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. |