Clinicopathological characteristics
A final 9,958 patients with histologically confirmed resected PDAC without distant metastasis were identified after applying the inclusion and exclusion criteria mentioned in Fig. 1. Among this retrieved cohort, the median age was 67 (ranging from 17 to 95) years, and female patients accounted for 50.4%. Lesions located in the head of the pancreas were almost ten times more common than those in the body or tail. Based on the pathological examinations, approximately 9%, 49%, and 34% of PDAC patients were confirmed as well, moderately and poorly or undifferentiated, respectively. The median number of examined and positive LNs was 20.8 (IQR 15.0–25.0) and 3.0 (IQR 0–4.0), respectively. N0 stage was found in 2,891 patients while 3,985 were stage N1 and 3,082 were stage N2. In addition, the median tumor diameter of the total cohort was 31.0 mm (IQR 25.0–40.0 mm), and the population of each 5 mm segment is displayed in Table 1. According to the National Comprehensive Cancer Network (NCCN) guideline, radiotherapy was administered in 34.1% of patients while 72.3% received chemotherapy.
Table 1
Univariate and multivariate analysis of prognostic indicators for overall survival and cancer-specific survival in resected PDAC patients.
Variables
|
No. of patients (N = 9958)
|
Overall survival
|
Cancer-specific survival
|
Univariate P value
|
Multivariate P value
|
Hazard Ratio
(95% CI)
|
Univariate P value
|
Multivariate P value
|
Hazard Ratio
(95% CI)
|
Age (years)
≤65
༞65
|
4523
5435
|
< 0.001
|
< 0.001
|
1.203
1.145–1.263
|
< 0.001
|
< 0.001
|
1.156
1.097–1.217
|
Gender
Female
Male
|
5015
4943
|
0.012
|
0.130
|
1.038
0.989–1.089
|
0.022
|
0.296
|
1.028
0.977–1.081
|
Location
Head
Body
Tail
Others
|
7672
674
751
861
|
0.016
|
0.001
|
0.955
0.931–0.980
|
0.003
|
0.001
|
0.952
0.926 − 0.919
|
Grade
Well differentiated (I)
Moderately differentiated (II)
Poorly differentiated or
Undifferentiated (III or IV)
Unknown
|
906
4911
3404
737
|
< 0.001
|
< 0.001
|
1.169
1.132–1.206
|
< 0.001
|
< 0.001
|
1.188
1.149–1.228
|
Radiotherapy
None/Unknown
Yes
|
6563
3395
|
< 0.001
|
0.006
|
0.925
0.875–0.978
|
< 0.001
|
0.009
|
0.925
0.872–0.980
|
Chemotherapy
None/Unknown
Yes
|
2758
7200
|
< 0.001
|
< 0.001
|
0.548
0.518–0.580
|
< 0.001
|
< 0.001
|
0.577
0.543–0.613
|
AJCC 8th N staging
N0
N1
N2
|
2891
3985
3082
|
< 0.001
|
< 0.001
|
1.456
1.410–1.504
|
< 0.001
|
< 0.001
|
1.527
1.476–1.580
|
Tumor size (mm)
1–5
6–10
11–15
16–20
21–25
26–30
31–35
36–40
41–45
46–50
51–55
56–60
61–65
66–70
71–85
86–100
|
63
115
424
957
1643
1677
1549
1236
779
556
319
236
134
89
119
62
|
< 0.001
|
< 0.001
|
1.050
1.040–1.059
|
< 0.001
|
< 0.001
|
1.051
1.041–1.061
|
PDAC, pancreatic ductal adenocarcinoma; CI, confidence interval. |
The median OS of this cohort was 21.0 months (IQR 11.0–43.0 months), and its accumulative 5-year OS rate was 17.9%. Referring to CSS, its median was 23.0 months (IQR 12.0–49.0 months), and the accumulative 5-year CSS rate was 21.2%.
Prognostic Indicators For Resected PDAC
Many indicators have been verified as predicators of resected PDAC. Univariate analysis revealed that age (P < 0.001), gender (P = 0.012), tumor site (P = 0.016), tumor grade (P < 0.001), AJCC 8th N staging (P < 0.001), tumor size (P < 0.001), radiotherapy (P < 0.001) and chemotherapy (P < 0.001) were all significant prognostic factors for OS, as well as those for CSS (Table 1). Furthermore, multivariate analysis showed that age [P < 0.001; hazard ratio (HR), 1.203; 95% confidence interval (CI), 1.145–1.263], tumor site (P = 0.001; HR, 0.955; 95% CI, 0.931–0.980), tumor grade (P < 0.001; HR, 1.169; 95% CI, 1.132–1.206), AJCC 8th N staging (P < 0.001; HR, 1.456; 95% CI, 1.410–1.504), tumor size (P < 0.001; HR, 1.050; 95% CI, 1.040–1.059), radiotherapy (P = 0.006; HR, 0.925; 95% CI, 0.875–0.978) and chemotherapy (P < 0.001; HR, 0.548; 95% CI, 0.518–0.580) remained as significant independent predictors for OS, as well as those for CSS (Table 1).
Correlations between tumor sizes and prevalence of lymph node metastases
The prevalence of LN metastases in this cohort was 71.0%. There was a non-linear relation between increasing tumor sizes and the prevalence of LN metastases across the tumor size spectrum (Fig. 2). Patients with tumors between 1 and 5 mm in size had the lowest prevalence of LN metastases (less than 15%). Then, the prevalence increased in a stepwise fashion as tumor size increased from 6–10 mm (40.0%) to 36–40 mm (75.7%); however, beyond 40 mm, the prevalence of LN metastases plateaued between 70.0% and 80.0%. Observing the tracing pattern of the initial part of the curve (1–40 mm), which conformed to non-linear correlation, we tried to use the logarithmic regression to match this non-linear curve. As expected, the established curve was highly matched (Figure S1), and its formula was
Y = [0.249 × ln (X) + 0.452] × 100%
Correlation coefficient R2 = 0.991 (Y, prevalence of LN metastases; X, tumor size in centimeter)
Thus, the prevalence of LN metastases was limited within 80% no matter the size of tumors. The probability for PDAC patients with tumors within 1–40 mm in size to be detected with positive LN metastasis was subjected to the formulated matched curve, and when tumors larger than 40 mm, its probability was steadily within 70%-80%.
Patterns Between Tumor Sizes And Lymph Node Metastatic Status
LNR measures the metastatic ability of each examined LN. The global LNR of the total cohort was 0.145 (IQR 0-0.214), and in patients with at least one positive LN metastasis was 0.205 (IQR 0.077–0.278). Following the tracing pattern of average LNR across the tumor size spectrum, the average LNR increased stepwise as tumor size rose from 1–5 mm (LNR = 0.024) to 41–45 mm (LNR = 0.177); then, beyond 45 mm, it too plateaued near 0.170 (Fig. 2). Thus, when tumor size reaches 41–45 mm or more, the probability of metastasis in each regional LN was steadily near 17.0%.
Expectedly, patients with a higher N stage revealed a higher metastatic presence. The number of stage N2 patients/the number of stage N1 patients (N2/N1) represents the distribution of patients with different LN metastatic severity. The tracing pattern of N2/N1 was similar to the curve for average LNR. N2/N1 ratio gradually increased along with greater tumor size from 1–5 mm (0.286) to 41–45 mm (1.016), and when tumor size reached 41–45 mm or more, the ratio stably wavered around 1.000 except for size group 61–65 mm. Therefore, nearly half of LN positive patients may have an N2 stage when tumor size reaches 40 mm.
Prognostic significance of AJCC 8th N staging in different tumor sizes
In the analysis of the prognostic significance of AJCC 8th N staging for OS, there was no significant difference in patients with tumor between 1 and 5 mm in size. Additionally, no significant difference was obtained between stage N2 and N1 when tumor size from 6 to 15 mm. However, once tumor sizes ranged from 16 to 45 mm, the survival curves could be stratified significantly based on N stage. Again, when tumor size ranged between 46 and 65 mm, there was no significant difference between stage N1 and N0. Furthermore, no significant difference was reached when tumor size was greater than 66 mm except for stage N2 and N0 in size group 86–100 mm (Table 2).
Table 2
Prognostic significance of AJCC 8th N staging in different tumor sizes.
Tumor size (mm)
|
JACC 8th
N staging
|
No. of patients
|
Overall survival P value
|
Cancer-specific survival P value
|
N0
|
N1
|
N2
|
N0
|
N1
|
N2
|
1–5
|
N0
N1
N2
|
54
6
3
|
0.14
0.21
|
0.14
0.683
|
0.21
0.683
|
0.031
0.003
|
0.031
0.683
|
0.003
0.683
|
6–10
|
N0
N1
N2
|
69
35
11
|
0.001
< 0.001
|
0.001
0.525
|
< 0.001
0.525
|
< 0.001
< 0.001
|
< 0.001
0.315
|
< 0.001
0.315
|
11–15
|
N0
N1
N2
|
211
158
55
|
0.012
< 0.001
|
0.012
0.051
|
< 0.001
0.051
|
0.003
< 0.001
|
0.003
0.127
|
< 0.001
0.127
|
16–20
|
N0
N1
N2
|
372
391
194
|
0.030
< 0.001
|
0.030
< 0.001
|
< 0.001
< 0.001
|
0.008
< 0.001
|
0.008
< 0.001
|
< 0.001
< 0.001
|
21–25
|
N0
N1
N2
|
508
688
447
|
< 0.001
< 0.001
|
< 0.001
< 0.001
|
< 0.001
< 0.001
|
< 0.001
< 0.001
|
< 0.001
< 0.001
|
< 0.001
< 0.001
|
26–30
|
N0
N1
N2
|
451
717
509
|
< 0.001
< 0.001
|
< 0.001
< 0.001
|
< 0.001
< 0.001
|
< 0.001
< 0.001
|
< 0.001
< 0.001
|
< 0.001
< 0.001
|
31–35
|
N0
N1
N2
|
381
637
531
|
< 0.001
< 0.001
|
< 0.001
< 0.001
|
< 0.001
< 0.001
|
< 0.001
< 0.001
|
< 0.001
< 0.001
|
< 0.001
< 0.001
|
36–40
|
N0
N1
N2
|
300
478
458
|
< 0.001
< 0.001
|
< 0.001
0.002
|
< 0.001
0.002
|
< 0.001
< 0.001
|
< 0.001
< 0.001
|
< 0.001
< 0.001
|
41–45
|
N0
N1
N2
|
160
307
312
|
0.001
< 0.001
|
0.001
0.036
|
< 0.001
0.036
|
< 0.001
< 0.001
|
< 0.001
0.018
|
< 0.001
0.018
|
46–50
|
N0
N1
N2
|
134
203
219
|
0.072
< 0.001
|
0.072
< 0.001
|
< 0.001
< 0.001
|
0.115
< 0.001
|
0.115
< 0.001
|
< 0.001
< 0.001
|
51–55
|
N0
N1
N2
|
73
123
123
|
0.372
0.033
|
0.372
0.179
|
0.033
0.179
|
0.478
0.021
|
0.478
0.081
|
0.021
0.081
|
56–60
|
N0
N1
N2
|
62
88
86
|
0.044
0.001
|
0.044
0.227
|
0.001
0.227
|
0.032
< 0.001
|
0.032
0.065
|
< 0.001
0.065
|
61–65
|
N0
N1
N2
|
39
55
40
|
0.698
0.025
|
0.698
0.023
|
0.025
0.023
|
0.318
0.003
|
0.318
0.012
|
0.003
0.012
|
66–70
|
N0
N1
N2
|
28
31
30
|
0.124
0.074
|
0.124
0.808
|
0.074
0.808
|
0.077
0.047
|
0.077
0.905
|
0.047
0.905
|
71–85
|
N0
N1
N2
|
31
46
42
|
0.124
0.074
|
0.124
0.808
|
0.074
0.808
|
0.185
0.017
|
0.185
0.233
|
0.017
0.233
|
86–100
|
N0
N1
N2
|
18
22
22
|
0.445
0.008
|
0.445
0.234
|
0.008
0.234
|
0.356
0.018
|
0.356
0.292
|
0.018
0.292
|
AJCC, American Joint Committee on Cancer. |
Concurrently, in the analysis for CSS, significant differences and discriminations by N stage were found in tumor size of 16–45 mm, similar to OS. The other detailed descriptions when tumor size was less than 16 mm or more than 45 mm are displayed in Table 2. Overall, remarkable stratification and discrimination was only achieved in tumors ranging between 16 and 45 mm in size. Furthermore, other detailed prognostic indicators, such as age, gender, grade, chemotherapy and radiotherapy in different tumor sizes, were analyzed and displayed in Supplementary Tables 1–3.