At present, the most widely used lymph node (LN) staging system in colon cancer is number of metastatic LNs in pathological assessment (pN) from the 8th edition of the TNM American Joint Committee on Cancer/Union for International Cancer Control staging system, which considers the number of metastatic LNs, omitting the total number of dissected LNs. The aim of the present study was to compare the prognostic performance of pN with alternative LN staging systems, including LN ratio (LNR) and log odds of positive LNs (LODDS). The clinical and histopathological data of 298 patients with colon cancer who underwent elective surgical resection in a single surgical centre were analysed. LNR and LODDS cut-off values according to two previous studies were selected to separate patients into different subgroups. Univariate and multivariate analyses were performed to distinguish prognostic factors. The three-step multivariate analysis showed that LNR was a superior prognostic indicator compared with pN and LODDS. Additionally, the Akaike Information Criterion, a measure of the relative quality of statistical models, confirmed that LNR displayed the best prognostic performance. Similarly, in a subpopulation of patients with number of dissected LNs (NDLN) ≥12, LNR was the most accurate LN staging system in relation to prognosis. In a subpopulation with NDLN <12, there was no significant difference in LN classification prognosis of 5-year overall survival; however, LNR and LODDS were more independent of NDLN than pN. Among the three LN classifications, LNR is the most accurate LN staging system for predicting prognosis for patients with colon cancer who have undergone surgical resection, particularly those with metastatic LNs subjected to adequate lymphadenectomy.
Lymph node (LN) status is a key prognostic factor in colon cancer (
Evaluation of LN status based only on the number of metastatic LNs and omitting the total number of dissected LNs (as in pN) may be insufficient and lead to understaging. For that reason, two novel systems analysing not only the number of positive LNs, but also number of dissected LNs (NDLNs) were developed: LN ratio (LNR) (
The aim of the present study was to compare three LN staging systems in patients with colon cancer who underwent elective tumour resection.
The present study recruited 298 patients who were operated on between September 2006 and May 2014 in the Department of Oncological Surgery, Gdynia Centre of Oncology, Pomeranian Hospitals, Poland. The inclusion criteria were as follows: Patients aged >18 years; histologically proven adenocarcinoma of the colon; curative surgical tumor resection and minimal follow-up period of 65 months or until death. Patients with
LN status according to pN from TNM staging system is defined by the number of metastatic LNs (
LNR is defined as the ratio of metastatic to examined LNs. Previous studies used distinct methods to determine LNR cut-off values to discriminate patients by their prognosis, with only a few studies using statistical methods (
LODDS is the log of the ratio between the numbers of positive and negative LNs: loge [(pN + 0.5)/(nN + 0.5)], where pN is the number of positive LNs and nN is the number of negative LNs and 0.5 is added to both the numerator and denominator to avoid an infinite value. In the present study, cut-off values determined statistically by Zhang
Statistical analysis was performed using Statistica (version 13; TIBCO Software, Inc.). Pearson's χ2 test was performed to evaluate the association between clinical and histopathological parameters and investigate the LN staging systems. Univariate analysis of survival was performed using the Kaplan-Meier method and differences in survival rates between subgroups were compared using log-rank test. The end point of the present study was 5-year overall survival (OS). A multivariate analysis was conducted using the Cox proportional hazard model. The three-step multivariate analysis was applied to assess the prognostic discriminating power of different LN staging systems. In step one, all relevant factors from the univariate analysis were encompassed, including pN, but excluding LNR and LODDS. In step 2, LODDS was added, but not LNR. In step 3, all three LN classifications were included. Additionally, Akaike Information Criterion (AIC) was used to assess which model fit best. Principally, the predictive model with the lowest AIC displayed the best fit. The correlation between different LN classifications was analysed using Pearson correlation coefficient. P<0.05 was considered to indicate a statistically significant difference.
The results of the univariate analysis of survival and 5-year OS rates are presented in
Further analysis was performed in subpopulations of patients with NDLN ≥12 and <12. In univariate analysis in both subpopulations, all three LN classifications were significant prognostic factors. In the multivariate analysis of patients with NDLN≥12, the best LN staging system was LNR. In the multivariate analysis of patients with NDLN<12, when all three LN classifications were included, none of them displayed significant differences between levels of staging. However, when 5-year OS (according to pN) was directly compared in subgroups pN1b and pN2a, the prognosis was significantly worse in patients with inadequate lymphadenectomy (NDLN<12) compared with that in patients with adequate lymphadenectomy (NDLN≥12;
The prognostic value of LNR and LODDS have been investigated and proven by numerous researchers (
Numerous studies have investigated the prognostic value of each LN staging system assessed in the present study, but few surveys that have directly compared the three staging systems (
Fang
Pei
As aforementioned, the most suitable cut-off values for LNR and LODDS are still under discussion. In the present study, cut-off values developed by Rosenberg
A scatter plot demonstrated an association between LODDS and LNR. LODDS value was heterogeneous only when LNR was close to 0 or 1. This indicated that LODDS was particularly valuable in patients without metastatic LNs because when LNR and pN for all patients was 0, LODDS classification still divided patients into subgroups with different prognoses.
The present study has certain limitations because it was single centre retrospective study that included a relatively limited number of patients. Therefore, multicentre studies on larger populations of patients should be performed to verify the present conclusions. Patients without metastatic LNs could not be used for full analysis of prognosis according to LODDS due to small sample size of LODDS subgroups. Therefore, further studies on larger populations of patients are required to test the prognostic value of LOODS in pN0 patients operated on for colon adenocarcinoma.
In conclusion, the present study indicated that LNR is the most accurate LN staging system for predicting prognosis for patients with colon cancer who have undergone surgical resection, especially those with metastatic LNs subjected to adequate lymphadenectomy. Due to the limitations of LNR in pN0 patients and the promising prognostic results for LODDS, further studies are required in this group. Subsequent studies should also be performed to investigate patients with NDLN <12, as LNR or LODDS might be more suitable in estimating prognosis in this group than LN staging using pN from TNM.
Not applicable.
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
AMM conceptualized and designed the present study, collected and interpreted data and drafted the manuscript. MS analysed the data, generated figures and tables and drafted the manuscript. WJK conceived the study and revised the manuscript. AMM and MS confirm the authenticity of all the raw data. All authors have read and approved the final manuscript.
The present study was approved by the Independent Ethics Committee of the Regional Medical Chamber in Gdańsk (approval no. KB-2/20). Due to the retrospective design of the study based on data analysis, the requirement for informed consent was waived.
Not applicable.
The authors declare that they have no competing interests.
lymph node
lymph node ratio
log odds of positive lymph nodes
American Joint Committee on Cancer/Union for International Cancer Control
Akaike Information Criterion
number of dissected lymph nodes
Kaplan-Meier curves of 5-year overall survival for patients stratified by pN, according to pTNM 8th edition American Joint Committee on Cancer/Union for International Cancer Control staging system.
Kaplan-Meier curves of 5-year overall survival for patients stratified by LNR. LNR, lymph node ratio.
Kaplan-Meier curves of 5-year overall survival for patients stratified by LODDS. LODDS, log odds of positive LNs.
Scatter plot of the distribution of LNR vs. number of metastatic LNs (r=0.77, P<0.001). LN, lymph node; LNR, LN ratio.
Scatter plot of the distribution of LNR vs. LODDS (r=0.9, P<0.001). LNR, lymph node ratio; LODDS, log odds of positive lymph nodes.
Univariate survival analysis.
Parameter | n | 5-year OS probability | P-value |
---|---|---|---|
Age, years (median, 71 years) | 0.0005 | ||
≤71 | 156 | 0.75 | |
>71 | 142 | 0.57 | |
Sex | |||
Female | 143 | 0.69 | 0.5000 |
Male | 155 | 0.65 | |
Location | 0.4000 | ||
Right colon | 138 | 0.68 | |
Left colon | 160 | 0.65 | |
Depth of invasion, pT | 0.0200 | ||
1 + 2 | 50 | 0.80 | |
3 + 4a + 4b | 248 | 0.64 | |
pN | <0.0001 | ||
pN0 | 181 | 0.80 | |
pN1a | 27 | 0.66 | |
pN1b | 49 | 0.46 | |
pN2a | 17 | 0.35 | |
pN2b | 24 | 0.29 | |
LNR | <0.0001 | ||
LNR0 | 182 | 0.80 | |
LNR1 | 51 | 0.62 | |
LNR2 | 32 | 0.43 | |
LNR3 | 21 | 0.33 | |
LNR4 | 12 | 0.08 | |
LODDS | <0.0001 | ||
LODDS1 | 190 | 0.79 | |
LODDS2 | 78 | 0.55 | |
LODDS3 | 30 | 0.23 | |
Distant metastasis | <0.0001 | ||
M0 | 274 | 0.71 | |
M1a + 1b + 1c | 24 | 0.20 | |
Number of nodes retrieved by lymphadenectomy | 0.1000 | ||
<12 | 123 | 0.62 | |
≥12 | 175 | 0.70 | |
World Health Organization histological grade | 0.0200 | ||
G1 + G2 | 264 | 0.69 | |
G3 + G4 | 34 | 0.50 |
pN, pN from pTNM; LODDS, Log odds of positive lymph nodes; LNR, lymph node ratio.
Classification of LN staging systems.
A, pN | |
---|---|
Stage | Value (number of metastatic LN) |
pN0 | 0 |
pN1a | 1 |
pN1b | 2-3 |
pN1c | No metastatic LN but there are tumor deposits |
pN2a | 4-6 |
pN2b | ≥7 |
LNR0 | 0.00 |
LNR1 | 0.01-0.17 |
LNR2 | 0.18-0.41 |
LNR3 | 0.42-0.69 |
LNR4 | ≥0.70 |
LODDS1 | <-2.18 |
LODDS2 | -(2.18-0.23) |
LODDS3 | >-0.23 |
The pN classification was obtained from 8th edition of the TNM American Joint Committee on Cancer/Union for International Cancer Control. LNR classification was obtained from Rosenberg
Three-step multivariate analysis (Cox proportional hazards model).
Model 1 | Model 2 | Model 3 | |||||||
---|---|---|---|---|---|---|---|---|---|
Parameter | HR | 95% CI | P-value | HR | 95% CI | P-value | HR | 95% CI | P-value |
Median age, years | 0.45 | −1.220–0.380 | 0.0001 | 0.40 | −1.330–0.480 | <0.0001 | 0.37 | −1.410–0.550 | <0.0001 |
World Health | 1.57 | −0.080-0.980 | 0.0900 | 1.55 | −0.090-0.970 | 0.1000 | 1.67 | −0.010-1.050 | 0.0500 |
Organization histological grade | |||||||||
Depth of invasion, pT | 1.28 | −0.420-0.920 | 0.4600 | 1.52 | −0.260-1.100 | 0.2000 | 1.52 | −0.250-1.100 | 0.2000 |
Distant metastasis, M | 4.54 | 0.960-2.060 | <0.0001 | 3.84 | 0.770-1.910 | <0.0001 | 3.41 | 0.660-1.800 | <0.0001 |
pN from pTNM | 1.01 | 0.005-0.010 | <0.0001 | 1.00 | −0.002-0.009 | 0.3000 | 0.99 | −0.007-0.006 | 0.8000 |
LODDS | - | - | - | 1.87 | 0.200-1.040 | 0.0030 | 0.89 | −0.740-0.530 | 0.7000 |
LNR | - | - | - | - | - | - | 1.88 | 0.200-1.050 | 0.0030 |
LODDS, Log odds of positive lymph nodes; LNR, lymph node ratio.
Univariate analysis of 5-year OS depending on extent of lymphadenectomy.
A, pN | |||
---|---|---|---|
5-year OS probability | |||
Parameter | NDLN<12 | NDLN≥12 | P-value |
pN0 | 0.77 | 0.83 | 0.40 |
pN1a | 0.62 | 0.68 | 0.80 |
pN1b | 0.30 | 0.60 | 0.02 |
pN2a | 0.11 | 0.62 | 0.02 |
pN2b | 0.40 | 0.26 | 0.70 |
LNR0 | 0.76 | 0.83 | 0.30 |
LNR1 | 0.57 | 0.63 | 0.70 |
LNR2 | 0.31 | 0.61 | 0.10 |
LNR3 | 0.42 | 0.28 | 0.80 |
LNR4 | 0.12 | <0.001 | 0.10 |
LODDS1 | 0.75 | 0.81 | 0.4 |
LODDS2 | 0.51 | 0.58 | 0.5 |
LODDS3 | 0.21 | 0.25 | 0.6 |
LNR, lymph node ratio; LODDS, log odds of positive lymph nodes; OS, overall survival.