Clinical and pathological characteristics
Of 141 patients with rectal cancer and clinical LPNM, 29 (20.6%) patients were postoperatively diagnosed with pathological LPNM by histopathological evaluation. Region 283, the lymph nodes around the obturator, was the most common LPN metastatic site (n=14, 48.3%). The second most frequently involved LPN metastatic site was region 263, which consisted of the proximal and distal internal iliac lymph nodes (n=8, 27.6%). Six patients (20.7%) had metastatic disease involving the common iliac lymph nodes (Region 273), and 5 patients (17.2%) had LPN metastatic sites in the external iliac lymph nodes (Region 293) (Figure 1).
The clinicopathological characteristics of the patients are listed in Table 1. Before matching, patients in the LPNM group were diagnosed with poor/mucinous/signet adenocarcinoma more frequently (44.8% vs. 25.9%, P = 0.047), showed deeper infiltration (T3-T4: 93.1% vs. 70.5%, P=0.012), had more than 4 metastatic lymph nodes (N2: 48.3% vs. 20.5%, P <0.001), and were more likely to develop lymphatic invasion (44.8 vs. 25.0%, P=0.036). After matching, the LPNM group and non-LPNM group were well balanced in terms of age, sex, BMI, CEA level, CA19-9 level, ASA category, preoperative chemotherapy, histology, pT stage, pN stage, perineural invasion, lymphatic invasion, vascular invasion, and adjuvant chemotherapy.
Table 1 Clinical and pathological characteristics of 141 rectal cancer patients with or without pathological LPNM before and after matching
Variables
|
Original cohort
|
Matched cohort
|
LPNM
(n=29)
|
Non-LPNM
(n=112)
|
P
|
LPNM
(n=29)
|
Non-LPNM
(n=29)
|
P
|
Age (years, mean±SD)
|
57.5 ± 11.7
|
56.2 ± 10.4
|
0.551
|
57.5 ± 11.7
|
58.8 ± 10.2
|
0.667
|
Gender
|
|
|
0.462
|
|
|
0.788
|
Male
|
18 (62.1)
|
61 (54.5)
|
|
18 (62.1)
|
17 (58.6)
|
|
Female
|
11 (37.9)
|
51 (45.5)
|
|
11 (37.9)
|
12 (41.4)
|
|
BMI (kg/m2, mean±SD)
|
24.3 ± 3.0
|
25.0 ± 3.2
|
0.295
|
24.3 ± 3.0
|
24.4 ± 2.5
|
0.933
|
CEA level (ng/mL, mean ± SD)
|
15.0 ± 32.0
|
8.4 ± 15.1
|
0.124
|
15.0 ± 32.0
|
12.6 ± 22.7
|
0.793
|
CA19-9 level (ng/mL, mean ± SD)
|
47.9 ± 101.8
|
19.0 ± 17.3
|
0.169
|
47.9 ± 101.8
|
31.4 ± 23.4
|
0.273
|
ASA category
|
|
|
0.580
|
|
|
1.000
|
I-II
|
26 (89.7)
|
106 (94.6)
|
|
26 (89.7)
|
27 (93.1)
|
|
III-IV
|
3 (10.3)
|
6 (5.4)
|
|
3 (10.3)
|
2 (6.9)
|
|
Preoperative chemotherapy
|
16 (55.2)
|
58 (51.8)
|
0.745
|
16 (55.2)
|
17 (58.6)
|
0.791
|
Histology
|
|
|
0.047
|
|
|
0.788
|
Moderate
|
16 (55.2)
|
83 (74.1)
|
|
17 (58.6)
|
18 (62.1)
|
|
Poor/Mucinous/signet
|
13 (44.8)
|
29 (25.9)
|
|
12 (41.4)
|
11 (37.9)
|
|
pT stage
|
|
|
0.012
|
|
|
0.666
|
T1-T2
|
2 (6.9)
|
33 (29.5)
|
|
2 (6.9)
|
4 (13.8)
|
|
T3-T4
|
27 (93.1)
|
79 (70.5)
|
|
27 (93.1)
|
25 (86.2)
|
|
pN stage
|
|
|
<0.001
|
|
|
0.514
|
N0
|
3 (10.3)
|
56 (50.0)
|
|
3 (10.3)
|
5 (17.2)
|
|
N1
|
12 (41.4)
|
33 (29.5)
|
|
12 (41.4)
|
14 (48.3)
|
|
N2
|
14 (48.3)
|
23 (20.5)
|
|
14 (48.3)
|
10 (34.5)
|
|
Perineural invasion
|
14 (48.3)
|
41 (36.6)
|
0.251
|
14 (48.3)
|
11 (37.9)
|
0.791
|
Lymphatic invasion
|
13 (44.8)
|
28 (25.0)
|
0.036
|
13 (44.8)
|
12 (41.4)
|
|
Vascular invasion
|
13 (44.8)
|
33 (29.5)
|
0.116
|
13 (44.8)
|
10 (34.5)
|
0.421
|
Mesorectal lymph nodes harvested
|
15.6 ± 8.2
|
18.7 ± 10.2
|
0.137
|
15.6 ± 8.2
|
19.5 ± 11.6
|
0.200
|
LPLNs harvested
|
9.3 ± 5.5
|
9.9 ± 6.1
|
0.773
|
9.3 ± 5.5
|
10.4 ± 6.3
|
0.602
|
Adjuvant chemotherapy
|
23 (79.3)
|
68 (60.7)
|
0.062
|
23 (79.3)
|
18 (62.1)
|
0.149
|
Operative And Perioperative Data
Perioperative outcomes including surgical outcomes, postoperative complications, and postoperative recovery are shown in Table 2. Patients in both groups had comparable types of operations, LPND, operative time, estimated blood loss, postoperative complications, time to first flatus, and postoperative hospital stay before and after matching (P > 0.05). No deaths were recorded during the perioperative period in either group.
Table 2
Perioperative outcomes of 141 rectal cancer patients with or without pathological LPNM before and after matching
Variables
|
Original cohort
|
Matched cohort
|
LPNM
(n = 29)
|
Non-LPNM
(n = 112)
|
P
|
LPNM
(n = 29)
|
Non-LPNM
(n = 29)
|
P
|
Types of operation (%)
|
|
|
0.428
|
|
|
0.890
|
Low anterior resection
|
11 (37.9)
|
54 (48.2)
|
|
11 (37.9)
|
11 (37.9)
|
|
Abdominoperineal resection
|
16 (55.2)
|
55 (49.1)
|
|
16 (55.2)
|
15 (51.7)
|
|
Hartmann procedure
|
2 (6.9)
|
3 (2.7)
|
|
2 (6.9)
|
3 (10.4)
|
|
LPND
|
|
|
0.997
|
|
|
0.517
|
Unilateral dissection
|
22 (75.9)
|
85 (75.9)
|
|
22 (75.9)
|
24 (82.8)
|
|
Bilateral dissection
|
7 (24.1)
|
27 (24.1)
|
|
7 (24.1)
|
5 (17.2)
|
|
Operative time, min (mean ± SD)
|
275.4 ± 72.8
|
265.8 ± 76.5
|
0.542
|
275.4 ± 72.8
|
283.1 ± 77.1
|
0.699
|
Estimated blood loss, ml (mean ± SD)
|
83.1 ± 61.9
|
84.3 ± 108.7
|
0.955
|
83.1 ± 61.9
|
80.3 ± 91.7
|
0.894
|
Postoperative complications
|
4 (13.8)
|
21 (18.8)
|
0.533
|
4 (13.8)
|
6 (20.7)
|
0.487
|
Postoperative bleeding
|
0 (0)
|
2 (1.8)
|
|
0 (0)
|
1 (3.4)
|
|
Ileus
|
1 (3.4)
|
2 (1.8)
|
|
1 (3.4)
|
1 (3.4)
|
|
Anastomosis leakage
|
0 (0)
|
3 (2.7)
|
|
0 (0)
|
1 (3.4)
|
|
Pelvic cavity abscess
|
1 (3.4)
|
2 (1.8)
|
|
1 (3.4)
|
1 (3.4)
|
|
Pneumonia
|
1 (3.4)
|
8 (7.1)
|
|
1 (3.4)
|
2 (6.9)
|
|
Wound infection
|
1 (3.4)
|
4 (3.6)
|
|
1 (3.4)
|
1 (3.4)
|
|
Urinary retention
|
0 (0)
|
2 (1.8)
|
|
0 (0)
|
0 (0)
|
|
Time to first flatus (day, mean ± SD)
|
3.1 ± 1.3
|
3.1 ± 1.4
|
0.868
|
3.1 ± 1.3
|
3.2 ± 1.6
|
0.715
|
Postoperative hospital stay (day, mean ± SD)
|
8.9 ± 4.5
|
8.7 ± 5.1
|
0.872
|
8.9 ± 4.5
|
9.2 ± 5.6
|
0.817
|
Re-operation
|
0 (0)
|
1 (0.9)
|
1.000
|
0 (0)
|
0 (0)
|
-
|
Mortality
|
0 (0)
|
0 (0)
|
-
|
0 (0)
|
0 (0)
|
-
|
Postoperative Recurrence Pattern
Postoperative recurrence is shown in Table 3. The postoperative overall recurrence rate (51.7% vs 21.4%, P = 0.001) and local recurrence rate (27.6% vs. 4.5%, P = 0.001) were significantly higher in the LPNM group than in the non-LPNM group before matching. Although the proportion of patients with distant metastases in the LPNM group was higher (27.6% vs 17.0, P = 0.195), the difference was not statistically significant. After eliminating confounding factors through matching, the differences in the total recurrence rate (51.7% vs 31.0%, P = 0.110) and distant metastasis rate (27.6% vs 27.6%, P = 1.000) were not significant between the two groups. Notably, more patients in the LPNM group developed local recurrence (27.6% vs 3.4%, P = 0.025) after surgery.
Table 3
Postoperative recurrence of 141 rectal cancer patients with or without pathological LPNM before and after matching
Variables
|
Original cohort
|
Matched cohort
|
LPNM
(n = 29)
|
Non-LPNM
(n = 112)
|
P
|
LPNM
(n = 29)
|
Non-LPNM
(n = 29)
|
P
|
Overall recurrence (%)
|
15 (51.7)
|
24 (21.4)
|
0.001
|
15 (51.7)
|
9 (31.0)
|
0.110
|
Local recurrence
|
8 (27.6)
|
5 (4.5)
|
0.001
|
8 (27.6)
|
1 (3.4)
|
0.025
|
Distant metastasis
|
8 (27.6)
|
19 (17.0)
|
0.195
|
8 (27.6)
|
8 (27.6)
|
1.000
|
Liver metastasis
|
5 (17.2)
|
11 (9.8)
|
|
5 (17.2)
|
5 (17.2)
|
|
Lung metastasis
|
1 (3.4)
|
11 (9.8)
|
|
1 (3.4)
|
5 (17.2)
|
|
Bone metastasis
|
2 (6.9)
|
2 (1.8)
|
|
2 (6.9)
|
2 (6.9)
|
|
Peritoneal metastasis
|
1 (3.4)
|
0 (0)
|
|
1 (3.4)
|
0 (0)
|
|
Others
|
0 (0)
|
2 (1.8)
|
|
0 (0)
|
0 (0)
|
|
Survival Analysis
The median follow-up period of the whole group was 25.0 (range, 2–66) months. In total, 22 (15.6%) patients died and 43 (30.5%) patients developed local recurrence or distant metastasis during follow-up. Before matching, the OS and DFS of patients in the LPNM group were significantly worse than those of patients in the non-LPNM group (Figs. 2 and 3). The 1-, 2- and 3-year OS rates were 92.0% vs. 97.9%, 71.7% vs. 92.4% and 57.9% vs. 85.7% in the LPNM group and non-LPNM group, respectively (P < 0.001) (Table 4). The 1-, 2- and 3-year DFS rates were 52.3% vs. 85.3%, 43.2% vs. 77.9% and 36.0% vs. 68.4% in the LPNM group and non-LPNM group, respectively (P < 0.001) (Table 4). After matching, the DFS of patients in the LPNM group was also found to be significantly worse than that in the non-LPNM group (P = 0.044) (Fig. 5), while there was no significant difference in OS between the two groups (P = 0.168) (Fig. 4). The 1-, 2- and 3-year OS rates were 92.0% vs. 96.0%, 71.7% vs. 85.3 and 73.0% vs. 56.5% in the LPNM group and non-LPNM group, respectively (P = 0.168) (Table 4). The 1-, 2- and 3-year DFS rates were 52.3% vs. 81.4%, 43.2% vs. 77.3% and 36.0% vs. 49.2% in the LPNM group and non-LPNM group, respectively (P = 0.044) (Table 4).
Table 4
Overall survival and disease-free survival of 141 rectal cancer patients with or without pathological LPNM before and after matching
|
N
|
Overall survival
1-year 2-year 3-year
|
Disease-free survival
1-year 2-year 3-year
|
Before matching
|
|
|
|
LPNM
|
29
|
92.0% 71.7% 57.9%
|
52.3% 43.2% 36.0%
|
Non-LPNM
|
112
|
97.9% 92.4% 85.7%
|
85.3% 77.9% 68.4%
|
After matching
|
|
|
|
LPNM
|
29
|
92.0% 71.7% 56.5%
|
52.3% 43.2% 36.0%
|
Non-LPNM
|
29
|
96.0% 85.3% 73.0%
|
81.4% 77.3% 49.2%
|
Univariate and multivariate regression analyses were performed to identify prognostic factors for OS and DFS of patients with clinical LPNM who underwent TME + LPND. In univariate analysis, histology, perineural invasion, lymphatic invasion, N stage, and LPNM significantly affected OS (P < 0.05). In addition, DFS was significantly affected by the preoperative CEA level, perineural invasion, lymphatic invasion, N stage, and LPNM (P < 0.05). In multivariate regression analysis, LPNM was an independent risk factor not only for OS (HR: 3.06; 95% CI, 1.15–8.17; P = 0.025) but also for DFS (HR: 2.39; 95% CI, 1.18–4.87; P = 0.016). Moreover, lymphatic invasion was another independent risk factor for OS (HR: 3.34; 95% CI, 1.13–9.88; P = 0.003) (Table 5).
Table 5
Univariate and multivariate analyses for overall survival and disease-free survival of the 141 rectal patients with clinical LPNM who underwent TME + LPND
Variables
|
Overall survival
|
Disease-free survival
|
Univariate analysis
|
Multivariate analysis
|
Univariate analysis
|
Multivariate analysis
|
HR(95%CI)
|
P
|
HR(95%CI)
|
P
|
HR(95%CI)
|
P
|
HR(95%CI)
|
P
|
Gender: male/female
|
0.86 (0.37–1.98)
|
0.716
|
|
|
0.85 (0.46–1.56)
|
0.600
|
|
|
Age
|
1.02 (0.97–1.06)
|
0.459
|
|
|
0.99 (0.97–1.03)
|
0.817
|
|
|
Preoperative chemotherapy
|
1.70 (0.65–4.48)
|
0.283
|
|
|
1.59 (0.85-3.00)
|
0.149
|
|
|
Preoperative CEA level
|
1.01 (0.98–1.03)
|
0.587
|
|
|
1.01 (1.00-1.03)
|
0.050
|
1.01 (0.99–1.02)
|
0.165
|
Preoperative CA19-9 level
|
1.00 (0.99–1.01)
|
0.160
|
|
|
1.00 (0.99–1.01)
|
0.512
|
|
|
Histology
|
2.83 (1.21–6.64)
|
0.017
|
1.38 (0.55–3.44)
|
0.489
|
1.77 (0.95–3.29)
|
0.073
|
|
|
Perineural invasion
|
2.78 (1.19–6.46)
|
0.018
|
1.48 (0.54–4.09)
|
0.450
|
2.06 (1.13–3.76)
|
0.019
|
1.77 (0.86–3.65)
|
0.121
|
Vascular invasion
|
1.29 (0.52–3.19)
|
0.589
|
|
|
0.98 (0.50–1.91)
|
0.953
|
|
|
Lymphatic invasion
|
6.00 (2.42–14.89)
|
< 0.001
|
3.34 (1.13–9.88)
|
0.003
|
2.31 (1.24–4.29)
|
0.008
|
1.48 (0.70–3.12)
|
0.303
|
T stage: T3-4/T1-2
|
2.36 (0.70-8.00)
|
0.168
|
|
|
1.24 (0.61–2.51)
|
0.557
|
|
|
N stage
|
|
|
|
|
|
|
|
|
N0
|
Reference
|
|
Reference
|
|
Reference
|
|
Reference
|
|
N1
|
1.67 (0.51–5.50)
|
0.398
|
1.08 (0.30–3.89)
|
0.905
|
1.38 (0.66–2.90)
|
0.390
|
0.87 (0.38–2.03)
|
0.751
|
N2
|
5.06 (1.74–14.76)
|
0.003
|
2.68 (0.84–8.54)
|
0.096
|
2.32 (1.12–4.83)
|
0.024
|
1.16 (0.48–2.85)
|
0.741
|
LPN metastasis
|
4.49 (1.82–11.12)
|
0.001
|
3.06 (1.15–8.17)
|
0.025
|
2.95 (1.59–5.50)
|
0.001
|
2.39 (1.18–4.87)
|
0.016
|
Mesorectal LN harvested
|
0.98 (0.93–1.03)
|
0.411
|
|
|
0.99 (0.96–1.03)
|
0.698
|
|
|
LPN harvested
|
0.99 (0.98–1.01)
|
0.345
|
|
|
1.00 (0.99–1.01)
|
0.264
|
|
|
Adjuvant chemotherapy
|
0.58 (0.25–1.35)
|
0.209
|
|
|
0.72 (0.39–1.33)
|
0.292
|
|
|
Postoperative complications
|
0.49 (0.14–1.68)
|
0.255
|
|
|
0.82 (0.38–1.79)
|
0.618
|
|
|
Univariate and multivariate regression analyses were performed to identify prognostic factors for OS and DFS of patients with pathological LPNM. These patients were divided into a high-risk LPNM group and a low-risk LPNM group according to the site (obturator or internal iliac artery region) and number (< 2 positive LPNs) of LPNMs. The OS and DFS of the patients in the high-risk LPNM group were significantly worse than those of patients in the low-risk LPNM group and non-LPNM group (Figs. 6 and 7). In univariate analysis, lymphatic invasion and high-risk LPNM significantly affected both OS and DFS (P < 0.05). According to multivariate analysis, high-risk LPNM was an independent risk factor affecting both OS (HR: 9.23; 95% CI, 1.46–87.35; P = 0.032) and DFS (HR: 4.39; 95% CI, 1.33–13.16; P = 0.041) (Table 6).
Table 6
Univariate and multivariate analyses for overall survival and disease-free survival of the 29 rectal patients with pathological LPNM.
Variables
|
Overall survival
|
Disease-free survival
|
Univariate analysis
|
Multivariate analysis
|
Univariate analysis
|
Multivariate analysis
|
HR(95%CI)
|
P
|
HR(95%CI)
|
P
|
HR(95%CI)
|
P
|
HR(95%CI)
|
P
|
Gender: male/female
|
0.72 (0.19–2.71)
|
0.625
|
|
|
0.99 (0.37–2.71)
|
0.998
|
|
|
Age
|
1.01 (0.95–1.06)
|
0.811
|
|
|
0.99 (0.96–1.03)
|
0.767
|
|
|
Preoperative chemotherapy
|
2.73 (0.56–13.34)
|
0.214
|
|
|
1.78 (0.65–4.94)
|
0.265
|
|
|
Preoperative CEA level
|
0.99 (0.93–1.05)
|
0.705
|
|
|
1.01 (1.00-1.02)
|
0.181
|
|
|
Preoperative CA19-9 level
|
1.00 (0.99–1.01)
|
0.858
|
|
|
1.00 (0.99–1.01)
|
0.677
|
|
|
Histology
|
0.89 (0.22–3.64)
|
0.870
|
|
|
1.00 (0.36–2.78)
|
0.999
|
|
|
Perineural invasion
|
3.89 (0.34–18.10)
|
0.083
|
|
|
2.03 (0.70–5.90)
|
0.195
|
|
|
Vascular invasion
|
1.06 (0.28–3.99)
|
0.935
|
|
|
0.77 (0.28–2.14)
|
0.612
|
|
|
Lymphatic invasion
|
6.64 (1.35–32.78)
|
0.020
|
2.74 (0.44–17.15)
|
0.280
|
3.03 (1.01–9.10)
|
0.048
|
1.65 (0.45–5.99)
|
0.447
|
T stage: T3-4/T1-2
|
1.17 (0.15–9.42)
|
0.884
|
|
|
0.50 (0.14–1.80)
|
0.289
|
|
|
N stage
|
|
|
|
|
|
|
|
|
N0
|
Reference
|
|
|
|
Reference
|
|
|
|
N1
|
0.17 (0.15–185)
|
0.145
|
|
|
0.62 (0.15–2.63)
|
0.517
|
|
|
N2
|
1.83(0.35–9.68)
|
0.477
|
|
|
1.38 (0.34–5.57)
|
0.654
|
|
|
Mesorectal LN harvested
|
0.98 (0.91–1.06)
|
0.638
|
|
|
1.00 (0.94–1.06)
|
0.994
|
|
|
LPN harvested
|
1.01 (0.95–1.08)
|
0.742
|
|
|
0.98 (0.92–1.05)
|
0.605
|
|
|
Adjuvant chemotherapy
|
0.69 (0.17–2.77)
|
0.598
|
|
|
0.39 (0.14–1.08)
|
0.071
|
|
|
Postoperative complications
|
0.52 (0.06–4.33)
|
0.547
|
|
|
0.42 (0.09–1.93)
|
0.263
|
|
|
High risk LPNM
|
15.33 (1.77-133.46)
|
0.013
|
9.23 ( 1.46–87.35)
|
0.032
|
4.46 (1.38–14.46)
|
0.013
|
4.39 (1.33–13.16)
|
0.041
|