Article Figures & Data
Figures
- Figure 1
Kaplan–Meier curves of overall survival (OS) and recurrence-free survival (RFS) according to the Ki-67 index or histopathological differentiation. (A) OS curves according to Ki-67 expression level. (B) RFS curves according to Ki-67 expression level. (C) OS curves according to histopathological differentiation. (D) RFS curves according to histopathological differentiation.
- Figure 2
Survival curves based on histological differentiation and Ki-67 index. The survival of patients with well and moderately differentiated tumors with high expression of Ki-67 was comparable to that of patients with poorly differentiated tumors with low expression of Ki-67. (A) Overall survival. (B) Recurrence-free survival.
- Figure 3
The proposed malignancy grading system and its algorithm.
- Figure 4
Ki-67 immunohistochemical staining in pancreatic ductal adenocarcinoma. (A) Well-differentiated tumor with a Ki-67 index of 20%. (B) Moderately differentiated tumor with a Ki-67 index of 60%. (C) Poorly differentiated tumor with a Ki-67 index of 5%. (D) Poorly differentiated tumor with a Ki-67 index of 70% (X+number).
- Figure 5
Survival curves according to the grade of malignancy (GOM). The GOM stratified patients into 3 distinct groups with significantly differing prognosis. (A) Overall survival. (B) Recurrence-free survival.
- Figure 6
Survival curves based on TNM stage and the grade of malignancy (GOM). Survival was comparable between patients with stage II low-grade and stage I middle-grade disease. No statistically significant differences in survival were observed between patients with stage III middle-grade and stage II high-grade disease. Similarly, no significant disparities in survival were observed among patients with stage III low-grade, stage II middle-grade, and stage I high-grade disease. (A) Overall survival. (B) Recurrence-free survival.
- Figure 7
Proposed tumor-node-metastasis-grade of malignancy (TNMG) staging system for PDAC and its algorithm.
- Figure 8
Survival curves according to the TNMG stage. (A) Overall survival. (B) Recurrence-free survival.
- Figure 9
Receiver operating characteristic curves, demonstrating superior AUC values for the proposed TNMG stages compared with the TNM stages for OS and RFS at 1-, 3-, and 5-year after surgery. (A) OS at 1 year, (B) OS at 3 years, (C) OS at 5 years, (D) RFS at 1 year, (E) RFS at 3 years, and (F) RFS at 5 years.
Tables
Characteristic Cases, n (%) Ki-67 expression level χ2/Z P Low-expression group, n (%) High-expression group, n (%) Gender 2.082 0.149 Male 295 (56.7) 153 (53.9) 142 (60.2) Female 225 (43.3) 131 (46.1) 94 (39.8) Age (years) 0.141 0.707 < 70 444 (85.4) 244 (85.9) 200 (84.7) ≥ 70 76 (14.6) 40 (14.1) 36 (15.3) Preoperative serum CA19-9 (U/mL) −1.744 0.081 < 200 284 (54.6) 165 (50.4) 119 (50.4) 200–1000 157 (30.2) 80 (32.6) 77 (32.6) > 1000 79 (15.2) 39 (13.7) 40 (16.9) Preoperative serum CEA (ng/mL) 4.293 0.038 ≤ 5 361 (69.4) 208 (73.2) 153 (64.8) > 5 159 (30.6) 76 (26.8) 83 (35.2) Tumor location 3.418 0.064 Head 350 (67.3) 201 (70.8) 149 (63.1) Body and tail 170 (32.7) 83 (29.2) 87 (36.9) Type of pancreatectomy 3.059 0.080 PD 351 (67.5) 201 (70.8) 150 (63.6) DP 169 (32.5) 83 (29.2) 86 (36.4) Histopathologic differentiation 1.014 0.314 Well and moderate 208 (40.0) 108 (38.0) 100 (42.4) Poor 312 (60.0) 176 (62.0) 136 (57.6) T stage 3.285 0.350 T1 79 (15.2) 48 (16.9) 31 (13.1) T2 278 (53.5) 155 (54.6) 123 (52.1) T3 149 (28.7) 73 (25.7) 76 (32.2) T4 14 (2.7) 8 (2.8) 6 (2.5) N stage 2.979 0.225 N0 244 (46.9) 143 (50.4) 101 (42.8) N1 124 (23.8) 64 (22.5) 60 (25.4) N2 152 (29.2) 77 (27.1) 75 (31.8) TNM stage 4.489 0.106 I 168 (32.3) 103 (36.3) 65 (27.5) II 191 (36.7) 98 (34.5) 93 (39.4) III 161 (31.0) 83 (29.2) 78 (33.1) Perineural invasion 0.559 0.455 Absent 183 (35.2) 104 (36.6) 79 (33.5) Present 337 (64.8) 180 (63.4) 157 (66.5) Lymphovascular invasion 3.895 0.048 Absent 381 (73.3) 218 (76.8) 163 (69.1) Present 139 (26.7) 66 (23.2) 73 (30.9) Postoperative complications 0.590 0.442 Present 134 (25.8) 77 (27.1) 57 (24.2) Absent 386 (74.2) 207 (72.9) 179 (75.8) Postoperative adjuvant chemotherapy regimens 4.439 0.350 None 255 (49.0) 131 (46.1) 124 (52.5) mFOLFIRINOX 66 (12.7) 41 (14.4) 25 (10.6) GS/GX 109 (21.0) 58 (20.4) 51 (21.6) S-1 45 (8.7) 25 (8.8) 20 (8.5) Gemcitabine 45 (8.7) 29 (10.2) 16 (6.8) CA19-9, carbohydrate antigen 19-9; CEA, carcinoembryonic antigen; DP, distal pancreatectomy; PD, pancreaticoduodenectomy.
Characteristics n MST 5-year OS (%) Univariate analysis Multivariate analysis HR (95% CI) P HR (95% CI) P Gender Male 295 20.0 19.5 1 (ref) Female 225 24.0 18.8 0.912 (0.736–1.130) 0.400 Age at surgery < 70 444 22.0 20.3 1 (ref) 1 (ref) ≥ 70 76 16.0 12.4 1.421 (1.067–1.892) 0.016 1.611 (1.199–2.167) 0.002 Preoperative serum CA19-9 (U/mL) < 200.0 284 25.0 21.8 1 (ref) 1 (ref) 200.0–1000.0 157 20.0 18.1 1.322 (1.041–1.680) 0.022 1.323 (1.033–1.695) 0.027 > 1000.0 79 16.0 15.0 1.875 (1.398–2.514) < 0.001 1.524 (1.114–2.084) 0.008 Preoperative serum CEA (ng/mL) ≤ 5 361 24.0 22.0 1 (ref) 1 (ref) > 5 159 18.0 12.1 1.386 (1.105–1.738) 0.005 1.154 (0.898–1.483) 0.264 Tumor location Head 350 21.0 20.2 1 (ref) Body and tail 170 21.0 17.4 1.021 (0.813–1.282) 0.859 Type of pancreatectomy PD 351 21.0 20.0 1 (ref) DP 169 21.0 17.7 1.049 (0.836–1.318) 0.678 Histopathologic differentiation Well and moderate 208 32.0 27.0 1 (ref) 1 (ref) Poor 312 16.0 14.1 1.852 (1.481–2.318) < 0.001 1.875 (1.488–2.363) < 0.001 TNM stage I 168 35.0 30.7 1 (ref) 1 (ref) II 191 20.0 18.0 1.665 (1.269–2.184) < 0.001 1.371 (1.036–1.816) 0.027 III 161 14.0 8.0 2598 (1.98–3.407) < 0.001 2.496 (1.84–3.375) < 0.001 Perineural invasion Absent 183 28.8 24.0 1 (ref) 1 (ref) Present 337 12.2 20.0 1.377 (1.098–1.727) 0.006 1.123 (0.890–1.417) 0.329 Lymphovascular invasion Absent 381 20.4 24.0 1 (ref) 1 (ref) Present 139 16.0 17.0 1.383 (1.097–1.743) 0.006 1.160 (0.893–1.506) 0.266 Ki-67 expression level Low expression 284 25.0 25.0 1 (ref) 1 (ref) High expression 236 11.8 17.0 1.669 (1.350–2.063) < 0.001 1.707 (1.371–2.126) < 0.001 Postoperative adjuvant chemotherapy No 265 16.0 27.1 1 (ref) 1 (ref) Yes 255 26.0 11.4 1.813 (1.466–2.242) < 0.001 0.573 (0.432–0.667) < 0.001 Postoperative complications Absent 386 24.0 21.4 1 (ref) 1 (ref) Present 134 16.0 12.2 1.539 (1.215–1.950) < 0.001 1.434 (1.120–1.837) 0.004 CA19-9, carbohydrate antigen 19-9; CEA, carcinoembryonic antigen; DP, distal pancreatectomy; PD, pancreaticoduodenectomy; ref, reference category; HR, hazard ratio; OS, overall survival.
Characteristics n MRT 5-year RFS (%) Univariate analysis Multivariate analysis HR (95% CI) P HR (95% CI) P Gender Male 295 10.0 12.9 1 (ref) Female 225 12.0 14.5 0.931 (0.763–1.136) 0.483 Age at surgery < 70 444 11.0 13.6 1 (ref) ≥ 70 76 8.0 14.5 1.142 (0.864–1.509) 0.352 Preoperative serum CA19-9 (U/mL) < 200.0 284 14.0 18.6 1 (ref) 1 (ref) 200.0–1000.0 157 10.0 8.9 1.363 (1.090–1.703) 0.007 1.310 (1.041–1.649) 0.021 ≥ 1000.0 79 6.0 – 2.182 (1.658–2.871) < 0.001 1.806 (1.346–2.423) < 0.001 Preoperative serum CEA (ng/mL) ≤ 5 361 12.0 15.2 1 (ref) 1 (ref) > 5 159 8.0 9.8 1.382 (1.118–1.708) 0.003 1.158 (0.915–1.464) 0.222 Tumor location Head 350 10.0 13.5 1 (ref) Body and tail 170 10.0 12.9 0.993 (0.804–1.227) 0.951 Type of pancreatectomy PD 351 11.0 13.5 1 (ref) DP 169 10.0 13.1 1.027 (0.831–1.268) 0.808 Histopathologic differentiation Well and moderate 208 16.0 16.8 1 (ref) 1 (ref) Poor 312 8.0 11.1 1.705 (1.388–2.095) < 0.001 1.632 (1.323–2.012) < 0.001 TNM stage I 168 20.0 22.2 1 (ref) 1 (ref) II 191 11.0 15.3 1.448 (1.128–1.858) 0.004 1.191 (0.921–1.540) 0.182 III 161 6.0 3.4 2.519 (1.960–3.237) < 0.001 2.141 (1.623–2.826) < 0.001 Perineural invasion Absent 183 13.0 21.1 1 (ref) 1 (ref) Present 337 9.0 8.5 1.404 (1.136–1.736) 0.002 1.154 (0.929–1.435) 0.196 Lymphovascular invasion Absent 381 12.0 15.7 1 (ref) 1 (ref) Present 139 6.0 8.4 1.596 (1.289–1.977) < 0.001 1.061 (0.936–1.349) 0.625 Ki-67 expression level Low expression 284 14.0 16.5 1 (ref) 1 (ref) High expression 236 8.0 10.0 1.489 (1.222–1.816) < 0.001 1.453 (1.185–1.781) < 0.001 Postoperative adjuvant chemotherapy No 265 8.0 10.9 1 (ref) 1 (ref) Yes 255 13.0 16.2 1.367 (1.123–1.663) 0.002 0.734 (0.601–0.896) 0.002 Postoperative complications Absent 386 12.0 15.2 1 (ref) 1 (ref) Present 134 7.0 8.6 1.380 (1.105–1.723) 0.004 1.198 (0.952–1.507) 0.124 CA19-9, carbohydrate antigen 19-9; CEA, carcinoembryonic antigen; DP, distal pancreatectomy; PD, pancreaticoduodenectomy; ref, reference category; HR, hazard ratio; RFS, recurrence-free survival.
- Table 4
Multivariate survival analysis examining the prognostic value of the malignancy grading system in the context of known independent prognostic factors
Variable Category HR (95% CI) P Multivariate analysis for OS GOM High vs. low 3.302 (2.350–4.641) < 0.001 Middle vs. low 1.967 (1.433–2.700) < 0.001 TNM stage III vs. I 2.370 (1.791–3.137) < 0.001 II vs. I 1.401 (1.065–1.843) 0.016 Preoperative serum CA19-9 (U/mL) ≥ 1000.0 vs. < 200 1.622 (1.207–2.180) 0.001 200–1000 vs. < 200 1.364 (1.068–1.741) 0.013 Postoperative adjuvant chemotherapy Yes vs. no 0.539 (0.434–0.669) < 0.001 Age at surgery ≥ 70 vs. < 70 1.657 (1.235–2.223) 0.001 Postoperative complications Present vs. absent 1.443 (1.126–1.849) 0.004 Multivariate analysis for RFS GOM High vs. low 2.596 (1.904–3.538) < 0.001 Middle vs. low 1.751 (1.324–2.315) < 0.001 TNM stage III vs. I 2.244 (1.736–2.901) < 0.001 II vs. I 1.233 (0.957–1.588) 0.106 Preoperative serum CA19-9 (U/mL) ≥ 1000.0 vs. < 200 1.905 (1.442–2.516) < 0.001 200–1000 vs. < 200 1.350 (1.078–1.693) 0.009 Postoperative adjuvant chemotherapy Yes vs. no 0.748 (0.613–0.913) 0.004 Age at surgery ≥ 70 vs. < 70 1.226 (0.924–1.625) 0.157 Postoperative complication Present vs. absent 1.207 (0.958–1.520) 0.110 CA19-9, carbohydrate antigen 19-9; HR, hazard ratio; OS, overall survival; RFS, recurrence-free survival; GOM, grade of malignancy.
