Prognostic value of lymph node density on Cancer Staging System for non-metastatic gastric cancer: a population-based analysis of SEER database

DOI: https://doi.org/10.21203/rs.3.rs-1790097/v1

Abstract

Background

Accurate tumor staging is the cornerstone of tumor treatment. Current tumor staging system for gastric cancer (GC) is based on regional positive lymph nodes while ignoring the total number of examined lymph nodes. We aim to assess the prognostic value of lymph node density (LND), the ratio of positive nodes to the total number examined nodes, in non-metastatic GC.

Methods

Clinical information of patients with histologically confirmed GC and without distal metastasis was identified from the Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2015. The X-Tile software was used to identify the ideal prognosis-related cutoff point for LND. The prognostic value of LND on cancer-specific survival (CSS) and overall survival (OS) was assessed in Cox regression models. Subgroup analysis stratified by LND was performed on current lymph node staging system to further explore the interaction between LND and current lymph node staging system.

Results

A total of 4281 participants were identified from the SEER database for the final analysis. The optimal prognosis-related cutoff values of LND were calculated as 0.1 and 0.4, and LND was divided into three levels. The higher level of LND was associated with worse CSS and OS in GC patients. Compared to patients with the lower level of LND, those with the middle and higher level of LND had 2.43 (HR = 2.43, 95% CI 2.09–2.84, P < 0.001) and 4.69 (HR = 4.69, 95% CI 4.02–5.48, P < 0.001) folds increase in mortality in CSS, respectively. Similar results were found in the evaluation of OS in GC patients. Subgroup analysis stratified by LND also found that patients in the same current lymph node stage still had different prognosis due to the different LND levels after adjustment for other prognosis-related covariates (all P values < 0.001).

Conclusion

LND is an independent prognostic factor for non-metastatic GC. In the current lymph node staging system, LND has potential value in further accurately classifying non-metastatic GC patients.

Background

Gastric cancer (GC) is the fourth most commonly diagnosed cancer on the upper digestive system and remains the second most common cause of cancer-related deaths worldwide [1]. Cancer staging is the cornerstone of successful tumor therapy after surgery. Today, the American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) classification is the most widely used staging system for GC [2, 3]. Lymph node staging system, also defined as N category, is an essential factor for predicting prognosis and selecting the appropriate treatment [4]. In the AJCC staging system, only the number of positive regional nodes is taken into account and the number of the total examined regional nodes does not get enough attention [5, 6]. However, GC patients with same number of regional positive nodes accompanying with more total regional nodes examined tend to have a higher level of radical gastrectomy and lower risk with the residual tumor [7, 8]. New attempt and exploring an evaluating criterion of the lymph node staging system is needed.

Several studies have demonstrated that GC patients with more examined regional nodes were more likely to have better survival because they tended to have a higher level of radical gastrectomy [911]. With the development of surgical techniques, obtaining and examining an increasing number of total regional nodes is no longer difficult for an experienced surgeon. Lymph node density (LND), also called lymph node ratio (LNR), is calculated by the ratio of the number of positive nodes to the total examined nodes [12, 13]. This parameter has been proven as a potential prognostic factor in several cancers, including GC [1416]. From the 7th edition (the year 2010) of the AJCC staging system, resection of at least 16 regional lymph nodes was introduced into the guideline of GC surgery [17]. The number of lymph node dissection before 2010 was small, usually less than 15, and previous studies of LND in GC were limited because they enrolled the patients both before and after 2010 [16, 18]. The prognostic value of LND needs to be reassessed by only using data after 2010, which is same as the current lymph node dissection standard.

In the present study, we determined the impact of LND on cancer-specific survival (CSS) and overall survival (OS) in GC patients based on data after 2010 in the Surveillance, Epidemiology, and End Results (SEER) database. We hypothesize that LND is an independent prognostic factor in GC. The interaction between LND and current lymph node staging system was detected to provide evidence for the development of a novel accurate lymph node staging strategy.

Methods

Patients and data

This study had a retrospective design and included data from patients with histologically confirmed GC from the SEER database. Data were recorded according to the third edition of the International Classification of Diseases for Oncology. Enrollment occurred between 2010 and 2015, during which period the 7th AJCC staging strategies were applied and the follow-up and treatment information was complete. Patients were included if they were older than 18 years and had undergone gastrectomy. Patients with neoadjuvant radiotherapy were removed from the analysis, and only those with a histological type of adenocarcinoma were enrolled. Patients with incomplete data regarding tumor location or staging information were also excluded from the analysis. The primary variable in this study was lymph node data and patients lacking information regarding the exact number of nodes examined or positive nodes were not included in the analysis. The patient screening process is shown in Fig. 1. Finally, a total number of 4,281 patients with GC were included for analysis in the present study.

The following available information on pathological and clinical appearance was collected from data-mining: age at diagnosis, sex, year of diagnosis, race, marital status at diagnosis, insurance status, primary site, 7th AJCC stage group information, grade, chemotherapy, lymph node data, cause-specific death classification, vital status recode, and survival moths. Overall survival (OS) was determined with the vital status recode and survival months, while cancer-specific survival (CSS) was calculated with the cause-specific death classification and survival months. Informed consent was not obtained for the present study because of the open-source nature of the SEER database. This study was conducted in accordance with the Declaration of Helsinki.

Statistical Analyses

LND was calculated by the ratio between the number of positive nodes and the number of examined nodes. Means were calculated for continuous variables and proportions for categorical variables. To identify the ideal cutoff point of LND in predicting survival, the X-Tile software (3.6.1 version, Yale University) was used [19]. The chi-square test (categorical variables), one-way analysis of variance (normal distribution), or the Mann-Whitney U test (skewed distribution) was used to test for differences among different LND groups. The relationship between specific variables and survival were analyzed by the Kaplan-Meier Log-Rank test and Cox Proportional Hazards Regression. Univariate analyses of individual pathological and clinical features and CSS or OS were performed. To identify any independent association between LND and survival, we constructed three models: non-adjusted model, where no covariates were adjusted; adjusted I model, where only sociodemographic data of age, sex and race were adjusted and adjusted II model, where covariates in the adjusted I model and other elected covariates were adjusted. If the matched odds ratio changed at least 10 percent as the result of adding covariates, the variables were considered to be added in the adjusted II model, as described in a previous study [20]. To estimate the robustness of LND in predicting survival, sensitivity analyses were stratified according to different AJCC N stages. Tests for effect modification for those of subgroup indicators were followed by the likelihood ratio test. All the analyses were performed with the statistical software package R (http://www.R-project.org, The R Foundation) and EmpowerStats (http://www.empowerstats.com, X&Y Solutions, Inc, Boston, MA). P values less than 0.05 (two-sided) were considered statistically significant.

Results

Demographic characteristics and relationship between LND and clinical features

After screening by inclusion and exclusion criteria, a total of 4281 participants diagnosed with GC were selected from the SEER database for the final data analysis. Table 1 provides an overview of patient characteristics and clinicopathologic features. The average age at diagnosis was 69.73 years for the whole population enrolled, and almost two-thirds of the participants (63.78%) were male. The number of enrolled patients was evenly distributed throughout the enrollment period from 2010 to 2015. Other baseline demographic data and information on pathologic staging and grading are shown in Table 1. The X-Tile software was used to identify the ideal cutoff point for LND in predicting survival. As shown in Supplemental Figs. 1 and 2, cutoff points of 0.1 and 0.4 yielded the maximum chi-square of log-rank tests for CSS and OS. The survival difference was significant in the three groups both for CSS and OS when divided by the best cutoff points. The relationship between different groups of LND and clinical features is shown in Table 1. Insured patients tended to have a lower level of LND than that the uninsured or unknown categories, indicating that the insured population may have easier access to physical examinations and thus receive an earlier diagnosis. Tumors located on the upper stomach tended to have a lower level of LND and tumors with overlapping lesions tended to have a higher level of LND. A high rate of LND in advanced AJCC staging and grading is clearly shown in Table 1. This result is somewhat counterintuitive and requires further investigation since patients in the middle level of LND were more likely to receive chemotherapy.

Table 1

Patient characteristics and correction between LND and clinicopathologic variables.

Variables

Total

LND < 0.1

0.1 = < LND < 0.4

LND > = 0.4

P-value

Patients, n

4821

3170

871

780

 

Regional nodes examined

17.96 ± 12.67

17.63 ± 12.64

20.02 ± 12.65

17.01 ± 12.58

< 0.001

Regional nodes positive

2.69 ± 5.40

0.20 ± 0.57

4.27 ± 3.14

11.09 ± 8.32

< 0.001

Age at diagnosis (years)

69.73 ± 12.30

69.47 ± 11.98

70.18 ± 12.65

70.24 ± 13.12

0.143

Sex

       

0.291

Male

3075 (63.78%)

2033 (64.13%)

536 (61.54%)

506 (64.87%)

 

Female

1746 (36.22%)

1137 (35.87%)

335 (38.46%)

274 (35.13%)

 

Year of diagnosis

       

0.225

2010

842 (17.47%)

536 (16.91%)

170 (19.52%)

136 (17.44%)

 

2011

816 (16.93%)

523 (16.50%)

143 (16.42%)

150 (19.23%)

 

2012

826 (17.13%)

558 (17.60%)

138 (15.84%)

130 (16.67%)

 

2013

780 (16.18%)

500 (15.77%)

147 (16.88%)

133 (17.05%)

 

2014

800 (16.59%)

527 (16.62%)

147 (16.88%)

126 (16.15%)

 

2015

757 (15.70%)

526 (16.59%)

126 (14.47%)

105 (13.46%)

 

Race

     

0.229

White

3121 (64.74%)

2024 (63.85%)

573 (65.79%)

524 (67.18%)

 

Asian or pacific islander

1019 (21.14%)

692 (21.83%)

180 (20.67%)

147 (18.85%)

 

Black

629 (13.05%)

413 (13.03%)

113 (12.97%)

103 (13.21%)

 

Other

52 (1.08%)

41 (1.29%)

5 (0.57%)

6 (0.77%)

 

Marital status at diagnosis

     

0.068

Married

2840 (58.91%)

1900 (59.94%)

499 (57.29%)

441 (56.54%)

 

Widowed

738 (15.31%)

474 (14.95%)

140 (16.07%)

124 (15.90%)

 

Single

624 (12.94%)

377 (11.89%)

126 (14.47%)

121 (15.51%)

 

Other

619 (12.84%)

419 (13.22%)

106 (12.17%)

94 (12.05%)

 

Insurance

     

0.012

Insured

2950 (61.19%)

1981 (62.49%)

526 (60.39%)

443 (56.79%)

 

Uninsured or unknown

1871 (38.81%)

1189 (37.51%)

345 (39.61%)

337 (43.21%)

 

Primary Site

     

< 0.001

Upper

1300 (26.97%)

931 (29.37%)

230 (26.41%)

139 (17.82%)

 

Middle

1433 (29.72%)

955 (30.13%)

254 (29.16%)

224 (28.72%)

 

Lower

1702 (35.30%)

1092 (34.45%)

298 (34.21%)

312 (40.00%)

 

Overlapping lesion

386 (8.01%)

192 (6.06%)

89 (10.22%)

105 (13.46%)

 

AJCC Stage Group, 7th (2010–2015)

     

< 0.001

Stage I

1910 (39.62%)

1877 (59.21%)

27 (3.10%)

6 (0.77%)

 

Stage II

1287 (26.70%)

1010 (31.86%)

207 (23.77%)

70 (8.97%)

 

Stage III

1624 (33.69%)

283 (8.93%)

637 (73.13%)

704 (90.26%)

 

AJCC T, 7th (2010–2015)

     

< 0.001

T1

1644 (34.10%)

1539 (48.55%)

80 (9.18%)

25 (3.21%)

 

T2

708 (14.69%)

554 (17.48%)

98 (11.25%)

56 (7.18%)

 

T3

1577 (32.71%)

829 (26.15%)

416 (47.76%)

332 (42.56%)

 

T4

892 (18.50%)

248 (7.82%)

277 (31.80%)

367 (47.05%)

 

AJCC N, 7th (2010–2015)

     

< 0.001

N0

2607 (54.08%)

2607 (82.24%)

0 (0.00%)

0 (0.00%)

 

N1

913 (18.94%)

494 (15.58%)

317 (36.39%)

102 (13.08%)

 

N2

642 (13.32%)

67 (2.11%)

405 (46.50%)

170 (21.79%)

 

N3

659 (13.67%)

2 (0.06%)

149 (17.11%)

508 (65.13%)

 

Grade

       

< 0.001

Well differentiated

515 (10.68%)

474 (14.95%)

27 (3.10%)

14 (1.79%)

 

Moderately differentiated

1656 (34.35%)

1243 (39.21%)

258 (29.62%)

155 (19.87%)

 

Poorly differentiated

2570 (53.31%)

1404 (44.29%)

577 (66.25%)

589 (75.51%)

 

Undifferentiated; anaplastic

80 (1.66%)

49 (1.55%)

9 (1.03%)

22 (2.82%)

 

Chemotherapy

       

< 0.001

No/unknown

3362 (69.74%)

2434 (76.78%)

456 (52.35%)

472 (60.51%)

 

Yes

1459 (30.26%)

736 (23.22%)

415 (47.65%)

308 (39.49%)

 
Abbreviations: LND = lymph node density, OR = odds ratio, CI = confidence Interval.

Association Between Clinical Variables And Css And Os

Table 2 shows the prognostic factors affecting CSS and OS in GC patients based on univariate analysis. Older age was significantly associated with reduced CSS (HR = 1.01, 95% CI 1.01–1.01, P < 0.001) and OS (HR = 1.03, 95% CI 1.02–1.03, P < 0.001). Null associations of sex were observed with CSS and OS. The mortality of GC patients was reduced with an increase in the year of diagnosis, although this result was just short of being statistically significant. The effect of race was also assessed, with Asian or pacific islander populations showing a lower risk of mortality than white patients in CSS (HR = 0.79, 95% CI 0.68–0.92, P = 0.002) and OS (HR = 0.71, 95% CI 0.63–0.80, P < 0.001). Marital status at diagnosis was associated with GC survival and being widowed and single was associated with a dismal prognosis in CSS and OS analysis. Uninsured patients or those with unknown insurance status were at high risk of death in CSS (HR = 1.21, 95% CI 1.08–1.35, P = 0.001) and OS (HR = 1.13, 95% CI 1.03–1.23, P = 0.007). Compared to upper GC, primary tumors located at overlapping lesions significantly increased the risk of mortality both in CSS analysis (HR = 1.48, 95% CI 1.21–1.82, P = 0.001) and OS (HR = 1.36, 95% CI 1.16–1.60, P = 0.001). There was a significant positive correlation between advanced AJCC staging and survival both in CSS and OS (all P values < 0.001), which was in accordance with our clinical experience. In addition, patients with poorly or undifferentiated GC had an approximately doubled mortality risk compared to those with well-differentiated tumors. Patients receiving chemotherapy had a 1.33-fold increase in mortality risk in CSS analysis than those without chemotherapy or unknown chemotherapy status (HR = 1.33, 95% CI 1.19–1.50, P < 0.001), but the association was not significant in OS analysis. The primary variable in this study was LND and its survival predicting effects were fully investigated. Patients in the middle ( > = 0.1, < 0.4) or higher ( > = 0.4) level of LND had 3.98 (95% CI 3.45–4.60, P < 0.001), 8.57 (95% CI 7.48–9.82, P < 0.001) folds increase in mortality risk in CSS, respectively, than those with lower ( > = 0.4) LND level. Differences in mortality rate of OS were also shown for patients in the middle or higher level of LND which had 2.88 (95% CI 2.59–3.20, P < 0.001) and 5.54 (95% CI 4.99–6.15, P < 0.001) fold increase in mortality risk compared to those with the lower level. Kaplan–Meier survival curves for those patients according to LND status are presented in Fig. 2. Significant differences were observed among LND subgroups in predicting CSS (Fig. 2A, P < 0.001) and OS (Fig. 2B, P < 0.001).

Table 2

Association between clinical variables and gastric cancer specific survival or overall survival.

Variables

CSS, HR (95%CI) P value

OS, HR (95%CI) P value

Age at diagnosis (years)

1.01 (1.01, 1.01) < 0.001

1.03 (1.02, 1.03) < 0.001

Sex

   

Male

Ref.

Ref.

Female

0.96 (0.86, 1.08) 0.536

0.92 (0.84, 1.00) 0.061

Year of diagnosis

   

2010

Ref.

Ref.

2011

1.13 (0.95, 1.35) 0.151

0.99 (0.87, 1.13) 0.866

2012

0.90 (0.75, 1.08) 0.272

0.90 (0.78, 1.03) 0.121

2013

0.98 (0.81, 1.18) 0.841

0.95 (0.83, 1.10) 0.516

2014

0.91 (0.74, 1.11) 0.336

0.89 (0.77, 1.04) 0.141

2015

0.91 (0.72, 1.13) 0.384

0.79 (0.66, 0.94) 0.009

Race

   

White

Ref.

Ref.

Asian or pacific islander

0.79 (0.68, 0.92) 0.002

0.71 (0.63, 0.80) < 0.001

Black

1.03 (0.87, 1.21) 0.740

1.02 (0.90, 1.16) 0.757

Other

0.76 (0.42, 1.38) 0.372

0.65 (0.40, 1.05) 0.079

Marital status at diagnosis

   

Married

Ref.

Ref.

Widowed

1.40 (1.20, 1.63) < 0.001

1.52 (1.36, 1.71) < 0.001

Single

1.32 (1.12, 1.56) 0.001

1.26 (1.11, 1.43) 0.001

Other

0.99 (0.83, 1.18) 0.902

1.08 (0.95, 1.24) 0.242

Insurance

   

Insured

Ref.

Ref.

Uninsured or unknown

1.21 (1.08, 1.35) 0.001

1.13 (1.03, 1.23) 0.007

Primary Site

   

Upper

Ref.

Ref.

Middle

0.96 (0.82, 1.11) 0.553

0.98 (0.87, 1.10) 0.699

Lower

1.03 (0.90, 1.19) 0.646

1.10 (0.98, 1.22) 0.093

Overlapping lesion

1.48 (1.21, 1.82) 0.001

1.36 (1.16, 1.60) 0.001

AJCC Stage Group, 7th (2010–2015)

   

Stage I

Ref.

Ref.

Stage II

3.40 (2.79, 4.13) < 0.001

2.12 (1.87, 2.40) < 0.001

Stage III

9.75 (8.18, 11.62) < 0.001

4.80 (4.30, 5.35) < 0.001

AJCC T, 7th (2010–2015)

   

T1

Ref.

Ref.

T2

1.99 (1.56, 2.55) < 0.001

1.44 (1.23, 1.69) < 0.001

T3

4.76 (3.96, 5.73) < 0.001

2.81 (2.50, 3.16) < 0.001

T4

10.10 (8.36, 12.20) < 0.001

5.16 (4.55, 5.85) < 0.001

AJCC N, 7th (2010–2015)

   

N0

Ref.

Ref.

N1

3.35 (2.85, 3.94) < 0.001

2.27 (2.02, 2.55) < 0.001

N2

5.02 (4.24, 5.93) < 0.001

3.13 (2.77, 3.55) < 0.001

N3

9.14 (7.84, 10.67) < 0.00

5.32 (4.75, 5.96) < 0.001

Grade

   

Well differentiated

Ref.

Ref.

Moderately differentiated

1.91 (1.42, 2.56) < 0.001

1.57 (1.30, 1.89) < 0.001

Poorly differentiated

3.96 (2.99, 5.23) < 0.001

2.46 (2.06, 2.95) < 0.001

Undifferentiated; anaplastic

3.82 (2.35, 6.20) < 0.001

2.64 (1.86, 3.74) < 0.001

Chemotherapy

   

No/unknown

Ref.

Ref.

Yes

1.33 (1.19, 1.50) < 0.001

0.99 (0.90, 1.08) 0.776

LND

   

<0.1

Ref.

Ref.

>=0.1, < 0.4

3.98 (3.45, 4.60) < 0.001

2.88 (2.59, 3.20) < 0.001

>=0.4

8.57 (7.48, 9.82) < 0.001

5.54 (4.99, 6.15) < 0.001

Abbreviations: LND = lymph node density, CSS = cancer-specific survival, OS = overall survival, HR = hazard ratio, CI = confidence Interval.

Independent Prognostic Effect Of Lnd And Stratified Effect Analysis In Current Lymph Node Staging Systems

To further elucidate the prognostic impact of LND on GC patients who underwent gastrectomy, Cox multivariate analysis was performed (Table 3). We constructed three models to analyze the independent effects of LND on survival including a crude (non-adjusted) model, minimally adjusted (adjusted I) model and fully adjusted (adjusted II) model. As previously shown in the results of multivariate analysis, CSS and OS of GC patients decreased with an increase in LND in different models. In the fully adjusted model, compared to the lower LND group, patients with a middle and higher level of LND had 2.43- (HR = 2.43, 95% CI 2.09–2.84, P < 0.001) and 4.69- (HR = 4.69, 95% CI 4.02–5.48, P < 0.001) fold increase in mortality in CSS, respectively. Similar results were found in the evaluation of OS which showed that patients with a middle and higher level of LND had 2.04 (HR = 2.04, 95% CI 1.81–2.29, P < 0.001) and 3.61 (HR = 3.61, 95% CI 3.20–4.07, P < 0.001) fold increase in mortality, respectively. Taken together, these data suggest that LND had independent prognostic effects in patients with GC. To further elucidate whether LND had independent prognostic effects in the current nodal category strategies, subgroup analysis was performed. Each positive N category (N1-3) was stratified into different LND subgroups. In the N1 and N2 stages, patients with GC were divided into three groups according to the cutoff points of LND. As shown in Table 3, CSS and OS of GC patients significantly decreased with the increase in LND grade in different models (all P values < 0.05). For patients in the N3 stage, there were only two patients in the lower level (LND < 0.1) of the LND group (Table 1) and thus for patients in the N3 category the cutoff point was 0.4. Results repeatedly showed that a high level of LND was associated with worse survival in CSS and OS in different models (all P values < 0.05). In addition, survival curves were plotted using the Kaplan-Meier method to determine the independent prognostic effect of LND in subgroups of N categories. As presented in Fig. 3, patients in each positive N category were found to contain subgroups divided by LND, with significantly heterogeneous CSS and OS (all P values < 0.001).

Table 3

Multiple regression analysis to assess the independent effect in CSS and OS and stratified effect analysis in different N stages.

LND

Non-adjusted

Adjust I

Adjust II

 

CSS, HR (95%CI) P value

OS, HR (95%CI) P value

CSS, HR (95%CI) P value

OS, HR (95%CI) P value

CSS, HR (95%CI) P value

OS, HR (95%CI) P value

Total (n = 4821)

           

LND < 0.1

Ref.

Ref.

Ref.

Ref.

Ref.

Ref.

0.1 = < LND < 0.4

3.98 (3.45, 4.60) < 0.001

2.88 (2.59, 3.20) < 0.001

3.97 (3.44, 4.58) < 0.001

2.84 (2.56, 3.16) < 0.001

2.43 (2.09, 2.84) < 0.001

2.04 (1.81, 2.29) < 0.001

LND > = 0.4

8.57 (7.48, 9.82) < 0.001

5.54 (4.99, 6.15) < 0.001

8.62 (7.52, 9.87) < 0.001

5.58 (5.03, 6.19) < 0.001

4.69 (4.02, 5.48) < 0.001

3.61 (3.20, 4.07) < 0.001

Subgroup analysis

           

N1 (n = 913)

           

LND < 0.1

Ref.

Ref.

Ref.

Ref.

Ref.

Ref.

0.1 = < LND < 0.4

2.23 (1.72, 2.88) < 0.001

2.21 (1.81, 2.69) < 0.001

2.17 (1.67, 2.81) < 0.001

2.04 (1.67, 2.50) < 0.001

1.97 (1.51, 2.57) < 0.001

1.86 (1.52, 2.29) < 0.001

LND > = 0.4

3.59 (2.58, 4.98) < 0.001

3.18 (2.44, 4.14) < 0.001

3.39 (2.43, 4.72) < 0.001

2.88 (2.21, 3.76) < 0.001

3.12 (2.21, 4.39) < 0.001

2.65 (2.01, 3.49) < 0.001

N2 (n = 642)

           

LND < 0.1

Ref.

Ref.

Ref.

Ref.

Ref.

Ref.

0.1 = < LND < 0.4

2.17 (1.25, 3.75) 0.005

2.46 (1.54, 3.92) 0.002

2.15 (1.24, 3.73) 0.006

2.44 (1.53, 3.90) 0.002

2.07 (1.19, 3.60) 0.010

2.34 (1.46, 3.76) 0.001

LND > = 0.4

4.77 (2.72, 8.38) < 0.001

5.07 (3.13, 8.21) < 0.001

4.72 (2.68, 8.30) < 0.001

4.88 (3.01, 7.92) < 0.001

4.71 (2.63, 8.46) < 0.001

4.87 (2.96, 8.01) < 0.001

N3 (n = 659)

           

LND < 0.4

Ref.

Ref.

Ref.

Ref.

Ref.

Ref.

LND > = 0.4

2.51 (1.87, 3.38) < 0.001

1.86 (1.50, 2.31) < 0.001

2.07 (1.60, 2.70) < 0.001

1.92 (1.54, 2.39) < 0.001

1.94 (1.49, 2.53) < 0.001

1.80 (1.44, 2.25) < 0.001

Abbreviations: LND = lymph node density, CSS = cancer-specific survival, OS = overall survival, HR = hazard ratio, CI = confidence Interval.
Non-adjusted model did not adjust covariant.
Adjusted I model minimally adjusted for sex, age and race.
Adjusted II model fully adjusted for sex, age, race, marital status at diagnosis, insurance, AJCC Stage Group 7th (2010–2015), AJCC T 7th (2010–2015), and grade.

Discussion

Accurate staging is the cornerstone of optimal cancer care and therapy. The current staging system of N categories, the AJCC TNM system, for GC patients is based on the number of lymph nodes with metastases and the number of examined lymph nodes is not taken into account. The prognostic role of LND, calculated by the ratio of the number of positive nodes to the number of examined nodes, in GC staging was analyzed in the present study. Optimal cutoff values of LND were calculated as 0.1 and 0.4, and LND was divided into three levels. Significant differences in survival were observed among LND subgroups and in predicting CSS and OS by univariate analysis. We constructed three models to analyze the independent effects of LND on survival and results showed that LND had independent prognostic effects in patients with GC. To evaluate the performance of LND in the staging system, each N category was stratified by different levels of LND. Each N category was found to contain subgroups of GC patients with significantly heterogeneous CSS and OS.

Currently, the AJCC TNM system is the most commonly used staging system for GC. From the 7th edition AJCC staging manual, the N category was recommended to include resection of at least 16 regional lymph nodes [17]. A considerable amount of literature has been published on the topic of LND or LNR from 2010, when the 7th edition AJCC staging manual firstly came into efforts [16, 21, 22]. Many studies have demonstrated that regional positive nodes did not or insufficiently reflected the survival of patients with GC[13, 16, 23, 24]. For patients who were detected with the same number of regional positive nodes, those with more regional nodes examined were more likely to have better survival because those patients tended to be with a higher level of radical gastrectomy and have lower risk with the residual tumor. Wang et al retrospectively analyzed 18043 gastric patients from the SEER database and proposed a modified staging system utilizing the lymph node ratio which predicted survival more accurately than the 7th AJCC system [16]. Validation analysis from Taiwan University Hospital Cancer Registry also found the advantages of a staging system using a lymph node ratio using a patient cohort from Eastern medical centers [25]. One study from China showed that the lymph node ratio staging system is a reliable classification for GC patients after neoadjuvant radiotherapy [26].

In the present study, we demonstrated that LND was an independent predictor of patients’ survival and to have stratified effects in different N subgroups. Although these findings have already been reported in previous studies [16, 18, 21, 24, 25, 27], and some of these also used data from the SEER database [16, 18, 24], our study has distinct characteristics that make it differ from previous studies. The time of enrolment in the present study was from 2010 to 2015, during which period the 7th AJCC staging strategies were applied and the follow-up and treatment information was complete. Most previous studies enrolled GC patients across a long-time span, and patients before 2010 were also included for analysis. Another consideration is that, before the application of the 7th AJCC staging system, the number of examined lymph nodes may have been lower. In Wang et al [16], GC patients from the SEER database between 1988 to 2007 were included and the number of examined nodes was lower than 15 in 69.3% patients. Another recent study by Yang et al included GC patients from the SEER database between 1988 to 2015 and 61.31% of patients had less than 15 examined lymph nodes [18]. LND or lymph node ratio is determined by the number of positive regional nodes and the number of examined regional nodes. With the development of surgical techniques, an increasing number of regional nodes can be resected and examined. Data before 2010 when the lower number of examined regional nodes was common may inevitably affect the lymph ratio and result in unstable evidence. In the present study, the median regional nodes examined were 17.96, which was higher than the 16 in the 7th edition AJCC staging system, thus providing a relatively higher level of evidence. Another distinct characteristic of our study is that we only enrolled patients with gastric adenocarcinoma according to histologic subtype codes of the SEER database. The significance of lymph node metastasis is different in different histologic types [28]. Gastric adenocarcinoma comprises nearly 90% of the total number of gastric malignancies and thus focusing on adenocarcinoma helps to better understand the characteristics of this histologic subtype and improve diagnosis and treatment [29].

Although the present study is a relatively large population-based study, it inevitably had several limitations. First, the SEER database is a public open-access cancer registry data and does not include certain information regarding neoadjuvant chemotherapy and surgical complications which may influence the survival of GC patients. Second, the retrospective nature of the SEER database does not allow to extrapolate the results. Third, the 8th edition of the AJCC TNM system has been recommended in clinical practice since 2017, but data from the SEER database from after 2017 cannot be used because of the limitation of lack of follow-up information.

In conclusion, by analyzing the SEER database from 2010, when the 7th edition of the AJCC TNM system came into efforts, the present study demonstrates that LND is an indicator of CSS an OS in GC. We calculated two optimal cutoff values of LND as 0.1 and 0.4. Significant differences in survival were observed among LND subgroups in predicting CSS and OS. Patients in each positive N category were found to contain subgroups divided by LND with significantly heterogeneous CSS and OS. Development of a new LND staging strategy may help improve patient care and to better informed and precise treatment decisions. However, due to the retrospective nature of data from the SEER database, further prospective cohort studies are needed.

Conclusion

Through analysis of a population-based SEER database, we found that LND is an independent prognostic factor for non-metastatic GC. In the current lymph node staging system, LND has potential value in further accurately classifying non-metastatic GC patients.

Abbreviations

SEER

Surveillance, Epidemiology, and End Results

GC

Gastric cancer

LND

Lymph node density

CSS

cancer-specific survival

OS

Overall survival

AJCC

the American Joint Committee on Cancer

TNM

tumor-node-metastasis.

Declarations

Supplementary Information

This article contains an additional file named Supplementary Files.

Acknowledgements

We would like to thank the staff members of the National Cancer Institute and their colleagues across the United States and at Information management Services, Inc., who have been involved with the SEER Program.

Authors’ contributions

LWQ designed and constructed study. LYH conceived of the study and participated in its design and coordination, collected and assembled data. LYH, CH and XXX wrote the manuscript and analyzed data. All authors read and approved the final manuscript.

Funding: None.

Availability of data

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Informed consent for publication was obtained from all authors.

Competing interests

The authors declare no competing interests.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist

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