A total of 3651 patients with stage I-III CRC diagnosed in Yunnan Cancer Hospital and the Sixth Affiliated Hospital of Sun Yat-Sen University from 2010 to 2020 were retrospectively and continuously collected. We excluded 2571 patients with following criteria: (1) Patients with cancer history < 5 years (n = 12); (2) Patients with preoperative chemotherapy or radiotherapy (n = 734); (3) Patients with missing tumor deposition data (n = 98); (4) Patients with no regional lymph node metastases or missing nodal data (n = 1727). Finally, 1080 stage III CRC patients (634 [58.7%] men; median [IQR] age, 60 [50–68] years) who underwent radical surgical resection were included in this study. Among the 1080 patients, 745 patients (68.9%) had stage N1 and 335 patients (31.1%) had stage N2 by incorporating the number of tumor deposits into the number of lymph node metastases. Of the 745 patients with stage N1 disease, 687 patients had 1–3 tumor deposits + lymph node metastases and 58 patients had 4 or more tumor deposits + lymph node metastases (Fig. 1).
The 3-year RFS of 745 patients with original N1 stage was 79.8% (95% CI, 71.6%-83.9%), and the 3-year RFS of 335 patients with N2 stage was 62.3% (95% CI, 58.5%-68.1%). There was a statistically significant difference between the two groups (HR, 1.82; 95% CI, 1.47–2.26; P < 0.0001) (Fig. 2A). The 3-year RFS of 844 patients without tumor deposits was 82.7% (95% CI, 78.6%-88.5%), and the 3-year RFS of 236 patients with tumor deposits was 69.9% (95% CI, 63.4%-74.7%) And there was a statistically significant difference between the two groups (HR, 1.65; 95% CI, 1.31–2.09; P < 0.001) (Fig. 2B). The 3-year RFS of 571 patients with stage N1 without tumor deposition was 84.2% (95% CI, 78.6%-88.5%). The 3-year RFS of 273 patients with stage N2 without tumor deposits was 65.1% (95% CI, 61.5%-68.7%), which was similar to the 3-year RFS of 174 patients with stage N1 tumor deposits of 63.3% (95% CI, 60.6%-66.9%) (N2 patients without tumor deposits vs N1 patients with tumor deposits: HR, 0.95; 95% CI, 0.71–1.28; P = 0.76). The 3-year RFS of the 62 patients with stage N2 tumor deposits was 57.8% (95% CI, 51.5%-59.7%), with the highest risk of recurrence compared with the other three groups. (over all log-rank P < 0.0001) (Fig. 2C). Among them, the 3-year RFS of 687 patients with tumor deposits and lymph node metastases < 4 was 77.2% (95% CI, 73.8%-79.6%), and the 3-year RFS of 335 patients with lymph node metastasis ≥ 4 was 62.3% (95% CI, 58.5%-68.1%), the 3-year RFS of 58 patients with tumor deposits and lymph node metastases ≥ 4 was 61.4% (95% CI, 57.2%-65.1%) (Patients with tumor deposits and lymph node metastases < 4 vs Patients with tumor deposits and ≥ 4 lymph node metastases: HR, 1.40; 95% CI, 1.14–1.73; P = 0.001; Patients with ≥ 4 lymph node metastases vs Patients with tumor deposits and ≥ 4 lymph node metastases: HR, 1.02; 95% CI, 0.67–1.56 ; P = 0.91) (Fig. 2D).
In the univariate analysis of 3-year RFS, the presence or absence of tumor deposition, lymphatic invasion, perineural invasion, tumor deposition, preoperative CEA, CA199, tumor deposition plus number of lymph node metastases were significantly associated with 3-year RFS (P < 0.05). In multivariate analysis, tumor deposition (HR, 1.31; 95% CI, 1.08–2.95; P = 0.001), neural invasion (HR, 1.60; 95% CI, 1.17–2.19; P = 0.002), preoperative high level of CEA (HR, 1.46; 95% CI, 1.20–1.85; P = 0.01), lymph node metastases ≥ 4 patient group (HR, 1.86; 95% CI, 1.49–2.23; P = 0.01), tumor deposition plus lymph node metastases ≥ 4 patient group (HR, 1.88; 95% CI, 1.24–2.87; P = 0.003) was associated with a shorter 3-year RFS (Table 2). After adjusting confounding factors and incorporating multiple Cox models, the new pathological stages method consisting of tumor deposits and number of lymph node metastases were independently associated with 3-year RFS (Table 3).
Table 1
Characteristic | All (N = 1080) | TD-negative (n = 844) | TD-positive (n = 236) | P-value⇑ |
Age (years) | | | | 0.077 |
Median (IQR) | 60.000[50.0,68.0] | 60.000[50.0,68.0] | 61.000[51.0,68.0] | |
Sex, no. (%) of patients | | | | 0.328 |
Male | 634(58.704) | 502(59.479) | 132(55.932) | |
Female | 446(41.296) | 342(40.521) | 104(44.068) | |
BMI(Kg/m2) | | | | 0.169 |
Median (IQR) | 22.53[20.76,24.97] | 22.50[20.76,24.87] | 22.83[20.76,25.26] | |
Surgical approach | | | | 0.633 |
OR | 687(63.611) | 540(63.981) | 147(62.288) | |
LR | 393(36.389) | 304(36.019) | 89(37.712) | |
Primary site, no. (%) of patients | | | | 0.053 |
Right colon | 246(22.778) | 206(24.408) | 40(16.949) | |
Left colon | 281(26.019) | 216(25.592) | 65(27.542) | |
rectum | 553(51.204) | 422(50.000) | 131(55.508) | |
Tumor differentiation, no. (%) of patients | | | | 0.713 |
Well | 41(3.796) | 34(4.028) | 7(2.966) | |
Moderate | 577(53.426) | 444(52.607) | 133(56.356) | |
Poor-undifferentiated | 397(36.759) | 315(37.322) | 82(34.746) | |
Unknown | 65(6.019) | 51(6.043) | 14(5.932) | |
Mucinous type | | | | 0.429 |
No | 997(92.315) | 782(92.654) | 215(91.102) | |
Yes | 83(7.685) | 62(7.346) | 21(8.898) | |
T stage, no. (%) of patients | | | | 0.080 |
T1 | 14(1.296) | 13(1.540) | 1(0.424) | |
T2 | 107(9.907) | 88(10.427) | 19(8.051) | |
T3 | 908(84.074) | 709(84.005) | 199(84.322) | |
T4 | 51(4.722) | 34(4.028) | 17(7.203) | |
N stage, no. (%) of patients | | | | < 0.001 |
N1a | 314(29.074) | 266(31.517) | 48(20.339) | |
N1b | 377(34.907) | 305(36.137) | 72(30.508) | |
N1c | 54(5.000) | 0(0.000) | 54(22.881) | |
N2a | 218(20.185) | 175(20.735) | 43(18.220) | |
N2b | 117(10.833) | 98(11.611) | 19(8.051) | |
AJCC 7th ed. stage | | | | 0.857 |
IIIA | 94(8.704) | 75(8.886) | 19(8.051) | |
IIIB | 851(78.796) | 662(78.436) | 189(80.085) | |
IIIC | 135(12.500) | 107(12.678) | 28(11.864) | |
LVI | | | | 0.005 |
Yes | 135(12.500) | 93(11.019) | 42(17.797) | |
No | 945(87.500) | 751(88.981) | 194(82.203) | |
PNI | | | | 0.207 |
Yes | 44(4.074) | 31(3.673) | 13(5.508) | |
No | 1036(95.926) | 813(96.327) | 223(94.492) | |
Lymph node yield | | | | < 0.001 |
≥ 12 | 876(81.111) | 708(83.886) | 168(71.186) | |
< 12 | 204(18.889) | 136(16.114) | 68(28.814) | |
Adjuvant chemotherapy, no. (%) of patients | | | | 0.312 |
Yes | 834(77.222) | 646(76.540) | 188(79.661) | |
No | 246(22.778) | 198(23.460) | 48(20.339) | |
Preoperative CEA, ng/mL | | | | 0.750 |
Mean (SD) | 20.320(157.172) | 21.128(176.676) | 17.431(37.287) | |
Preoperative CA199, ng/mL | | | | 0.820 |
Mean (SD) | 39.864(197.658) | 40.592(220.663) | 37.260(68.224) | |
Note: 1 Data are median (IQR), Mean (SD) or n (%). |
2Abbreviations: BMI, Body Mass Index; CEA, carcinoembryonic antigen; LR, laparoscopic resection; LVI, lymphovascular invasion; OR, open resection; PNI, perineural invasion. TD, tumor deposits |
3 P value, using Wilcoxon Mann-Whitney test, chi-square test or exact Fisher test depending on whether the variable is continuous or categorica. |
Table 2
Univariate and multivariate analyses of 3-year recurrence free survival.
Variables | % 3-year RFS(95% CI) | Univariate | | Multivariate | |
HR (95% CI) | P-value | HR (95% CI) | P-value |
Age | | | | | |
< 60 | 78.01 (74.16, 82.06) | 1.0 (reference) | | | |
≥ 60 | 77.13 (73.00, 81.50) | 1.03 (0.72, 1.09) | 0.27 | | |
BMI | | | | | |
< 24 | 76.54 (73.02, 80.20) | 1.0 (reference) | | | |
≥ 24 | 79.79 (75.07, 84.80) | 0.99 (0.79, 1.23) | 0.93 | | |
Sex | | | | | |
Male | 77.95 (74.26, 81.82) | 1.0 (reference) | | | |
Female | 77.10 (72.74, 81.73) | 1.13 (0.91, 1.39) | 0.24 | | |
Tumor location | | | | | |
right colon | 78.01 (74.16, 82.06) | 1.0 (reference) | | | |
left colon | 77.13 (73.00, 81.50) | 0.97 (0.72, 1.31) | 0.86 | | |
rectum | 75.13 (71.29, 79.91) | 0.99 (0.76, 1.29) | 0.54 | | |
Surgical approach | | | | | |
OR | 76.31 (72.54, 80.28) | 1.0 (reference) | | | |
LR | 79.39 (75.17, 83.85) | 0.93 (0.78, 1.16) | 0.52 | | |
Tumor differentiation | | | | | |
Well | 85.71 (77.02, 95.39) | 1.0 (reference) | | | |
Moderate | 79.05 (75.53, 82.73) | 1.23 (0.72, 2.10) | 0.43 | | |
Poor-undifferentiated | 69.91 (63.77, 76.65) | 2.15 (0.98, 3.21) | 0.07 | | |
Mucinous type | | | | | |
No | 77.52 (74.63, 80.53) | 1.0 (reference) | | | |
Yes | 79.62 (66.30, 95.61) | 0.81 (0.53, 1.26) | 0.76 | | |
Pathology T stage | | | | | |
T1 | 92.35 (86.13, 99.03) | 1.0 (reference) | | | |
T2 | 90.14 (85.66, 94.84) | 1.61 (0.21, 12.35) | 0.64 | | |
T3 | 73.04 (69.42, 76.85) | 5.48 (0.77, 39.07) | 0.08 | | |
T4 | 53.03 (35.38, 79.49) | 5.24 (0.69, 39.42) | 0.10 | | |
Lymph node yield | | | | | |
≥ 12 | 92.35 (86.13, 99.03) | 1.0 (reference) | | | |
<12 | 90.14 (85.66, 94.84) | 0.93 (0.72, 1.21) | 0.62 | | |
Adjuvant chemotherapy | | | | | |
Yes | 62.67 (51.41, 76.41) | 1.0 (reference) | | | |
No | 70.67 (59.71, 75.38) | 1.22 (0.93, 1.59) | 0.13 | | |
Tumor deposit | | | | | |
No | 82.70 (78.62, 88.54) | 1.0 (reference) | | 1.0 (reference) | |
Yes | 69.90 (63.43, 74.71) | 1.46 (1.18, 1.80) | < 0.001 | 1.31 (1.08, 2.95) | 0.001 |
Lymphovascular invasion | | | | | |
No | 80.06 (77.17, 83.05) | 1.0 (reference) | | 1.0 (reference) | |
Yes | 57.33 (47.80, 68.75) | 2.45 (1.63, 3.69) | < 0.001 | 1.50 (0.94, 2.41) | 0.08 |
Perineural invasion | | | | | |
No | 78.87 (76.02, 81.84) | 1.0 (reference) | | 1.0 (reference) | |
Yes | 54.25 (41.00, 71.78) | 1.94 (1.48, 2.54) | < 0.001 | 1.60 (1.17, 2.19) | 0.002 |
Postoperative CEA, ng/mL | | | | | |
≤ 5 | 88.59 (86.48, 91.73) | 1.0 (reference) | | 1.0 (reference) | |
>5 | 76.65 (69.83, 82.31) | 1.46 (1.18, 1.80) | < 0.001 | 1.49 (1.20, 1.85) | 0.01 |
Postoperative CA19-9, ng/mL | | | | | |
≤ 37 | 85.64 (78.92, 89.93) | 1.0 (reference) | | 1.0 (reference) | |
>37 | 75.44 (70.65, 84.14) | 1.52 (1.19, 1.95) | 0..001 | 1.04 (0.91, 2.67) | 0.85 |
New Pathology N stage group | | | | | |
Tumor deposit + lymph node metastases<4 | 77.23 (73.81,79.60) | 1.0 (reference) | | 1.0 (reference) | |
lymph node metastases ≥ 4 | 62.30 (58.49, 68.11) | 1.94 (1.56, 2.42) | < 0.001 | 1.86 (1.49, 2.33) | 0.01 |
Tumor deposit + lymph node metastases ≥ 4 | 61.42 (57.19, 65.13) | 1.98 (1.30, 3.00) | 0.001 | 1.88 (1.24, 2.87) | 0.003 |
Note: 1 Abbreviations: APR, abdominoperineal resection; BMI, Body Mass Index; CEA, carcinoembryonic antigen; LR, laparoscopic resection; OR, open resection. |
Table 3
Adjusted hazard ratios of 3-year RFS by New Pathology N stage group.
New Pathology N stage group | N | Events (%) | Model 1 | Model 2 | Model 3 |
HR (95% CI) | P-value | HR (95% CI) | P Value | HR (95% CI) | P-value |
Tumor deposit + lymph node metastases<4 | 627 | 93(14.83) | 1.0 (Ref.) | | 1.0 (Ref.) | | 1.0 (Ref.) | |
lymph node metastases ≥ 4 | 255 | 61(23.92) | 1.94 (1.56, 2.42) | < 0.001 | 1.89 (1.50, 2.31) | 0.009 | 1.86 (1.49, 2.33) | 0.01 |
Tumor deposit + lymph node metastases ≥ 4 | 67 | 36(53.73) | 1.98 (1.30, 3.00) | 0.001 | 1.91 (1.28, 2.59) | 0.001 | 1.88 (1.24, 2.87) | 0.003 |
Note : Abbreviations: HR, hazard ratios; Ref., reference. |
a Model 1 was unadjusted. |
b Model 2 was adjusted for age (< 60 vs. ≥60), body mass index (< 24 vs. ≥24), and sex (male vs. female). |
c Model 3 was adjusted for age (< 60 vs. ≥60), body mass index (< 24 vs. ≥24), sex (male vs. female), surgical approach (open resection vs. laparoscopic resection), location (right colon vs. left colon vs. rectum), tumor differentiation (well vs. moderate vs. poor-undifferentiated), mucinous type (yes vs. no), pathology T stage (T4 vs. T3 vs. T2 vs. T1), lymphovascular invasion (yes vs. no), perineural invasion (yes vs. no), Adjuvant chemotherapy (yes vs. no), Lymph node yield(≥ 12 vs.<12), Postoperative CEA, ng/mL (≤ 5 vs.>5), Postoperative CA19-9, ng/mL (≤ 37 vs.>37) and tumor deposit (yes vs. no). |