patterns in patient characteristics, tumor features, cancer treatments as well as survival outcomes.
Conclusion
In conclusion, patients under the age of 40 constitute a minority of all CC patients, but the incidence of CC in this age group has increased over the past decades. Compared with older patients, young patients often retrieved more than 12 nodes. Based on our results, we suggested that patients younger than 40 should examined no less than 22 nodes instead of 12-node measure. However, whether this revised 22-node measure could impact the adjuvant treatment decision-making for young patients, the current study could not provide a satisfactory answer, and more prospective studies focused on this group of patients should be designed in the future.