Patient characteristics are summarised in Table 1. The most common histopathological tumour type was squamous cell carcinoma (n = 694, 56.1%). Lobectomy and pneumonectomy were performed in 807 (65.3%) and in 429 (34.7%) patients, respectively. The median tumour diameter was 4.5 cm (min = 0.1 cm, maximum = 20 cm). The mean number of resected LN stations was 6.2 (min = 5 resected LN stations, maximum = 10 resected LN stations, median = 6 resected LN stations, IQR = 2). According to the IASLC-proposed N classification, 512 patients (41.4%) were pathologically identified as having N1a disease, 271 (21.9%) had N1b, 119 (9.6%) had N2a1, 201 (16.3%) had N2a2, and 133 (10.8%) had N2b disease (783 patients with pN1 disease and 453 with pN2 disease). The mean number of stations with metastasis was 1.7 ± 1.0 (min = 1, max = 7, median = 1, IQR = 1). It was 1.4 ± 0.6 in pN1 patients (min = 1 LN station metastasis, max = 4 LN station metastasis, median = 1 LN station metastasis, IQR = 1), and 2.4 ± 1.2 in pN2 patients (min = 1 LN station metastasis, max = 7 LN stations metastasis, median = 2 LN stations metastasis, IQR = 2).
Table 1
Patients’ characteristics
Variables | Data |
Age, year, median (IQR) | 60 (11) |
Sex, n/% women men | 155/12.5 1081/87.5 |
Cell type n/% Sqcc Ade Others | 694/56.1 457/37.0 85/6.9 |
Tumour diameter, cm, median (IQR) | 4.5/2.8 |
pT status, n/% T1 T2 T3 T4 | 194/15.7 497/40.2 293/23.7 252/20.4 |
pN status, n/% N1a N1b N2a1 N2a2 N2b | 512/41.4 271/21.9 119/9.6 201/16.3 133/10.8 |
Resection type, n/% Lobectomy Pneumonectomy | 807/65.3 429/34.7 |
No. of resected LN stations, mean ± SD | 6.1 ± 1.3 |
Surgical mortality, n/% | 37/3.0 |
Adjuvant treatment, n/% | 905/73.2 |
SD, standard deviation; n, number; Sqcc, squamous cell carcinoma; Ade, adenocarcinoma; LN, lymph node; IQR, interquartile range. |
Kaplan-Meier survival estimates according to the IASLC proposed N classification (new-N category) and according to the redefining N prognostic subgroups based on the number of involved LN stations (sN-category)
The 5-year survival rates were 56.0% for pN1 patients (median survival, 73 months) and 29.9% for pN2 patients (median survival, 31 months) (p < 0.001). The difference in survival between N1a and N1b patients was statistically significant (61.6% vs. 45.2%, p < 0.001); however, there was no statistically significant difference between N1b and N2a1 patients in terms of survival (45.2% vs. 41.7%, p = 0.259). N2a1 patients had a better prognosis than N2a2 patients (41.7% vs. 30.7%), although the difference was not statistically significant (p = 0.111). N2a2 patients had significantly better survival rates than N2b patients (35.8% vs. 17.4%, p = 0.01) (Supplementary Fig. 1).
The overall survival deteriorated as the number of metastatic LN stations increased (Supplementary Fig. 2). When survival was analysed per LN station metastasis increment, a progressive degradation of survival was observed for each cut-off point (Table 2a). However, some cut-off points were not statistically significant (Table 2b). We observed that two cut-off points for station(s) metastases provided additional prognostic information after the other cut-off points were considered in the stepwise selection process. The highest chi-square and HR values in the survival comparisons per LN station metastases were the comparisons between one LN station metastasis and two LN station metastases (chi-square = 17.993, hazard ratio = 1.455, 95% CI = 1.210–1.750), and three LN station metastases and four LN station metastases (chi-square = 10.746, hazard ratio = 1.668, 95%CI = 1.185–2.348). Only these comparisons were statistically significant in terms of survival (p < 0.001 and p = 0.001, respectively). According to these results, the sN prognostic subgroups were created as follows: sN-αlfa, a single LN station metastasis; sN-βeta, 2–3 LN stations metastasis; and sN-Ɣamma, 4 and above (≥ 4) LN stations metastasis.
Table 2
Survival analysis for per lymph node stations metastases and for gradual lymph node station(s) metastasis
Survival analysis for LN station(s) metastases |
Number of metastatic LN station(s) | No. of patients | MST (months) | 5-year survival rate | P | Chi-square | HR (%95 CI) |
1 versus ≥ 2 LN stations metastases | 632 vs 604 | 75 vs 35 | 57.7% vs %34.9 | < 0.001 | 52.914 | 1.721 (1.482–1.999) |
≤ 2 versus ≥ 3 LN stations metastases | 990 vs 246 | 63 vs 26 | 51.5% vs 26.9% | < 0.001 | 60.607 | 1.919 (1.566–2.351) |
≤ 3 versus ≥ 4 stations metastases | 1137 vs 99 | 58 vs 19 | 49.6% vs %12.7 | < 0.001 | 70.222 | 2.545 (1.816–3.565) |
≤ 4 versus ≥ 5 LN stations metastases | 1213 vs 23 | 51 vs 12 | 47.2% vs %6.2 | < 0.001 | 23.062 | 2.822 (1.355–5.877) |
Survival analysis for per LN station(s) metastases |
Number of metastatic LN station(s) | No. of patients | MST (months) | 5-year survival rate | P | Chi-square | HR (%95CI) |
1 versus 2 LN stations metastases | 632 vs 358 | 75 vs 40 | 57.7% vs 40.6% | < 0.001a | 17.993 | 1.455 (1.210–1.750) |
2 versus 3 LN stations metastases | 358 vs 147 | 40 vs 34 | 40.6% vs 36.7% | 0.09 | 2.962 | 1.229 (0.960–1.574) |
3 versus 4 LN stations metastases | 147 vs 76 | 34 vs 20 | 36.7% vs 13.4% | 0.001 a | 10.746 | 1.668 (1.185–2.348) |
4 versus 5 LN stations metastases | 76 vs 16 | 20 vs 12 | 13.4% vs 12.5%# | 0.547 | 0.362 | 1.164 (0.689–1.964) |
5 versus 6 + 7 LN stations metastases* | 16 vs 7 | 12 vs 9 | 12.5%# vs 0.0%# | 0.898 | 0.016 | 1.098 (0.882–1.345) |
a It was accepted as a cutpoint (threshold) for LN station(s) metastases since these cutpoints had the highest chi-square and HR values. * There were only two patients who had seven different LN station metastases. # Four-year survival rate; HR, hazard ratio; CI, confidence interval. |
The survival rates were statistically different among the sN prognostic subgroups and deteriorated from sN-αlfa to sN-Ɣamma (Fig. 1). The 5-year survival rate was 57.7% for sN-αlfa patients (median survival = 75 months), 39.2% for sN-βeta patients (median survival = 39 months), and 12.7% for sN-Ɣamma (median survival = 19 months) (p < 0.001, log-rank). The differences in survival between sN-αlfa and sN-βeta and between sN-βeta and sN-Ɣamma were statistically significant (p < 0.001, HR = 1.545, 95% CI = 1.315–1.815, and p < 0.001, HR = 1.985, 95%CI = 1.465–2.690, respectively).
Multivariate analyses for survival
Multivariate analysis revealed that age (p < 0.001), sex (p = 0.002), tumour histology (p < 0.001), IASLC-proposed N classification (p < 0.001), and sN prognostic subgroups (p < 0.001) were independent prognostic factors for overall survival (Table 3).
Table 3
Multivariate Analyses for overall survival
Variables | Multivariate analysis 1 | Multivariate analysis 2 |
HR | 95%CI | p value | HR | 95%CI | p value |
Age (per year) | 1.025 | 1.016–1.034 | < 0.001 | 1.020 | 1.011–1.029 | < 0.001 |
Sex Women Men | Ref 0.678 | 0.528–0.871 | 0.002 | Ref 0.693 | 0.540–0.891 | 0.004 |
Cell type Non-Adenocarcinoma Adenocarcinoma | Ref 1.253 | 1.057–1.486 | 0.001 | Ref 1.346 | 1.137–1.592 | 0.001 |
Tumour diameter (per cm) | 1.019 | 0.968–1.074 | 0.473 | 1.020 | 0.968–1.076 | 0.457 |
pT status T1 T2 T3 T4 | Ref 1.082 1.263 1.352 | 0.861–1.359 0.975–1.636 1.054–1.734 | 0.06 0.499 0.07 0.01 | Ref 1.079 1.252 1.327 | 0.859–1.355 0.968–1.621 1.035–1.702 | 0.06 0.513 0.08 0.02 |
pN status N1a N1b N2a1 N2a2 N2b | Ref 1.403 1.830 2.219 3.055 | 1.138–1.730 1.410–2.376 1.784–2.760 2.400-3.889 | < 0.001 0.04 < 0.001 < 0.001 < 0.001 | | | |
sN status sN-αlfa sN-βeta sN-Ɣamma | | | | Ref 1.524 3.023 | 1.297–1.791 2.346–3.894 | < 0.001 < 0.001 < 0.001 |
Resection type Lobectomy Pneumonectomy | Ref 1.149 | 0.967–1.365 | 0.116 | Ref 1.087 | 0.916–1.289 | 0.338 |
No. of resected LN stations (per LN station) | 0.996 | 0.942–1.053 | 0.883 | 0.998 | 0.950–1.062 | 0.877 |
Adjuvant treatment No Yes | Ref 0.953 | 0.802–1.131 | 0.580 | Ref 0.960 | 0.808–1140 | 0.960 |
Multivariate analysis 1 for pN categories that was proposed by IASLC, Multivariate analysis 2 for sN prognostic subgroups, pN, pathological-N; N1a, single N1 station metastasis; N1b, multiple N1 stations metastasis; N2a1, pN2 single with skip metastasis; N2a2, pN2 single without skip metastasis; N2b, multiple N2 statios metastasis; sN; classification based on the number of metastatic lymph node stations, sN-αlfa, a single LN station metastasis; sN-βeta, 2–3 LN stations metastasis; and sN-Ɣamma, 4 and above (≥ 4) LN stations metastasis, LN, lymph nodes; pT, pathological tumour stage; HR, hazard ratio; CI, confidence interval. |
Internal Validation of the sN subcategories with each pT status and Cross-Validation of the Prognostic Significance for sN subcategories in N1 and N2 patients
Internal validation of the sN subcategories in terms of survival was performed for each pT status. We observed a clear tendency of deterioration of survival from sN-αlfa to sN-Ɣamma in the same pT stage except in pT4 stage. In pT4 stage, the differences in the survival curves among neighbouring sN subcategories decreased (Fig. 2).
Cross-validation of the sN categories for prognostic significance was performed separately for N1 and N2 patients. When patients with N1 disease or N2 disease were divided into sN-αlfa, sN-βeta, and sN-Ɣamma subgroups, the prognostic differences between each pair of sN subcategories were statistically significant in survival (Supplementary Fig. 3a and 3b).
In contrast, there were significant differences in overall survival between patients with N1 and N2 disease when staging in the same sN-α and sN-β categories. In sN-α, the 5-year survival rate for pN1 patients was 61.0% whereas it was 41.7% in pN2 patients (p < 0.001) (Supplementary Fig. 4a). In sN-β, pN1 patients had a better survival rate than pN2 patients (46.5% versus 31.4%, p = 0.001) (Supplementary Fig. 4b). However, there was no significant difference between patients with N1 and N2 disease when staging in the same sN-Ɣ category (p = 0.793). In sN-Ɣ, the 5-year survival rates were almost similar between N1 and N2 disease (16.7% versus 11.0%) (Supplementary Fig. 4c).