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Journal of Thoracic Disease logoLink to Journal of Thoracic Disease
. 2019 Jun;11(6):2251–2266. doi: 10.21037/jtd.2019.06.24

Age at diagnosis is a heterogeneous factor for non-small cell lung cancer patients

Tao Chen 1, Fangyu Zhou 1, Weili Jiang 2,3, Rui Mao 1, Hui Zheng 1, Linlin Qin 1, Chang Chen 1,✉
PMCID: PMC6626822  PMID: 31372262

Abstract

Background

The incidence of lung cancer is reported as age dependent. However, the link between survival and age at diagnosis remains controversial. To date, few studies have examined the relationship between age and the clinicopathologic characteristics of patients with non-small cell lung cancer (NSCLC).

Methods

Using the Surveillance, Epidemiology, and End Results (SEER) database, we included in our analysis 151,919 patients diagnosed with NSCLC between 2004 and 2013. Logistic regression was used to evaluate the associations between age and clinicopathological characteristics. N and M stages were separately assessed in each T stage.

Results

Of the patients enrolled, 60,271 patients were diagnosed at the M1 stage, 147,263 patients had lymph node metastasis, and 49,862 patients underwent surgery. Younger age was inversely associated with high N stage and M stage (P<0.001, respectively). For each T stage, the inverse associations with M1 stage and lymph node metastasis were also presented (P<0.001, respectively). Age was an independent risk predictor for NSCLC patients by using univariate and multivariate analyses.

Conclusions

Age at diagnosis is a heterogeneous factor for NSCLC patients: younger patients have an increased risk of lymph node and distant metastases, yet have a better prognosis.

Keywords: Age at diagnosis, lymph node metastasis, distant metastasis, prognosis, non-small cell lung cancer (NSCLC)

Introduction

Lung cancer is the second most common malignant cancer and the leading cause of death from malignancy in the United States (1). Moreover, the prevalence of lung cancer has paralleled our increased life expectancy, with the median age at diagnosis 63 years (2). Elderly patients exhibit higher rates of mortality than younger patients with various solid cancers, regardless of the clinical characteristics of the primary tumor, including patients with advanced or metastatic non-small cell lung cancer (NSCLC) (3-5). In retrospective studies, younger lung cancer patients exhibited a higher incidence of adenocarcinoma, female, and an advanced stage disease (3,6). In addition, these patients tended to present with a higher malignant potential (7,8). Therefore, age is regarded as a heterogeneous fact for lung cancer patients. Interestingly, elder patients typically exhibit a lower frequency of lymph node metastasis, compared to patients with early-stage rectal cancer (9). The impact of age at diagnosis on clinicopathologic characteristics is not well known for lung cancer patients.

We hypothesize that the behavior of NSCLC will differ between patients diagnosed at different ages. In the present study, we sought to assess the association between age and lymph node metastasis, M stage, and overall survival (OS) by examining surveillance, epidemiology, and end results (SEER) Database.

Methods

SEER database and patient selection

Lung cancer patient records were obtained from the special SEER database from 2004 to 2013. The inclusion criteria were definitive NSCLC diagnosis by pathology; no radiotherapy prior to surgery; pathological TNM stage information; complete follow-up data after treatment. And the exclusion criteria are as follows: (I) patients with small cell lung cancer (ICD-0-3 histology code 8041–8045); (II) patients without pathologic diagnosis; (III) patients received neoadjuvant chemotherapy; (IV) patients without any TNM information; (V) patients with non-cancer specific death (cardiovascular related mortality, and other causes).

SEER*Stat Version 8.2.1 (2015; National Cancer Institute Cancer Statistics Branch, Bethesda, MD; www.seer.Cancer.gov/seerstat) was used to identify all patients with NSCLC based on the International Classification of Diseases for Oncology. Patients’ demographics on each case, including gender, age at diagnosis, extent of disease, primary site, histology, vital status, number of lymph nodes examined and positive, T stage, N stage, and M stage, were included. Adjuvant chemotherapy and neoadjuvant chemotherapy were not evaluated as the SEER registry does not include this information. The proportion of NSCLC patients was classified by 5-year intervals (0–44, 45–49, 50–54, 55–59, 60–64, 65–69, 70–74, 75–79, 80–84, and 85+). The primary endpoint of the study was calculated from the date of diagnosis to the date of cancer specific death or the last follow-up. The study was approved by institutional ethics committee of Shanghai Pulmonary Hospital (No. K16-264).

Statistical analysis

All statistical analyses were performed using the Statistical Package for Social Science (SPSS, Inc., Chicago, IL, USA) software, version 16.0 for Windows. The descriptive data were expressed as mean ± standard deviation. Baseline characteristics were analyzed by the chi-squared (χ2) test or Student’s t-test for continuous variables. The association between age at diagnosis and distant metastasis, and lymph node metastasis were evaluated by using Poisson regression. OS was displayed using Kaplan-Meier survival curves with 95% confidence intervals (CIs); the differences between curves were displayed using the log-rank test. All risk factors identified by univariate analysis were adopted in multivariate Cox proportional hazard analysis. A two-tailed test of a P value of ≤0.05 was considered statistically significant.

Results

Demographic and clinical characteristics

In this retrospective study, 151,919 patients met the eligibility criteria. There were 72455 female patients (47.7%) and 79,464 male patients (52.3%). A total of 121,970 (80.3%) patients identified as white race. The median age at diagnosis was 68 years (range, 4–104 years). Of these patients, the 65–69 years old patient was also the greatest proportion (26,310, 17.3%), and 0–44 years old patient was the smallest proportion (3,134, 2.1%). As for treatment, 60,611 (39.9%) patients received radiation, and 49,862 (32.8%) patients received surgery. At follow-up, 54,004 (35.5%) patients were still alive. The 1-, 3-, and 5-year survival rates were 47.8%, 20.3%, and 10.3%. The median time of OS was 16.0 (95% CI: 15.813–16.187) months. According to AJCC TNM stage classification, 81,501 patients (53.6%) had at least one lymph node metastasis, 60,271 patients (39.7%) had M1 stage (including M1a and M1b). The greatest proportion was T4 stage (35,226 patients, 23.2% for T1 stage; 50,759 patients, 33.4% for T2 stage; 9,946 patients, 6.5% for T3 stage; 55,988 patients, 36.9% for T4 stage). In our cohort, 29.6%, 52.4%, 61.8%, and 68.5% of patients had stage T1, T2, T3, and T4 patients respectively, with lymph node positive, and 19.3%, 32.2%, 38.6%, and 59.5% for T1, T2, T3, and T4 patients with M1 stage. The proportion of NSCLC patients is presented in Table 1.

Table 1. Clinicopathological features of patients.

Factors n=151,919 %
Sex
   Male 79,464 52.3
   Female 72,455 47.7
Age
   0–44 3,134 2.1
   45–49 5,553 3.7
   50–54 10,918 7.2
   55–59 16,530 10.9
   60–64 22,006 14.5
   65–69 26,310 17.3
   70–74 24,761 16.3
   75–79 21,451 14.1
   80–84 14,354 9.4
   85+ 6,902 4.5
Race
   White 121,970 80.3
   Black 17,778 11.7
   Others 11,837 7.8
   Unknown 334 0.2
Year of diagnosis
   2004 12,248 8.1
   2005 12,177 8.0
   2006 13,230 8.7
   2007 13,891 9.1
   2008 14,653 9.6
   2009 15,645 10.3
   2010 16,796 11.1
   2011 17,386 11.4
   2012 18,143 11.9
   2013 17,750 11.7
Histology
   Adenocarcinoma 101,085 66.5
   Squamous 50,834 33.5
Surgery
   No 102,057 67.2
   Yes 49,862 32.8
Radiation
   Yes 60,611 39.9
   No 89,054 58.6
   Unknown 4,656 3.1
TNM stage
   Ia 21,962 14.5
   Ib 18,781 12.4
   IIa 2,069 1.4
   Iib 7,099 4.7
   IIIa 14,638 9.6
   IIIb 25,028 16.5
   IV 60,271 39.7
   Unstaged 2,071 1.4
N stage
   N0 65,762 43.3
   N1 14,460 9.5
   N2 50,507 33.2
   N3 16,534 10.9
   Unstaged 4656 3.1
Tumor location
   Left 87,244 57.4
   Right 61,530 40.5
   Paired sites 2,843 1.9
   Unknown 302 0.2
T stage
   T1 35,226 23.2
   T2 50,759 33.4
   T3 9,946 6.5
   T4 55,988 36.9
M stage
   M0 90,035 59.3
   M1 60,271 39.7
   Unstaged 1,613 1.1
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T stage, tumor stage; N stage, node stage; M stage, metastasis stage.

Age increases risks of lymph node metastasis and distant metastasis

As illustrated in Table 2, younger patients tended to have more node-positive disease, distant disease, adenocarcinoma, and black patients (P<0.001, respectively). Individuals younger than 45 years had a higher incidence of lymph node involvement (from 64.0% in patients 0–44 years old to 45.3% in patients 85 and over) and distant metastases (from 53.7% in patients 0–44 years old to 35.3% in patients 85 and over) (P<0.001, respectively) in each increasing age category (Figure 1A,B). And the percentage of population gradually increased by increasing age (Table 2 and Figure 1).

Table 2. The association of the clinicopathological characteristics.

Factors (n) 0–44 45–49 50–54 55–59 60–64 65–69 70–74 75–79 80–84 85+ P
Sex <0.01
   Female 1,718 2,862 5,173 7,299 9,787 12,063 11,775 10,631 7,385 3,762
   Male 1,416 2,691 5,745 9,231 12,219 14,247 12,986 10,820 6,969 3,140
Race <0.01
   White 2,235 4,072 8,051 12,536 17,337 21,382 20,465 17,907 12,208 5,777
   Black 465 957 1,962 2,706 3,006 3,039 2,372 1,840 953 478
   Others 419 508 877 1,246 1,618 1,840 1,863 1,668 1,164 634
   Unknown 15 16 28 42 45 49 61 36 29 13
Histology <0.01
   Adenocarcinoma 2,633 4,363 8,180 11,743 14,841 16,955 15,505 13,276 9,041 4,548
   Squamous 501 1,190 2,738 4,787 7,165 9,355 9,256 8,175 5,313 2,354
Surgery <0.01
   No 2,147 3,801 7,441 10,958 14,188 16,429 15,941 14,433 10,745 5,974
   Yes 987 1,752 3,477 5,572 7,818 9,881 8,820 7,018 3,609 928
Radiation <0.01
   No 1,586 2,847 5,590 8,785 12,533 15,595 15,114 13,533 9,075 2,416
   Yes 1,490 2,624 5,168 7,483 9,159 10,301 9,252 7,648 5,070 4,396
   Unknown 58 82 160 262 314 414 395 270 209 90
LNM stage <0.01
   Ia 282 555 1,265 2,082 3,279 4,272 4,088 3,330 820 820
   Ib 254 488 948 1,626 2,550 3,403 3,291 3,119 1,009 1,009
   IIa 44 81 130 245 304 391 364 283 48 48
   IIb 105 259 479 772 1,008 1,353 1,165 1,034 276 276
   IIIa 255 476 1,052 1,601 2,128 2,654 2,465 2,098 592 592
   IIIb 484 867 1,738 2,663 3,504 3,989 3,998 3,626 1,553 1,553
   IV 1,684 2,764 5,200 7,350 9,003 9,923 9,050 7,625 2,437 2,437
   Unknown 26 63 106 191 230 325 340 336 167 167
N stage <0.01
   N0 1,009 1,924 3,873 6,123 9,082 11,685 11,466 10,271 6,941 3,388
   N1 289 584 1,050 1,685 2,192 2,605 2,284 1,980 1,264 527
   N2 1,172 2,012 4,045 6,023 7,514 8,608 7,946 6,708 4,388 2,091
   N3 546 888 1,649 2,251 2,657 2,714 2,366 1,789 1,164 510
   Unknown 118 145 301 448 561 698 699 703 597 386
Lymph node metastasis <0.01
   No 1,009 1,924 3,873 6,123 9,082 11,685 11,466 10,271 6,941 3,388
   Yes 2,007 3,484 6,744 9,959 12,363 13,927 12,596 10,477 6,816 3,128
   Unknown 118 145 301 448 561 698 699 703 597 386
Tumor location <0.01
   Left 1,854 3,216 6,457 9,601 12,652 15,123 14,116 12,236 8,148 3,841
   Right 1,150 2,175 4,204 6,562 8,935 10,694 10,222 8,829 5,901 2,858
   Paired sites 119 147 234 335 386 438 380 346 273 185
   Unknown 11 15 23 32 33 55 43 40 32 18
T stage <0.01
   T1 587 1,112 2,312 3,641 5,187 6,620 6,270 5,117 3,122 1,258
   T2 862 1,663 3,421 5,308 7,216 9,032 8,370 7,564 5,007 2,316
   T3 201 368 766 1,197 1,454 1,769 1,606 1,338 872 375
   T4 1,484 2,410 4,419 6,384 8,149 8,889 8,515 7,432 5,353 2,953
M stage <0.01
   M0 1,426 2,733 5,626 9,021 12,812 16,131 15,447 13,589 8,914 4,336
   M1 1,684 2,764 5,200 7,350 9,003 9,923 9,050 7,625 5,235 2,437
   Unknown 24 56 92 159 191 256 264 237 205 129
Year of diagnosis <0.01
   2004 337 512 877 1,344 1,777 2,069 2,025 1,818 1,063 426
   2005 318 524 873 1,355 1,767 2,011 1,982 1,768 1,142 437
   2006 332 582 1,010 1,460 1,877 2,199 2,168 1,855 1,205 542
   2007 305 587 966 1,491 2,058 2,430 2,277 1,979 1,233 565
   2008 298 583 1,096 1,566 2,124 2,602 2,310 2,056 1,365 653
   2009 309 609 1,142 1,673 2,319 2,622 2,537 2,205 1,501 728
   2010 302 573 1,272 1,842 2,357 2,932 2,661 2,374 1,661 822
   2011 339 569 1,298 1,852 2,569 3,046 2,784 2,383 1,725 821
   2012 303 537 1,226 2,007 2,589 3,237 2,961 2,557 1,794 932
   2013 291 477 1,158 1,940 2,569 3,162 3,056 2,456 1,665 976
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Figure 1.

Figure 1

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Young age was inversely associated with lymph node metastasis (A, P<0.001) and M stage (B, P<0.001).

Subgroup analysis according to different T stages (T1, T2, T3, and T4 stage) showed that the risk of lymph node metastasis (Figure 2A,B,C,D) and M1 stage (Figure 3A,B,C,D) were also decreased regardless of T stage. The incidence of distant metastasis and lymph node metastasis gradually decreased with increasing age in different stages (P<0.001, respectively) (Figures 2 and 3).

Figure 2.

Figure 2

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The associations between age and lymph node metastasis according to T stage (A: T1; B: T2; C: T3; and D: T4) (P<0.001, respectively).

Figure 3.

Figure 3

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The associations between age and distant metastasis according to T stage (A: T1; B: T2; C: T3; D: T4) (P<0.001, respectively).

Age at diagnosis is an independent factor for predicting outcome

Age at diagnosis (Figure 4A,B,C), sex, race, year of diagnosis, histology, location of tumor, T stage, N stage, M stage, TNM, radiotherapy, and surgery (P<0.001, respectively) were statistically significant risk predictors for survival in the univariate analyses. In the multivariate analyses, age at diagnosis, sex, race, year of diagnosis, histology, location of tumor, T stage, N stage, M stage, TNM, radiotherapy, and surgery were analyzed as continuous or categorized variables and were significantly associated with an increased risk of death, independent of tumor location (Table 3).

Figure 4.

Figure 4

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Kaplan-Meier survival curves for overall survival: all patients (A); patients with distant metastasis (B); patients with received surgery (C).

Table 3. Univariate and multivariate analyses of factors associated with OS.

Factors OS
Univariate Multivariate
HR 95% CI P value P’ value HR 95% CI P value P’ value
All patients
   Age at diagnosis
       0–44 1.000 (reference) <0.001 1.000 (reference) <0.001
       45–49 1.071 1.013–1.131 <0.001 1.128 1.065–1.195 <0.001
       50–54 1.079 1.026–1.135 <0.001 1.164 1.105–1.227 <0.001
       55–59 1.061 1.011–1.114 <0.001 1.204 1.145–1.267 <0.001
       60–64 1.025 0.978–1.075 <0.001 1.236 1.176–1.299 <0.001
       65–69 1.027 0.980–1.077 <0.001 1.330 1.266–1.397 <0.001
       70–74 1.122 1.070–1.176 <0.001 1.469 1.398–1.544 <0.001
       75–79 1.255 1.197–1.315 <0.001 1.653 1.572–1.737 <0.001
       80–84 1.470 1.401–1.543 <0.001 1.855 1.763–1.953 <0.001
       85+ 1.835 1.742–1.933 <0.001 2.141 2.026–2.262 <0.001
   Sex
       Female 1.000 (reference) <0.001 1.000 (reference) <0.001
       Male 1.325 1.309–1.342 <0.001 1.229 1.213–1.246 <0.001
   Race
       White 1.000 (reference) <0.001 1.000 (reference) <0.001
       Black 1.618 1.368–1.913 <0.001 1.040 1.019–1.061 <0.001
       Others 1.897 1.603–2.245 <0.001 0.755 0.736–0.775 <0.001
   Year of diagnosis
       2004 1.000 (reference) <0.001 1.000 (reference) <0.001
       2005 0.950 0.924–0.976 <0.001 0.959 0.931–0.987 0.005
       2006 0.928 0.903–0.954 <0.001 0.915 0.889–0.942 <0.001
       2007 0.894 0.870–0.919 <0.001 0.896 0.871–0.922 <0.001
       2008 0.876 0.853–0.900 <0.001 0.860 0.836–0.885 <0.001
       2009 0.859 0.836–0.882 <0.001 0.827 0.804–0.851 <0.001
       2010 0.871 0.848–0.895 <0.001 0.822 0.799–0.845 <0.001
       2011 0.798 0.776–0.820 <0.001 0.746 0.725–0.768 <0.001
       2012 0.808 0.785–0.831 <0.001 0.750 0.728–0.773 <0.001
       2013 0.730 0.703–0.757 <0.001 0.689 0.663–0.715 <0.001
   Histology
       Adenocarcinoma 1.000 (reference) <0.001 1.000 (reference) <0.001
       Squamous 1.209 1.193–1.225 <0.001 1.143 1.127–1.160 <0.001
   Surgery
       Yes 1.000 (reference) <0.001 1.000 (reference) <0.001
       No 5.789 5.689–5.892 <0.001 0.336 0.328–0.344 <0.001
   Radiation
       Yes 1.000 (reference) <0.001 1.000 (reference) <0.001
       No 1.742 1.719–1.764 <0.001 0.931 0.918–0.945 <0.001
   TNM stage
       Ia 1.000 (reference) <0.001 1.000 (reference) <0.001
       Ib 1.927 1.859–1.998 <0.001 1.424 1.361–1.490 <0.001
       IIa 2.097 1.953–2.252 <0.001 1.816 1.682–1.961 <0.001
       IIb 3.172 3.041–3.308 <0.001 1.930 1.831–2.034 <0.001
       IIIa 4.569 4.415–4.729 <0.001 1.836 1.7551.921 <0.001
       IIIb 6.516 6.314–6.924 <0.001 2.154 2.063–2.249 <0.001
       IV 10.282 9.982–10.592 <0.001 3.534 3.393–3.682 <0.001
   N stage
       N0 1.000 (reference) <0.001 1.000 (reference) <0.001
       N1 1.670 1.632–1.710 <0.001 1.164 1.132–1.197 <0.001
       N2 2.877 2.833–2.921 <0.001 1.279 1.255–1.304 <0.001
       N3 3.358 3.290–3.428 <0.001 1.259 1.230–1.289 <0.001
   Tumor location
       Left 1.000 (reference) <0.001 1.000 (reference) <0.001 0.104
       Right 1.001 0.989–1.014 0.827 1.005 0.992–1.019 0.452
       Paired sites 2.207 2.119–2.299 <0.001 1.049 1.002–1.097 0.039
   T stage
       T1 1.000 (reference) <0.001 1.000 (reference) <0.001
       T2 1.982 1.943–2.023 <0.001 1.222 1.190–1.255 <0.001
       T3 3.154 3.066–3.244 <0.001 1.410 1.363–1.459 <0.001
       T4 4.179 4.099–4.261 <0.001 1.412 1.375–1.449 <0.001
   M stage
       M0 1.000 (reference) <0.001 1.000 (reference) <0.001
       M1 3.320 3.277–3.364 <0.001 3.534 3.393–3.682 <0.001
Patients received surgery
   Age at diagnosis
       0–44 1.000 (reference) <0.001 1.000 (reference) <0.001
       45–49 1.085 1.022–1.151 0.007 1.275 1.094–1.486 0.002
       50–54 1.114 1.055–1.176 <0.001 1.266 1.100–1.457 0.001
       55–59 1.136 1.078–1.196 <0.001 1.328 1.161–1.520 <0.001
       60–64 1.127 1.070–1.186 <0.001 1.428 1.251–1.629 <0.001
       65–69 1.158 1.101–1.219 <0.001 1.592 1.396–1.815 <0.001
       70–74 1.216 1.156–1.279 <0.001 1.926 1.690–2.196 <0.001
       75–79 1.275 1.211–1.342 <0.001 2.404 2.108–2.743 <0.001
       80–84 1.332 1.264–1.403 <0.001 2.812 2.454–3.221 <0.001
       85+ 1.394 1.319–1.474 <0.001 3.895 3.322–4.566 <0.001
   Sex
       Female 1.000 (reference) <0.001 1.000 (reference) <0.001
       Male 1.474 1.429–1.520 <0.001 1.352 1.308–1.396 <0.001
   Race
       White 1.000 (reference) <0.001 1.000 (reference) <0.001
       Black 1.029 0.974–1.088 0.303 1.063 1.004–1.125 0.037
       Others 0.831 0.779–0.886 <0.001 0.792 0.741–0.846 <0.001
       Unknown 0.269 0.145–0.500 <0.001 0.371 0.193–0.714 0.003
   Year of diagnosis
       2004 1.000 (reference) <0.001 1.000 (reference) <0.001
       2005 0.973 0.943–1.004 0.089 0.982 0.925–1.042 0.551
       2006 0.941 0.913–0.971 <0.001 0.903 0.850–0.959 0.001
       2007 0.921 0.894–0.950 <0.001 0.832 0.782–0.884 <0.001
       2008 0.876 0.850–0.903 <0.001 0.827 0.777–0.880 <0.001
       2009 0.846 0.820–0.871 <0.001 0.744 0.698–0.794 <0.001
       2010 0.840 0.816–0.865 <0.001 0.697 0.651–0.746 <0.001
       2011 0.754 0.731–0.777 <0.001 0.645 0.598–0.695 <0.001
       2012 0.746 0.724–0.770 <0.001 0.645 0.590–0.704 <0.001
       2013 0.686 0.660–0.713 <0.001 0.551 0.476–0.638 <0.001
   Histology
       Adenocarcinoma 1.000 (reference) <0.001 1.000 (reference) <0.001
       Squamous 1.380 1.336–1.425 <0.001 1.198 1.157–1.240 <0.001
   M stage
       M0 1.000 (reference) <0.001 1.000 (reference) <0.001
       M1 1.763 1.738–1.788 <0.001 1.758 1.730–1.786 <0.001
   Radiation
       No 1.000 (reference) <0.001 1.000 (reference) <0.001
       Yes 2.590 2.491–2.694 <0.001 1.485 1.421–1.552 <0.001
   TNM stage
       Ia 1.000 (reference) <0.001 1.000 (reference) <0.001
       Ib 1.764 1.682–1.849 <0.001 1.221 1.113–1.339 <0.001
       IIa 2.453 2.250–2.673 <0.001 1.680 1.505–1.876 <0.001
       IIb 3.346 3.165–3.536 <0.001 1.540 1.386–1.710 <0.001
       IIIa 3.986 3.775–4.208 <0.001 1.402 1.263–1.556 <0.001
       IIIb 3.721 3.508–3.947 <0.001 1.315 1.170–1.479 <0.001
       IV 6.718 6.362–7.093 <0.001 3.055 2.785–3.351 <0.001
   N stage
       N0 1.000 (reference) <0.001 1.000 (reference) <0.001
       N1 2.145 2.059–2.235 <0.001 1.446 1.351–1.548 1.548
       N2 3.097 2.977–3.222 <0.001 2.003 1.863–2.152 2.152
       N3 6.129 5.415–6.938 <0.001 3.026 2.645–3.461 3.461
   Tumor location
       Left <0.001 1.000 (reference) 0.053
       Right 1.023 0.992–1.056 0.148 0.970 0.939–1.001 0.058
       Paired sites 4.171 3.268–5.323 <0.001 1.218 0.9281.600 0.156
   T stage
       T1 1.000 (reference) <0.001 1.000 (reference) <0.001
       T2 1.883 1.816–1.954 <0.001 1.334 1.233–1.444 <0.001
       T3 3.594 3.375–3.826 <0.001 1.949 1.772–2.142 <0.001
       T4 3.681 3.511–3.860 <0.001 1.967 1.780–2.172 <0.001
Patients with distant metastasis
   Age at diagnosis
       0–44 1.000 (reference) <0.001 1.000 (reference) <0.001
       45–49 1.133 0.977–1.314 0.100 1.113 1.046–1.184 0.001
       50–54 1.132 0.988–1.297 0.075 1.156 1.092–1.223 <0.001
       55–59 1.152 1.011–1.313 0.034 1.194 1.130–1.261 <0.001
       60–64 1.151 1.013–1.308 0.031 1.215 1.152–1.282 <0.001
       65–69 1.236 1.089–1.402 0.001 1.295 1.228–1.366 <0.001
       70–74 1.423 1.254–1.614 <0.001 1.395 1.323–1.472 <0.001
       75–79 1.689 1.487–1.917 <0.001 1.528 1.448–1.613 <0.001
       80–84 1.976 1.733–2.253 <0.001 1.679 1.589–1.774 <0.001
       85+ 2.522 2.162–2.941 <0.001 1.884 1.776–1.999 <0.001
   Sex
       Female 1.000 (reference) <0.001 1.000 (reference) <0.001
       Male 1.202 1.185–1.218 <0.001 1.202 1.185–1.220 <0.001
   Race
       White 1.000 (reference) <0.001 1.000 (reference) <0.001
       Black 0.993 0.973–1.014 0.523 1.032 1.010–1.054 0.004
       Others 0.814 0.793–0.835 <0.001 0.750 0.729–0.771 <0.001
       Unknown 0.667 0.560–0.793 <0.001 0.666 0.549–0.808 <0.001
   Year of diagnosis
       2004 1.000 (reference) <0.001 1.000 (reference) <0.001
       2005 0.949 0.896–1.006 0.078 0.960 0.928–0.992 0.015
       2006 0.878 0.828–0.931 <0.001 0.926 0.896–0.956 <0.001
       2007 0.814 0.767–0.864 <0.001 0.919 0.889–0.949 <0.001
       2008 0.797 0.750–0.847 <0.001 0.877 0.849–0.905 <0.001
       2009 0.730 0.685–0.778 <0.001 0.851 0.824–0.878 <0.001
       2010 0.687 0.643–0.735 <0.001 0.850 0.824–0.877 <0.001
       2011 0.624 0.580–0.672 <0.001 0.769 0.745–0.794 <0.001
       2012 0.635 0.583–0.693 <0.001 0.768 0.743–0.793 <0.001
       2013 0.525 0.455–0.605 <0.001 0.705 0.677–0.734 <0.001
   Histology
       Adenocarcinoma 1.000 (reference) <0.001 1.000 (reference) <0.001
       Squamous 1.039 1.024–1.054 <0.001 1.136 1.118–1.154 <0.001
   M stage
       M0 1.000 (reference) <0.001 1.000 (reference) <0.001
       M1 3.475 3.324–3.633 <0.001 2.830 2.681–2.987 <0.001
   Radiation
       No 1.000 (reference) <0.001 1.000 (reference) <0.001
       Yes 0.777 0.766–0.788 <0.001 0.872 0.859–0.885 0.885
   TNM stage
       Ia 1.000 (reference) <0.001 1.000 (reference) <0.001
       Ib 1.787 1.689–1.890 <0.001 1.415 1.328–1.508 <0.001
       IIa 1.533 1.351–1.741 <0.001 1.370 1.201–1.564 <0.001
       IIb 2.143 2.008–2.286 <0.001 1.559 1.449–1.678 <0.001
       IIIa 2.032 1.932–2.137 <0.001 1.447 1.365–1.535 <0.001
       IIIb 2.695 2.570–2.826 <0.001 1.795 1.697–1.899 <0.001
       IV 3.808 3.637–3.987 <0.001 2.830 2.681–2.987 <0.001
   N stage
       N0 1.000 (reference) <0.001 1.000 (reference) <0.001
       N1 1.254 1.219–1.290 <0.001 1.131 1.097–1.166 <0.001
       N2 1.375 1.352–1.298 <0.001 1.235 1.211–1.260 <0.001
       N3 1.419 1.388–1.450 <0.001 1.212 1.184–1.242 <0.001
   Tumor location
       Left 1.000 (reference) <0.001 1.000 (reference) 0.261
       Right 1.003 0.988–1.017 0.729 1.004 0.990–1.019 0.562
       Paired sites 1.387 1.331–1.446 <0.001 1.038 0.992–1.087 0.110
   T stage
       T1 1.000 (reference) <0.001 1.000 (reference) <0.001
       T2 1.441 1.406–1.476 <0.001 1.213 1.179–1.249 1.249
       T3 1.640 1.588–1.693 <0.001 1.380 1.33–1.431 1.431
       T4 1.903 1.861–1.947 <0.001 1.383 1.346–1.422 1.422
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OS, overall survival; CI, confidence interval.

Discussion

In recent decades, the cancer-associated death rate in lung cancer patients has decreased. Improvements in medical treatment and increased public awareness have been considered to play a role. Previous studies showed that elderly NSCLC patients represent a heterogeneous group (10) with unfavorable clinicopathologic characteristics (11). For example, elderly patients have significantly more chemotherapy-related toxicity (12,13), and less possibility for adenocarcinoma histology compared with younger patients (4). However, the impact of age on clinicopathologic characteristics was assessed in small-scale populations, and there is still debate as to what this means for lung cancer patients. To address this, we assessed the effects of age on N stage and M stage using the SEER Database.

TNM stage is an independent prognostic factor for all solid cancers, including NSCLC (14,15). The relationship between the age at diagnosis and the risk of lymph node positivity in NSCLC has not been previous described. In this study, we demonstrated that younger patients diagnosed with NSCLC have an increased predisposition for lymph node positivity compared with older patients. The risk of metastasis in older patients is nearly double of the younger patients. We also assessed the incidence of distant metastasis in our cohort. The risk of distant metastasis followed a similar trend as that of lymph node metastasis in NSCLC patients. In order to further validate our results, patients were divided into four subgroups according to T stages. Remarkably, the inverse relationship between age and distant metastasis, and lymph node metastasis remained. These results support the idea that younger patients have a higher malignant potential compared to the elderly.

The relationship between age and survival is still controversial. In some small-scale studies, age as a continuous variable, was not a prognostic factor for advanced or metastatic NSCLC (10,16,17). Other studies have drawn the opposite conclusion that age is a prognostic factor for patients with NSCLC, and elderly patients have a worse outcome compared to younger individuals (3,18,19). In our current analysis, a large population-based study, we find that age is in fact a prognostic factor for this population (as assessed by the cancer-specific survival). We find an unexpected link between survival and lymph node metastasis. This is because younger patients may respond better to treatments, like surgery and chemoradiotherapy (20,21). Previous studies analyzed age as binary variable. In order to better assess the associations between age and clinicopathological characteristics, patients were classified by 5-year intervals.

Our data present an interesting phenomenon. However, we are unable to address the underlying mechanisms in our current study. One possible explanation for our results is a genetic difference between our patients. Tumor cells in younger patients may exhibit more aggressive behavior than those in older patients (22). Secondly, age-related changes are presented in immunologic surveillance, such as decreased lymphatic flow to nodes and/or nodal involution. It was reported that tumor-associated neutrophil is related to a metastatic disease (23,24), and age-related changes in natural killer cells can impact on their ability to perform immune surveillance (25). We must also consider that a higher proportion of elderly patients take aspirin regularly because of cardiovascular diseases, such as myocardial infarction (26,27), and coronary artery disease (28,29). Aspirin can inhibit the aggregation of platelet by influencing the activity of cyclooxygenase-1 (COX-1) (30). Platelets have been shown to promote tumor metastasis (31). Future studies will need to elucidate whether these variables support our findings.

Our study is inherently limited by its retrospective design. Although our study is based on a large population and multicenter analysis, some of the patients’ files have been miscoded. These clerical errors can lead to patients being excluded from the study. Additionally, some important information, such as details of treatment, surgery type and smoking status, were not available in the SEER Database. Previous studies reported that neoadjuvant chemotherapy increases pathological response and lymph nodal downstage, so it could reduce the incidence of lymph node metastasis (32). In this study, we excluded patients who received neoadjuvant radiotherapy to eliminate the effect of preoperative radiation on lymph node harvest and positivity. Another consideration is that incomplete lymph node dissections may lead to misdiagnosing a lymph node metastasis. Finally, the records were obtained from the SEER Database did not provide the sites of tumor invasion. Thus, it is not possible to accommodate the latest edition of TNM, and the T stage of these patients was defined by the 8th AJCC TNM staging classification (33).

In conclusion, age at diagnosis is a heterogeneous factor for NSCLC patients. This study demonstrates that young age is associated with increased rates of lymph node and distant metastases. However, in spite of this, we also find that age is an independent factor for predicting outcome: younger patients have a better prognosis.

Acknowledgments

Funding: This project is funded by the Shanghai Hospital Development Center (SHDC12015116).

Ethical Statement: The study was approved by institutional ethics committee of Shanghai Pulmonary Hospital (No. K16-264).

Footnotes

Conflicts of Interest: The authors have no conflicts of interest to declare.

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