Characteristics of patients with resected well-differentiated PanNEN
The demographic and clinicopathological features of the 120 patients who underwent curative resection of PanNEN are shown in Table 1. The median age was 60 years (range 12–88 years), and the median follow-up period in all patients was 64 months (range, 6-185 months). There were no perioperative deaths. The pathological findings (based on the 2017 WHO classification) were NET-G1 in 73 patients, NET-G2 in 45, and NET-G3 in 2. The median tumor size was 14.5 mm (range 4-168 mm). Pathology investigations confirmed lymph node metastasis in 18 patients (15.0%).
Table 1
Clinicopathological characteristics of 120 patients with well-differentiated PanNEN
Patient characteristics
|
n = 120
|
%
|
Age, median(range)
|
60 (12‒88)
|
|
Sex
|
|
|
Male
|
49
|
40.8
|
Female
|
71
|
59.2
|
NLR, median (range)
|
1.93 (0.44‒5.32)
|
|
MLR, median (range)
|
0.23 (0.11‒0.53)
|
|
PLR, median (range)
|
145.2 (42.5‒328.8)
|
|
PWR, median (range)
|
43.7 (11.9‒120)
|
|
Albumin(g/L), median (range)
|
41.0 (28‒49)
|
|
Tumor size (mm), median (range)
|
14.5 (4‒168)
|
|
Operative procedures
|
|
|
PD
|
38
|
31.7
|
DP
|
58
|
48.3
|
TP
|
2
|
1.7
|
Partial resection
|
22
|
18.3
|
Surgical approach
|
|
|
Open
|
78
|
65.0
|
Laparoscopy
|
42
|
35.0
|
Tumor location
|
|
|
Head
|
47
|
39.2
|
Body/tail
|
68
|
56.7
|
Multiple
|
5
|
4.2
|
Ki-67 (%), median (range)
|
1.83 (0.02‒28)
|
|
Clinical stage
|
|
|
Ⅰ
|
74
|
61.7
|
Ⅱ
|
27
|
23.3
|
Ⅲ
|
19
|
15.0
|
2017 WHO classification
|
|
|
G1
|
73
|
60.8
|
G2
|
45
|
37.5
|
G3
|
2
|
1.7
|
Hormonal function
|
|
|
No
|
70
|
58.3
|
Yes
|
50
|
41.7
|
Lymph node metastasis
|
|
|
No
|
102
|
85.0
|
Yes
|
18
|
15.0
|
Lymphatic invasion
|
|
|
No
|
105
|
87.5
|
Yes
|
15
|
12.5
|
Venous invasion
|
|
|
No
|
91
|
75.8
|
Yes
|
29
|
24.2
|
Data are expressed as the median (range) or as absolute number |
NLR neutrophil-lymphocyte, MLR monocyte-lymphocyte ratio, PLR platelet-lymphocyte, PWR platelet-white blood cell ratio, PD pancreaticoduodenectomy, DP distal pancreatectomy, TP total pancreatectomy |
Clinicopathological Features Associated With Recurrence And Nlr
Postoperative recurrences were observed in 12 cases (10%). The sites of recurrence were in the liver in 10 patients, the para-aortic lymph node in 1, and the lung in 1. The 5- and 10- year RFS rates for the entire cohort were 92.0% and 78.7%, respectively. Three patients died due to PanNEN, 10 patients died due to other diseases, and the remaining 107 patients were alive at the end of the surveillance period. Thus, the 5- and 10-year disease-specific survival rates were 100% and 92.5%, respectively. The NLR was significantly higher in patients with recurrence than in those without recurrence (median NLR: 2.40 vs 1.90, p = 0.001), while the MLR, PLR, and PWR were not statistically significantly different between those with and those without recurrence (Fig. 1).
An ROC curve was used to determine the cutoff value associated with postoperative recurrence. Each cutoff value of NLR and tumor size was defined as the highest log-rank statistic of any threshold. The optimal cutoff values for preoperative NLR and tumor size were 2.62 mm and 25 mm, respectively (Additional file1: Fig. S1.). The Ki-67 index was statistically higher in patients with high NLR (≥ 2.62) than in patients with low NLR (< 2.62) (mean: 5.46 vs 3.14, p = 0.042). In contrast, age, sex, albumin, clinical stage, 2017 WHO classification, tumor functionality, tumor size, tumor location, lymph node metastasis, and lymphovascular invasion were not associated with NLR status (Table 2). The recurrence rate was 33.3% and 31.0% in 18 patients with a high NLR (≥ 2.62) and 29 patients with larger tumors (≥ 25 mm), respectively.
Table 2
Relationship between NLR and clinicopathological characteristics (n = 120)
|
LNR < 2.62 (n = 102)
|
LNR ≥ 2.62 (n = 18)
|
P-value
|
Age (years)
|
57.7 ± 16.0
|
59.5 ± 14.7
|
0.763
|
Sex
|
|
|
|
Female
|
59
|
12
|
0.483
|
Male
|
43
|
6
|
|
Albumin (g/L)
|
3.98 ± 0.40
|
4.01 ± 0.41
|
0.915
|
Clinical stage
|
|
|
|
Ⅰ
|
64
|
10
|
0.714
|
Ⅱ
|
23
|
4
|
|
Ⅲ
|
25
|
4
|
|
Ki-67
|
3.14 ± 3.83
|
5.46 ± 6.97
|
0.042
|
2017 WHO classification
|
|
|
|
G1
|
64
|
9
|
0.361
|
G2
|
37
|
8
|
|
G3
|
1
|
1
|
|
Hormonal function
|
|
|
|
no
|
56
|
14
|
0.070
|
yes
|
46
|
4
|
|
Tumor size (mm)
|
19.0 ± 19.4
|
22.6 ± 15.1
|
0.194
|
Tumor location
|
|
|
|
head
|
39
|
8
|
0.595
|
body/tail
|
58
|
10
|
|
multiple
|
5
|
0
|
|
Lymph node metastasis
|
|
|
|
No
|
88
|
14
|
0.352
|
Yes
|
14
|
4
|
|
lymphatic invasion
|
|
|
|
No
|
88
|
17
|
0.334
|
Yes
|
14
|
1
|
|
venous invasion
|
|
|
|
No
|
77
|
14
|
0.834
|
Yes
|
25
|
4
|
|
Results are expressed as mean ± SD or as absolute number |
Comparison of clinical variables in relationship to RFS after curative resection
The results of the univariate and multivariate analyses for each of the clinicopathological variables are shown in Table 3. According to univariate analysis, the recurrence risk was about six times higher in patients with a high NLR than in those with a low NLR (95% CI 1.81–18.5, P = 0.004). Additionally, the TMN clinical-stage, 2017 WHO classification G2/3, tumor size, and venous invasion were also significantly predictive factors for recurrence (P < 0.05 for all). In contrast, age, sex, albumin, hormonal function, tumor location, lymph node metastasis, and lymphatic invasion were not significant predictors of recurrence. Moreover, in multivariate analysis, higher NLR (HR = 3.49, 95% CI 1.05–11.7, P = 0.042) and 2017 WHO classification G2/3 (HR = 8.81, 95% CI 1.46–168.2, P = 0.015) were independent predictive factors for recurrence. A higher NLR showed a significant correlation with shorter RFS (median RFS duration, 117.8 months, P < 0.001) (Fig. 2a) and poor OS (median OS duration, 95.2 months, P = 0.032) after curative resection (Fig. 2b).
Table 3
Prognostic factors for recurrence-free-survival in 120 patients with well-differentiated PanNEN
Independent factor
|
Univariate analysis
|
Multivariate analysis
|
Hazard ratio
|
95% CI
|
P‒value
|
Hazard ratio
|
95% CI
|
P‒value
|
Age (years)
|
|
|
0.101
|
|
|
|
< 60
|
Reference
|
|
|
|
|
|
≥ 60
|
0.36
|
0.08‒1.21
|
|
|
|
|
Sex
|
|
|
0.09
|
|
|
|
Female
|
Reference
|
|
|
|
|
|
Male
|
2.66
|
0.84‒9.05
|
|
|
|
|
NLR
|
|
|
0.004
|
|
|
0.042
|
< 2.62
|
Reference
|
|
|
Reference
|
|
|
≥ 2.62
|
5.78
|
1.81‒18.5
|
|
3.49
|
1.05‒11.7
|
|
Albumin (g/L)
|
|
|
0.829
|
|
|
|
< 35
|
Reference
|
|
|
|
|
|
≥ 35
|
0.79
|
0.15‒14.5
|
|
|
|
|
Tumor size (mm)
|
|
|
<0.001
|
|
|
0.052
|
< 25
|
Reference
|
|
|
Reference
|
|
|
≥ 25
|
10.2
|
3.05‒46.2
|
|
5.30
|
0.98‒81.5
|
|
Tumor location
|
|
|
0.619
|
|
|
|
Head
|
Reference
|
|
|
|
|
|
Body/tail
|
0.95
|
0.28‒2.99
|
|
|
|
|
Multiple
|
NA
|
NA
|
|
|
|
|
Clinical stage
|
|
|
0.001
|
|
|
0.736
|
Ⅰ
|
Reference
|
|
|
Reference
|
|
|
Ⅱ/Ⅲ
|
8.12
|
2.13‒52.9
|
|
1.19
|
0.06‒13.6
|
|
2017 WHO classification
|
|
|
<0.001
|
|
|
0.015
|
G1
|
Reference
|
|
|
Reference
|
|
|
G2/G3
|
15.6
|
3.02‒285.6
|
|
8.81
|
1.46‒168.2
|
|
Hormonal function
|
|
|
0.151
|
|
|
|
No
|
Reference
|
|
|
|
|
|
Yes
|
2.46
|
0.73‒11.1
|
|
|
|
|
Lymph node metastasis
|
|
|
0.063
|
|
|
|
No
|
Reference
|
|
|
|
|
|
Yes
|
3.49
|
0.93‒11.1
|
|
|
|
|
Lymphatic invasion
|
|
|
0.150
|
|
|
|
No
|
Reference
|
|
|
|
|
|
Yes
|
2.89
|
0.64‒9.77
|
|
|
|
|
Venous invasion
|
|
|
0.022
|
|
|
0.356
|
No
|
Reference
|
|
|
Reference
|
|
|
Yes
|
3.96
|
1.23‒12.7
|
|
1.17
|
0.29‒4.49
|
|
Variables associated with RFS according to the Cox proportional hazards regression model |
RFS Recurrence-free-survival, NLR neutrophil-lymphocyte ratio, NA not available |
P-value < 0.05 marked in bold font shows statistical significance |
Subgroup analyses of the hormonal function associated with the NLR
We then focused on the usefulness of the NLR for the classification of functional and nonfunctional PanNEN. We confirmed a strong association between NLR and RFS, especially in nonfunctional PanNEN (HR 4.95; 95% CI 1.430–20.1; P = 0.002) (Table 4). Additionally, a higher NLR was significantly associated with a shorter RFS in nonfunctional PanNEN (P = 0.009) (Fig. 3a). Contrary to nonfunctional PanNEN, NLR was not associated with RFS in functional PanNEN (P = 0.094) (Fig. 3b).
Table 4
Subgroup analysis for recurrence-free-survival according to neutrophil-lymphocyte ratio
|
NLR
|
n (%)
|
RFS
|
Hazard ratio
|
95% CI
|
P‒value
|
nonfunctional PanNEN
|
|
|
|
|
|
|
< 2.62
|
56 (80)
|
Reference
|
|
0.002
|
|
≥ 2.62
|
14 (20)
|
4.95
|
1.30‒20.1
|
|
functional PanNEN
|
|
|
|
|
|
|
< 2.62
|
47 (94)
|
Reference
|
|
0.198
|
|
≥ 2.62
|
3 (6)
|
6.18
|
0.28‒66.4
|
|
P-value < 0.05 marked in bold font shows statistical significance |