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10.1245/s10434-006-9322-3
Annals of Surgical Oncology 14:1712-1717 (2007)
© 2007 Society of Surgical Oncology
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Original Article

Prognostic Significance of Metastatic Lymph Node Ratio in Node-Positive Colon Carcinoma

Ho-Young Lee, MD1, Hong-Jo Choi, MD, FACS1, Ki-Jae Park, MD1, Jong-Sok Shin, MD1, Hyuk-Chan Kwon, MD2, Mee-Sook Roh, MD3 and Choongrak Kim, PhD4

1 Department of Surgery, Dong-A University College of Medicine, 3-1 Dongdaeshin-Dong, Seo-GuPusan, 602-714, South Korea
2 Department of Internal Medicine, Dong-A University College of Medicine, Pusan, South Korea
3 Department of Pathology, Dong-A University College of Medicine, Pusan, South Korea
4 Department of Statistics, Pusan National University College of Natural Sciences, Pusan, South Korea

Correspondence: Address correspondence and reprint requests to: Hong-Jo Choi, MD, FACS; E-mail: colonch{at}donga.ac.kr


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: The aim of this study was to evaluate the prognostic significance of the lymph node ratio between metastatic and examined lymph nodes (LNR) in patients with stage III colon cancer.

Methods: A review was made of 201 patients (106 men) with stage III colon cancer of R0 resection. Lymph node (LN) disease was stratified both by the American Joint Committee on Cancer and the International Union Against Cancer nodal staging system (pN) and by quartiles of the LNR. Survival curves were made by Kaplan-Meier analysis and assessed by the log rank test. Multivariate analysis was performed by the Cox proportional hazard model. Patients ranged in age from 22 to 82 (median, 59) years with median follow-up of 52 (range, 13–96) months.

Results: The LNR increased as a function of the number metastatic LNs (P < .0001; 95% confidence interval [95% CI], .7155–.8265). Cutoff points of LNR quartiles to be the best separating patients with regard to 5-year disease-free survival (DFS) were between quartile 1 and 2, and between 3 and 4 (pNr1, 2, and 3); the 5-year DFS according to such stratification was 83.6%, 61.1%, and 20% in pNr1, pNr2, and pNr3, respectively (P < .0001). The Cox model identified the pNr as the most statistically significant covariate: pNr2 was three times (95% CI, 1.407–6.280) and pNr3 eight times more risky than pNr1 (95% CI, 3.739–18.704).

Conclusions: Ratio-based LN staging, which reflects the number of LNs examined and the quality of LN dissection, is a potent modality for prognostic stratification in patients with LN-positive colon cancer.

Key Words: Colon cancer • Metastatic lymph node ratio • Prognostic factor


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
En-bloc surgical resection with draining mesenteric lymph nodes (LNs) remains the definite curative treatment option for colon carcinoma. Identification of LN metastasis is one of the most important factors to predict the likelihood of long-term survival, which is evidenced by the fact that 5-year survival decreases from approximately 80% in patient with stage II colon cancer to 50% with LN metastasis.1,2

In the American Joint Committee on Cancer and the International Union Against Cancer (AJCC/UICC) tumor, node, metastasis (TNM) staging system revised in 2002, the classification of LN metastasis (pN) in patients with stage III colorectal cancer is established on the basis of the number of LN involved (pN1, metastatic node ≤ 3; pN2, metastatic node ≥ 4).3 Total number of LNs collected has been suggested to be an important prognostic variable for outcome.4,5 In this regard, many studies have been performed to determine the optimal number of LNs to be examined to accurately stage nodal disease,6–8 but results showed a high degree of variability, and no definite consensus on the number of LNs to be examined for accurate staging has been made yet. More recent evidence emphasizes the importance of ratio-based LN staging as a predictor of survival, and it has been suggested to be an important prognostic factor in malignancies such as gastric, breast, bladder, and pancreatic cancers.9–14 A recent study also demonstrated the oncologic significance of metastatic LN ratio (LNR) in colon carcinoma.15 This nodal classification may obviate the risk of overstaging or understaging incurred in the pN staging used in the TNM system and may provide more accurate prognostic information from LN involvement.

The aim of this study was to discover whether the ratio between metastatic and examined LNs can predict survival in patients with stage III colon carcinoma.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
From the database of patients who underwent a surgical resection for colorectal cancer under the care of the Department of Surgery, Dong-A University Medical Center, from 1995 through 2001, stage III colon carcinomas where a radical R0 resection was performed were reviewed. This retrospective study, which used formalin-fixed surgical specimens, was approved by the Institutional Review Board of Dong-A University Medical Center. Excluding 2 patients with known familial adenomatous polyposis, 3 with synchronous tumors, 5 in whom fewer than 7 LNs were examined (as recommended by 2002 edition of AJCC/UICC cancer staging system), and 23 with inadequate follow-up data, 201 patients (106 men) were eligible for this study. Postoperative adjuvant chemotherapy using the Mayo Clinic regimen was our standard protocol for patients with stage II or III colon carcinoma. No patient received chemotherapy before surgery.

LN disease was stratified by both AJCC/UICC nodal staging system (pN) and by quartiles of the LNR. The LNR was defined as the number of metastatic LNs divided by the number of retrieved LNs for each patient. We interpreted oncologic outcome in terms of disease-free survival (DFS) rather than overall survival to avoid inherent bias associated with different inhomogeneous treatment options of postoperative metastatic or recurrent diseases, including surgeries and diverse chemotherapeutic modalities. Five-year DFS were made by Kaplan-Meier curves and assessed by the log rank test. To compare the prognostic value of LNR with other factors, multivariate analysis was performed by the Cox proportional hazard model in forward stepwise regression. Patients ranged in age from 22 to 82 (median, 59) years with median follow-up period of 52 (range, 13–96) months.

Data were entered into a spreadsheet and then imported into computer programs for statistical analysis (Prism version 4, GraphPad Software, San Diego, CA; SAS version 8.2, SAS Institute, Cary, NC). Correlation between the number of metastatic LNs and LNR was analyzed by the Pearson correlation coefficient. A simple linear regression test was performed to evaluate how much LNR increases as the number of metastatic LNs increases. Survival curves were calculated by the Kaplan-Meier method and analyzed by the log rank test. To assess the relative prognostic value of covariates associated with 5-year DFS, multivariate analyses were carried out by the Cox proportional hazard regression model. A P value of < .05 was considered statistically significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
A total of 3743 LNs with a median nodal yield of 17 (range, 7–58) per specimen were retrieved and examined, of which 713 (median, 3; range, 1–28) LNs proved to be metastatic. A statistically significant correlation was found between the number of meta-static LNs and LNR (Pearson correlation coefficient, .777; 95% confidence interval [95% CI], .7155–.8265; P < .0001), and a simple linear regression demonstrated that the LNR increases .0344 units as the number of metastatic LNs increases by 1 (95% CI, .0305–.0382; P < .0001). Overall 5-year DFS in this analysis was 57.7%. Essential clinicopathologic characteristics and their corresponding survivals in terms of 5-year DFS are listed in Table 1Go; significance was demonstrated between 5-year DFS and such variables as tumor grade (P = .0096), lymphovascular invasion (P = .0002), and pT and pN stage by AJCC/UICC classification (P = .0026 and.0065, respectively).


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  		TABLE 1. Clinicopathologic characteristics and survival
 
The median LNR in the present study was .16 (mean, .2; range, .01–.92). Patients were stratified into four groups on the basis of quartiles of the LNR to explore if a specific cutoff could affect oncologic outcome. On the basis of Kaplan-Meier plots (Fig. 1Go), cutoff points of quartiles of the LNR considered the best indicator for separating patients with regards to 5-year DFS were between quartiles 1 and 2 (95% CI, .2273–.7441; P = .0033), and between quartiles 3 and 4 (95% CI, .2109–.5998; P = .0001); they were restaged into 3 subgroups (pNr1, 2, and 3; Table 2Go). The 5-year DFS according to this LNR-based staging was 83.6%, 61.1%, and 20% for pNr1, pNr2, and pNr3, respectively (P < .0001; Fig. 2Go). Table 3Go shows that ratio-based staging (pNr) obviously discloses oncologically distinct subgroups within each AJCC/UICC pN1 and pN2 nodal category, and survival by each pNr category between pN1 and pN2 were not statistically different. Probability of stage migration in the AJCC/UICC nodal classification might be inferred from the finding that 5-year DFS of 26.7% for pN1 subgroup with pNr3 is significantly less favorable than that of 75% for pN2 subgroup with pNr2 (hazard ratio, 3.99; 95% CI, .0607–.4940; P = .0010).


Figure 1
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  		FIG. 1. Kaplan-Meier survival curves for 4 groups based on quartiles of distribution of metastatic lymph node ratio. Differences in 5-year disease-free survival between quartiles 1 and 2 and between quartiles 3 and 4 were statistically significant (P = .0033 and .0001, respectively). Q, quartile.

 

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  		TABLE 2. Metastatic lymph node ratio categories
 

Figure 2
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  		FIG. 2. Kaplan-Meier survival curves for ratio-based staging. Five-year disease-free survival was 83.6%, 61.1%, and 20% for pNr1, pNr2, and pNr3, respectively (P < .0001). pNr, ratio-based nodal staging.

 

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  		TABLE 3. Five-year disease-free survival by lymph node ratioa
 
To determine independent prognostic covariates for 5-year DFS, a multivariate analysis by the Cox proportional hazard regression model was performed. Both pN and pNr categories were considered as factors related to nodal status in this model. As shown in Table 4Go, pNr was the strongest prognostic covariate ({chi}2 = 30.7862; P < .0001), followed by lymphovascular invasion ({chi}2 = 10.4807; P = .006) and tumor differentiation ({chi}2 = 5.7538; P = .0165). In addition, evaluation of 95% CI for the relative risk (hazard ratio) at each covariate level also confirmed the strong predictive ability of the pNr: patients with pNr2 were three times at risk of experiencing relapse than patients with pNr1 (95% CI, 1.407–6.280) and pNr3, eight times at risk than patients with pNr1 (95% CI, 3.739–18.704). However, either of the AJCC/UICC pN or pT classification was not found to be an independent prognostic predictor in this model.


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  		TABLE 4. Multivariate analysis of Cox proportional hazard model
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Determination of regional LN status has long been considered the most important factor to predict a likelihood of long-term survival in colon and rectal carcinoma. LN disease in the most recent AJCC/UICC TNM system revised in 2002 is categorized simply according to the number of metastatic LNs present.3 This current nodal staging category of the TNM system, however, is now criticized by the fact that the number of metastatic LNs present may be influenced by the total number of LNs to be examined, and thus the probability of stage migration cannot be ignored.4–8

In an attempt to overcome these shortcomings, LNR, which defines the ratio of the number of metastatic to total number of LNs, has been proposed. This ratio-based nodal staging has been well studied in gastric cancer, and it proved to be better than the number-based AJCC/UICC classification (adopted in 1997) with respect to stage migration in the Japanese literature.9,16,17 Similar results have been also conducted in gastric cancer by European researchers.10,11

To our knowledge, this is the second study demonstrating the significance of the LNR relevant to oncologic prognosis in colon cancer, next to results from Intergroup 0089 data by Berger et al.15 The current study clearly indicated that nodal staging according to the LNR has important oncologic relevance. Findings in Table 3Go, which shows a redistribution of the AJCC/UICC pN stages and the ratio-based pNr stages, strongly suggest that the ratio-based nodal staging reflects the number of LNs examined and the quality of LN dissection, which has already been shown to be one of the most important prognostic factors in colon and rectal cancer.4,8 Considering these data in terms of stage migration, 5-year DFS for pN1 subgroup with pNr3 is 26.7%, which is far less favorable than 75% pNr2 in pN2 subgroup (95% CI, .0607–.4940; P = .0010). This finding strongly implies a probability of stage migration in pN staging that is not currently reflected in the AJCC/UICC classification. Because we only had a single pN2 patient with pNr1 in this study, it is of no worth statistically to compare pNr1 in each of pN1 and pN2 with other pNr categories. The large-scale study by Berger et al.15 demonstrated a similar result; the 5-year overall survival for pN1 patients with an LNR of >40% is much worse (60%) than that for N2 patients with an LNR of <20% (73%). As also is evidenced in gastric cancer, the ratio-based nodal staging greatly decreased the incidence of stage migration.9,17 The ratio-based nodal staging reflects the quality of LNs collected; nevertheless, an adequate number of examined LNs still seems to be important for accurate assessment of nodal disease. In patients in whom fewer than 10 LNs were recovered, the ratio-based nodal staging was not an important prognostic factor, and a minimum of 15 LNs should be examined to obtain an accurate assessment of LN involvement.15

Although the LNR has been emphasized to be an important prognostic factor, quantification should be followed for clinical validity. Contrary to the pN in the AJCC/UICC staging system where uniform categoric parameters are adapted for stratification, no universal categoric division for prognostic stratification has been established yet. In most literature, different levels of cutoff for its staging have been proposed, but the methodologic criteria of how these studies established their cutoff levels has not been described.9–12,14,16,17 Statistically, stratification according to quartiles of distribution seems to be the most sound and has been applied in diverse cancers.13,15,18 To make this study objectively valid, we first divided the ratio into 4 groups on the basis of quartiles of the distribution, and then the ratio above which the 5-year DFS drastically decreased was established as a cutoff point on the basis of Kaplan-Meier plots and log rank test. Further larger-scale investigations are imperative to establish a specific valid cutoff point of the LNR for prognostic stratification before this method can be routinely used in a clinical setting.

In this study, we compared the prognostic determinant of the number-based pN together with the ratio-based pNr. From the multiple stepwise regression analysis with the Cox proportional hazard model, the pNr was selected as the most important prognostic covariate, but the pN did not have an independent influence on DFS. Inoue et al.17 and Bando et al.9 also demonstrated that ratio-based nodal classification in gastric cancer was the only independent prognostic factor when a model including other nodal classifications was applied. When the effect of LNR according to the number of LNs examined was analyzed in colon cancer, the LNR was the most important prognostic factor in intermediate (10–15) and high (>15) LN count patients.15 Therefore, nodal classification according to the LNR is considered a better prognostic determinant than the number-based AJCC/UICC system. It is of note that pT was not an independent covariate for survival in this analysis either. Some biases inherent in retrospective study might intervene. The present study analyzed cases with positive LN metastasis only and found that T stage was not evenly distributed; most cases (83%) were T3 (no T1; T2, 11.4%; T4, 5.5%).

In conclusion, the ratio-based LN staging can be considered a simple and reproducible modality to assess prognosis of patients who underwent potentially curative radical resection for LN-positive colon cancer. Establishment of appropriate cutoff value of the LNR for prognostic stratification in colon cancer awaits further prospective large-scale studies.


   ACKNOWLEDGMENTS
 
C.K. was supported by a Korea Research Foundation grant, funded by Korea Government (MO-EHRD, Basic Research Promotion Fund, grant KRF-2005-070-C00020).

Received for publication October 20, 2006. Accepted for publication November 27, 2006.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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