Jinseok Hwang and Donghyoun Lee contributed equally to this work.
Various clinical practice guidelines recommend at least 12 regional lymph nodes should be removed for resected colon cancer. According to a recent study, the lymph node yield (LNY) in colon cancer surgery in the last 20 years has tended to increase from 14.91 to 21.30. However, it is unclear whether these guidelines adequately reflect recent findings on the number of harvested lymph nodes in colon cancer surgery. The aim of this study is to assess the impact of an LNY of more than 25 on survival in right-sided colon cancer.
We included 285 patients who underwent a right hemicolectomy during the period from January 2010 through December 2015. Patients were divided into two groups (<25 nodes and ≥25 nodes). Primary endpoints included 5-year and 10-year survival including disease-free and overall.
We found that survival outcomes of patients with a harvest of ≥25 nodes were not significantly different compared with a <25 group. Large tumor size (5 cm) is significantly associated with poor 5-year and 10-year overall survival.
Survival outcomes of patients with a harvest of ≥25 nodes were not significantly different compared with the <25 group in stage II colon cancer with no risk.
Colon cancer is the third most common malignant disease in the world with an estimated 1.1 million cases diagnosed in 2020 [
There have been multiple studies addressing the optimal number of harvested lymph nodes in colon cancer [
To date, few studies have investigated lymph node cut values of more than 20. However, it is unclear whether the current guidelines reflect the recent findings on the effectiveness of the resection of an increased number of lymph nodes. The aim of this study was to assess the impact of an LNY of more than 25 on survival in right-sided colon cancer stage II with no risk factors.
We included 285 patients who underwent a right or extended right hemicolectomy with D3 lymphadenectomy in stage II colon cancer (according to the 6th AJCC) during the period from January 2010 through December 2015. In this retrospective study, D3 dissection was mandatory in all patients who underwent elective right or extended right hemicolectomy. Surgeons in the unit followed a standardized operative approach for D3 dissection. Surgeons in the unit followed a standardized operative approach for D3 dissection. All patients had pathologically confirmed adenocarcinoma or mucinous adenocarcinoma, with tumor grade categorized as well differentiated, moderately differentiated, poorly differentiated, or undifferentiated. Colon cancer was evaluated as right-sided colon cancer including cecum, ascending colon, hepatic flexure, and transverse colon. The number of harvested lymph nodes was evaluated and recorded.
Exclusion criteria were as follows: double primary cancer, severe comorbidity as judged by an American Society of Anesthesiologists score of 4, patients who underwent an emergency operation, surgery with palliative intent, history of another malignancy, history of transplantation surgery, or colonic perforation or obstruction.
All patients had routine follow-up every 3 to 6 months for 10 years postoperatively with serial measurement of serum tumor markers including carbohydrate antigen 19-9 and carcinoembryonic antigen. Abdominopelvic and chest computed tomography scans were performed annually in addition to colonoscopy as deemed clinically appropriate. Follow-up was defined as the time from the date of primary surgery to a patient event, such as disease recurrence or death. There was no minimum duration of follow-up.
The study was approved by the Institutional Review Board of Samsung Medical Center (IRB No. SMC 2021-01-111-001) and performed in accordance with the principles of the Declaration of Helsinki. The informed consent was waived because this study design is a retrospective review.
After resection of the colon, specimens were fixed overnight in 10% formalin for at least 24 hours. After fixation, the mesenteric adipose tissue was separated into thin slices (4 μm thick) and lymph nodes were sampled. After conventional histological staining with hematoxylin and eosin, the lymph nodes were microscopically inspected for the presence of metastasis. To analyze microsatellite instability (MSI), DNA was extracted from the tumor and from paraffin-embedded paired normal tissue. Two mononucleotide repeat markers (BAT25 and BAT26) and three dinucleotide markers (D5S346, D2S123, and D17S250) were used to determine microsatellite status following amplification using the polymerase chain reaction [
The three main points of interest consist of the LNY per patient, recurrence of disease, and patient death. Patients were separated into two groups according to the number of harvested lymph nodes as follows: lymph node numbers from 0 to 24 and lymph node numbers ≥25. Patients were also grouped according to size of tumor into larger tumor (≥5 cm) and smaller tumor (<5 cm) groups. Overall survival (OS) was defined as the interval between the diagnosis date and time of death for any reason or the last follow-up. Disease-free survival (DFS) was measured from the date of surgery to the date of recurrence. Kaplan-Meier analysis was used to estimate the survival difference between the different subgroups. After surgery for the primary tumor, patients who developed local recurrence or metastasis were no longer considered disease free for statistical analysis. Patients who died at any time, for any reason, after surgery were counted as deaths in OS analysis. The chi-square test (Fisher test in small samples) was used to compare two qualitative samples in univariate analysis. Multivariate Cox proportional hazard model was used to evaluate the relationship between patient characteristics, tumor size, LNY, and survival including DFS and OS. Two-sided P<0.05 was considered statistically significant. All statistical analyses were performed using a standard software package (Stata, version 16.0; StataCorp, College Station, TX, USA).
A total of 1,992 patients who underwent right or extended right hemicolectomy in stage II colon cancer between 2010 and 2015 were identified in our hospital. Of these, 1,627 patients were excluded due to having risk factors, including lymphovascular or perineural invasion. Sixty-one patients were excluded due to obstruction by cancer. A total of 1,707 patients were excluded from our study because they met the exclusion criteria. Finally, 285 patients with no risk factors remained eligible for analysis. Of these, 169 patients (59.3%) underwent right hemicolectomy and 116 patients (40.7%) underwent extended right hemicolectomy. The median follow-up period and range was 65 months. Median age at diagnosis was 61.8 years, standard deviation (SD) 12.8 years. A total of 55.7% of patients were male. There were no significant differences as regards age, sex, body mass index (BMI), and other variables. The baseline characteristics of patients who underwent right hemicolectomy are summarized in
The results of this study showed that stage II right-sided colon cancer with no risk factors, even if the number of nodes was more than 25, was not related to survival. Since the 1990s, many studies have shown that LNY is associated with patient survival [
However, it is unclear whether these guidelines adequately reflect recent findings on the number of harvested lymph nodes in colon cancer surgery. According to a recent study, the LNY in colon cancer surgery in the last 20 years has tended to increase from 14.91 to 21.38 [
A recent study showed that LNY of 20 or more was associated with better survival outcomes [
Several studies investigated the change of node positivity as a result of increasing LNY [
It is well-known that tumor size is a predictor of LNY [
Before proposing a potential hypothesis to explain these findings, several confounders need to be taken into accounts. First, it can be assumed that although recurrence occurred, members of the small tumor size group survived longer. There is little research on whether the tumor size at first surgery influences chemotherapy in recurrent colon cancer. In our opinion, further research is necessary to answer this question. Second, our research used data from the Korean National Health Insurance Service and Statistics Korea to measure mortality. In the case of patients who died from causes other than cancer, it was difficult to accurately determine whether the cause of death was related to colon cancer. Due to this potential bias of data in our study, more research is required to explain the inconsistent discrepancy between DFS and OS.
We also examined the MSI status of right-sided cancers. MSI analysis of the 225 colon cancers revealed 83 (29.12%) cases of MSI-high cancer. It is well-known that MSI tumors are located predominantly in the right colon and tend to appear poorly differentiated [
To the best of our knowledge, the present study is the first to explore the significance of a cutoff value of 25 in colon cancer. Recent studies report outcomes that are similar to our study [
There are several limitations to the current study. First, these data are retrospective and there may be inherent biases which we attempted to control. Second, the surgeries were performed by many surgeons and the pathologic examination involved many pathologists. Third, as noted above, this research used data from Statistics Korea and the Korean National Health Insurance Service to measure mortality. It is possible that we had a measurement error when a person with colon cancer died of non-cancer disease.
In conclusion, survival outcomes of patients with a harvest of more than 25 nodes were not significantly different compared with the <25 group in stage II colon cancer with no risk factors. Nonetheless, the findings of our study should not compel surgeons to maximize LNY. These findings should be validated in other stages of colon cancer in larger prospective studies.
No potential conflict of interest relevant to this article was reported.
Five-year disease-free survival (DFS) and overall survival (OS) rates of patients with stage II colon cancer without risk factors. LNY, lymph node yield; KM, Kaplan-Meier.
Ten-year disease-free survival (DFS) and overall survival (OS) rates of patients with stage II colon cancer without risk factors. LNY, lymph node yield; KM, Kaplan-Meier.
Baseline characteristics of 285 patients who underwent right hemicolectomy
Variable | Total | No. of LN <25 (n=123) | No. of LN ≥25 (n=162) | P-value |
---|---|---|---|---|
Age (yr), mean±SD | 61.80±12.83 | 63.34±11.69 | 60.70±13.51 | 0.01 |
| ||||
Sex | 0.88 | |||
Male | 159 | 68 | 91 | |
Female | 126 | 55 | 71 | |
| ||||
ASA score | 0.27 | |||
1 | 160 | 67 | 93 | |
2&3 | 125 | 56 | 69 | |
| ||||
Preoperative CEA (ng/mL), mean±SD | 4.87±18.20 | 3.25±4.11 | 6.10±2.01 | 0.22 |
| ||||
Type of surgery | ||||
Right hemicolectomy | 169 | 74 | 95 | 0.06 |
Extended right hemicolectomy | 116 | 49 | 67 | |
| ||||
Surgical approach | 0.40 | |||
Laparoscopic (conventional+single port) | 217 | 72 | 99 | |
HALS | 42 | 36 | 50 | |
Open | 25 | 14 | 11 | |
Robotic | 1 | 1 | 0 | |
| ||||
Follow-up time (mo), mean±SD | 75.00±63.50 | 75.13±32.03 | 74.93±31.16 | 0.13 |
| ||||
Follow-up overall mortality 5 yr | 14 | 8 | 6 | 0.28 |
| ||||
Follow-up recurrence 5 yr | 10 | 3 | 7 | 0.39 |
| ||||
Follow-up overall mortality 10 yr | 18 | 14 | 10 | 0.11 |
| ||||
Follow-up recurrence 10 yr | 10 | 5 | 7 | 0.91 |
LN, lymph node; SD, standard deviation; ASA, American Society of Anesthesiology; CEA, carcinoembryonic antigen; HALS, hand assisted laparoscopic surgery.
Pathologic and genetic characteristics of patients who underwent right hemicolectomy
Variable | Total | No. of LN <25 (n=123) | No. of LN ≥25 (n=162) | P-value |
---|---|---|---|---|
No. of harvested LN, mean±SD | 27.40±11.00 | 18.01±3.80 | 34.60±91.00 | |
| ||||
Margin (cm), mean±SD | ||||
Proximal | 14.30±8.76 | 15.30±9.22 | 13.50±8.33 | 0.09 |
Distal | 15.18±7.98 | 15.70±8.00 | 14.70±7.96 | 0.27 |
| ||||
Site of tumor | ||||
Cecum (including appendix) | 49 | 24 | 25 | |
Ascending (including hepatic flexure) | 159 | 67 | 92 | |
Transverse colon | 77 | 32 | 45 | |
| ||||
Histologic type | 0.59 | |||
Well | 85 | 35 | 50 | |
Moderate | 184 | 82 | 102 | |
Poor | 11 | 3 | 8 | |
Mucinous | 4 | 2 | 2 | |
Signet | 1 | 1 | 0 | |
| ||||
Tumor size (5 cm cutoff) | <0.001 | |||
Small | 153 | 82 | 71 | |
Large | 132 | 41 | 91 | |
| ||||
T stage | 0.81 | |||
T3 | 254 | 108 | 146 | |
T4a | 21 | 11 | 10 | |
T4b | 10 | 4 | 6 | |
| ||||
Diabetes mellitus | 0.43 | |||
Yes | 40 | 15 | 25 | |
No | 245 | 108 | 137 | |
| ||||
Hypertension | 0.12 | |||
Yes | 97 | 48 | 49 | |
No | 188 | 75 | 113 | |
| ||||
MS status | <0.001 | |||
MSS | 202 | 100 | 102 | |
MSI (high+low) | 83 | 23 | 60 |
LN, lymph node; SD, standard deviation; MS, microsatellite; MSS, microsatellite stable; MSI, microsatellite instability.
Univariate analysis of clinicopathological factors influencing DFS
Variable | Number | 5-Year DFS (%) | P-value | 10-Year DFS (%) | P-value |
---|---|---|---|---|---|
Sex | 0.30 | 0.31 | |||
Male | 159 | 96.1 | 96.9 | ||
Female | 126 | 97.0 | 94.4 | ||
| |||||
Age | 0.97 | 0.90 | |||
≥65 yr | 141 | 96.5 | 95.8 | ||
<65 yr | 144 | 96.4 | 95.7 | ||
| |||||
Histologic type | 0.71 | 0.47 | |||
Well or moderately differentiated | 269 | 96.7 | 95.9 | ||
Poorly differentiated | 11 | 90.9 | 90.9 | ||
Mucinous | 4 | 100 | 100 | ||
Signet ring cell | 1 | 100 | 100 | ||
| |||||
Tumor size (5 cm cutoff) | 0.68 | 0.79 | |||
Small | 100 | 96.1 | 96.1 | ||
Large | 185 | 95.5 | 97.0 | ||
| |||||
MS status | 0.03 | 0.02 | |||
MSS | 202 | 95.1 | 94.1 | ||
MSI (high+low) | 83 | 100 | 100 | ||
| |||||
T stage | 0.14 | 0.27 | |||
T3 | 254 | 97.2 | 96.5 | ||
T4a | 20 | 90.0 | 90.0 | ||
T4b | 11 | 90.9 | 90.9 | ||
| |||||
No. of harvested lymph nodes | 0.38 | 0.91 | |||
<25 | 123 | 97.6 | 95.9 | ||
≥25 | 162 | 95.7 | 95.7 |
DFS, disease-free survival; MS, microsatellite; MSS, microsatellite stable; MSI, microsatellite instability.
Univariate analysis of clinicopathological factors influencing OS
Variable | Number | 5-Year OS (%) | P-value | 10-Year OS (%) | P-value |
---|---|---|---|---|---|
Sex | 0.55 | 0.18 | |||
Male | 159 | 95.8 | 93.8 | ||
Female | 126 | 94.3 | 89.4 | ||
| |||||
Age | 0.90 | 0.80 | |||
≥65 yr | 141 | 95.8 | 93.8 | ||
<65 yr | 144 | 94.3 | 89.4 | ||
| |||||
Histologic type | 0.31 | 0.18 | |||
Well or moderately differentiated | 269 | 95.7 | 92.6 | ||
Poorly differentiated | 11 | 92.3 | 84.6 | ||
Mucinous | 4 | 84.6 | 76.9 | ||
Signet ring cell | 1 | 100 | 100 | ||
| |||||
Tumor size (5 cm cutoff) | 0.16 | 0.30 | |||
Small | 100 | 96.7 | 94.8 | ||
Large | 185 | 93.2 | 87.9 | ||
| |||||
MS status | 0.21 | 0.16 | |||
MSS | 202 | 94.1 | 90.1 | ||
MSI (high+low) | 83 | 97.6 | 95.2 | ||
| |||||
T stage | 0.30 | 0.43 | |||
T3 | 254 | 95.3 | 91.7 | ||
T4a | 20 | 95 | 95 | ||
T4b | 11 | 90 | 81 | ||
| |||||
No. of harvested lymph nodes | 0.28 | 0.11 | |||
<25 | 123 | 93.5 | 88.6 | ||
≥25 | 162 | 96.3 | 93.8 |
OS, overall survival; MS, microsatellite; MSS, microsatellite stable; MSI, microsatellite instability.
Multivariate analysis (Cox proportional hazard model) of prognostic factors
Variable | 5-Year DFS | 5-Year OS | ||||||
---|---|---|---|---|---|---|---|---|
|
| |||||||
DFS (%) | HR | 95% CI | P-value | OS (%) | HR | 95% CI | P-value | |
No. of harvested lymph node | ||||||||
<25 (n=123) | 97.6 | 1.00 | - | 93.5 | - | |||
≥25 (n=162) | 95.7 | 2.51 | 0.63–9.96 | 0.19 | 96.3 | 0.67 | 0.21–2.08 | 0.49 |
| ||||||||
Tumor size | ||||||||
<5 cm | 96.1 | 1.00 | - | 96.7 | - | |||
≥5 cm | 97.0 | 1.03 | 0.28–3.78 | 0.95 | 93.2 | 3.09 | 1.00–9.49 | 0.04 |
DFS, disease-free survival; OS, overall survival; HR, hazard ratio; CI, confidence interval.
Adjusted for gender, age, body mass index, tumor size and variables listed.
Multivariate analysis (Cox proportional hazard model) of prognostic factors
Variable | 10-Year DFS | 10-Year OS | ||||||
---|---|---|---|---|---|---|---|---|
|
| |||||||
DFS (%) | HR | 95% CI | P-value | OS (%) | HR | 95% CI | P-value | |
No. of harvested lymph node | ||||||||
<25 (n=123) | 95.9 | 1.00 | 88.6 | - | ||||
≥25 (n=162) | 95.6 | 1.37 | 0.42–4.46 | 0.59 | 93.8 | 0.58 | 0.24–3.61 | 0.23 |
| ||||||||
Tumor size | ||||||||
<5 cm | 96.1 | 1.00 | 94.7 | - | ||||
≥5 cm | 95.5 | 1.77 | 0.55–5.60 | 0.97 | 87.9 | 4.16 | 1.69–10.26 | 0.002 |
DFS, disease-free survival; OS, overall survival; HR, hazard ratio; CI, confidence interval.
Adjusted for gender, age, body mass index, tumor size and variables listed.