Background
Methods
Patient selection
Patient evaluation
DNA extraction and methylation analysis
Follow-up schedule
Statistical analysis
Results
Clinical characteristics
Tumor location | Univariate analysis | ||||
---|---|---|---|---|---|
All | Renal pelvis | Ureter | Chi-square or Z | p value | |
Patients, no. (%) | 612 (100) | 341 (55.7) | 271 (44.3) | ||
Pre-operative characteristic | |||||
Gender, no. (%) | 0.160 | 0.743 | |||
Male | 340 (55.6) | 187 (54.8) | 153 (56.5) | ||
Female | 272 (44.4) | 154 (45.2) | 118 (43.5) | ||
Age, no. (%) | 4.929 | 0.027* | |||
<70 | 340 (55.6) | 203 (59.5) | 137 (50.6) | ||
≥ 70 | 272 (44.4) | 138 (40.5) | 134 (49.4) | ||
Age, mean ± SD | 65.29 ± 11.11 | 68.07 ± 10.20 | −3.173 | 0.002* | |
Previous or concomitant bladder cancer, no. (%) | 1.931 | 0.193 | |||
Absent | 545 (89.1) | 309 (90.6) | 236 (87.1) | ||
Present | 67 (10.9) | 32 (9.4) | 35 (12.9) | ||
Initial complaint, no. (%) | 24.205 | < 0.001* | |||
Absent | 84 (13.7) | 26 (7.6) | 58 (21.4) | ||
Present | 528 (86.3) | 315 (92.4) | 213 (78.6) | ||
Gross hematuria, no. (%) | 65.132 | < 0.001* | |||
Absent | 148 (24.2) | 40 (11.7) | 108 (39.9) | ||
Present | 464 (75.8) | 301 (88.3) | 163 (60.1) | ||
Preoperative renal function, no. (%) | 23.703 | < 0.001* | |||
End-stage CKD (eGFR<15) | 34 (5.6) | 24 (7.0) | 10 (3.7) | ||
Moderate CKD (60>eGFR≥15) | 198 (32.4) | 83 (24.3) | 115 (42.4) | ||
Early CKD (eGFR≥60) | 378 (61.8) | 233 (68.3) | 145 (53.5) | ||
eGFR, mean ± SD | 69.69 ± 30.11 | 62.43 ± 22.32 | −4.329 | < 0.001* | |
Side, no. (%) | 1.115 | 0.329 | |||
Left | 315 (51.5) | 182 (53.4) | 133 (49.1) | ||
Right | 297 (48.5) | 159 (46.6) | 138 (50.9) | ||
Hydronephrosis, no. (%) | 134.680 | < 0.001* | |||
Absent | 273 (44.6) | 223 (65.4) | 50 (18.5) | ||
Present | 339 (55.4) | 118 (34.6) | 221 (81.5) | ||
Multifocality, no. (%) | 0.339 | 0.563 | |||
Single | 472 (77.1) | 266 (78.0) | 206 (76.0) | ||
Multiple | 140 (22.9) | 75 (22.0) | 65 (24.0) | ||
Smoking, no. (%) | 0.050 | 0.836 | |||
No | 497 (81.2) | 278 (81.5) | 219 (80.8) | ||
Yes | 115 (18.8) | 63 (18.5) | 52 (19.2) | ||
Alcohol, no. (%) | 0.697 | 0.452 | |||
No | 539 (88.1) | 297 (87.1) | 242 (89.3) | ||
Yes | 73 (11.9) | 44 (12.9) | 29 (10.7) | ||
Diabetes, no. (%) | 0.249 | 0.661 | |||
No | 511 (83.5) | 287 (84.2) | 224 (82.7) | ||
Yes | 101 (16.5) | 54 (15.8) | 47 (17.3) | ||
Hypertension, no. (%) | 4.454 | 0.038* | |||
No | 363 (59.3) | 215 (63.0) | 148 (54.6) | ||
Yes | 249 (40.7) | 126 (37.0) | 123 (45.4) | ||
Pre-RNU ureteroscopy, no. (%) | 20.495 | < 0.001* | |||
No | 536 (87.6) | 317 (93.0) | 219 (80.8) | ||
Yes | 76 (12.4) | 24 (7.0) | 52 (19.2) | ||
Pathological outcomes | |||||
Architecture, no. (%) | 40.135 | < 0.001* | |||
Papillary | 479 (78.3) | 299 (87.7) | 180 (66.4) | ||
Sessile | 133 (21.7) | 42 (12.3) | 91 (33.6) | ||
Tumor stage, no. (%) | 0.094 | 0.796 | |||
Ta-T1 | 206 (33.7) | 113 (33.1) | 93 (34.3) | ||
T2–4 | 406 (66.3) | 228 (66.9) | 178 (65.7) | ||
Tumor grade, no. (%) | 31.628 | < 0.001* | |||
G1 | 19 (3.1) | 4 (1.2) | 15 (5.5) | ||
G2 | 334 (54.6) | 218 (63.9) | 116 (42.8) | ||
G3 | 259 (42.3) | 119 (34.9) | 140 (51.7) | ||
Lymph node status, no. (%) | 4.014 | 0.051 | |||
N0 or Nx | 571 (93.3) | 312 (91.5) | 259 (95.6) | ||
N+ | 41 (6.7) | 29 (8.5) | 12 (4.4) | ||
Non-organ-confined disease, no. (%) | 8.257 | 0.004* | |||
No | 412 (67.3) | 213 (62.5) | 199 (73.4) | ||
Yes | 200 (32.7) | 128 (37.5) | 72 (26.6) | ||
Tumor size, mean ± SD | 3.58 ± 2.15 | 3.27 ± 2.41 | −3.342 | 0.001* | |
Histologic Subtype | |||||
Tumor necrosis, no. (%) | 0.038 | 0.901 | |||
No | 537 (87.7) | 300 (88.0) | 237 (87.5) | ||
Yes | 75 (12.3) | 41 (12.0) | 34 (12.5) | ||
Squamous metaplasia, no. (%) | 0.038 | 0.878 | |||
No | 566 (92.5) | 316 (92.7) | 250 (92.3) | ||
Yes | 46 (7.5) | 25 (7.3) | 21 (7.7) | ||
Sarcomatoid metaplasia, no. (%) | 0.039 | 0.843 | |||
No | 586 (95.8) | 327 (95.9) | 259 (95.6) | ||
Yes | 26 (4.2) | 14 (4.1) | 12 (4.4) | ||
Gland-like differentiation, no. (%) | 2.738 | 0.119 | |||
No | 591 (96.6) | 333(97.7) | 258 (95.2) | ||
Yes | 21 (3.4) | 8(2.3) | 13 (4.8) | ||
Presence of CIS, no. (%) | 3.987 | 0.071 | |||
No | 596 (97.4) | 336 (98.5) | 260 (95.9) | ||
Yes | 16 (2.6) | 5 (1.5) | 11 (4.1) |
Pathological outcomes
Molecular biomarkers
All | Renal pelvis | Ureter | Chi-square or Z | p value | |
---|---|---|---|---|---|
Patients, no. (%) | 612 (100) | 341 (55.7) | 271 (44.3) | ||
TMEFF2, no. (%) | 6.717 | 0.011* | |||
Unmethylated | 346 (56.5) | 177 (51.9) | 169 (62.4) | ||
Methylated | 266 (43.5) | 164 (48.1) | 102 (37.6) | ||
HSPA2, no. (%) | 3.172 | 0.083 | |||
Unmethylated | 355 (58.0) | 187 (54.8) | 168 (62.0) | ||
Methylated | 257 (42.0) | 154 (45.2) | 103 (38.0) | ||
GDF15, no. (%) | 57.000 | < 0.001* | |||
Unmethylated | 304 (49.7) | 123 (36.1) | 181 (66.8) | ||
Methylated | 308 (50.3) | 218 (63.9) | 90 (33.2) | ||
RASSF1A, no. (%) | 20.465 | < 0.001* | |||
Unmethylated | 448 (73.2) | 225 (66.0) | 223 (82.3) | ||
Methylated | 164 (26.8) | 116 (34.0) | 48 (17.7) | ||
SALL3, no. (%) | 7.119 | 0.008* | |||
Unmethylated | 403 (65.8) | 209 (61.3) | 194 (71.6) | ||
Methylated | 209 (34.2) | 132 (38.7) | 77 (28.4) | ||
VIM, no. (%) | 2.347 | 0.128 | |||
Unmethylated | 219 (35.8) | 113 (33.1) | 106 (39.1) | ||
Methylated | 393 (64.2) | 228 (66.9) | 165 (60.9) | ||
ABCC6, no. (%) | 4.719 | 0.037* | |||
Unmethylated | 523 (85.5) | 282 (82.7) | 241 (88.9) | ||
Methylated | 89 (14.5) | 59 (17.3) | 30 (11.1) | ||
CDH1, no. (%) | 0.208 | 0.728 | |||
Unmethylated | 524 (85.6) | 290 (85.0) | 234 (86.3) | ||
Methylated | 88 (14.4) | 51 (15.0) | 37 (13.7) | ||
THBS1, no. (%) | 0.005 | 1.000 | |||
Unmethylated | 457 (74.7) | 255 (74.8) | 202 (74.5) | ||
Methylated | 155 (25.3) | 86 (25.2) | 69 (25.5) | ||
BRCA1, no. (%) | 0.460 | 0.523 | |||
Unmethylated | 504 (82.4) | 284 (83.3) | 220 (81.2) | ||
Methylated | 108 (17.6) | 57 (16.7) | 51 (18.8) | ||
Presence of hypermethylation in any gene, no. (%) | 9.420 | 0.003* | |||
Unmethylated | 70 (11.4) | 27 (7.9) | 43 (15.9) | ||
Methylated | 542 (88.6) | 314 (92.1) | 228 (84.1) | ||
Mean methylated genes | 3.71 ± 2.33 | 2.85 ± 2.19 | −4.503 | < 0.001* | |
Number of methylated genes, no. (%) | 17.202 | < 0.001* | |||
0–2 | 254 (41.5) | 118 (34.6) | 136 (50.2) | ||
3–5 | 243 (39.7) | 145 (42.5) | 98 (36.2) | ||
6–10 | 115 (18.8) | 78 (22.9) | 37 (13.7) | ||
Number of methylated genes, no. (%) in Ta-1 | 11.251 | 0.004* | |||
All | 206 (100) | 113 (54.9) | 93 (45.1) | ||
0–2 | 95 (46.1) | 41 (36.3) | 54 (58.1) | ||
3–5 | 80 (38.8) | 49 (43.4) | 31 (33.3) | ||
6–10 | 31 (15.0) | 23 (20.4) | 8 (8.6) | ||
Number of methylated genes, no. (%) in T2–4 | 7.318 | 0.026* | |||
All | 406 (100) | 228 (56.2) | 178 (43.8) | ||
0–2 | 159 (39.2) | 77 (33.8) | 82 (46.1) | ||
3–5 | 163 (40.1) | 96 (42.1) | 67 (37.6) | ||
6–10 | 84 (20.7) | 55 (24.1) | 29 (16.3) | ||
Number of methylated genes, no. (%) in G1–2 | 18.433 | < 0.001* | |||
All | 353 (100) | 222 (62.9) | 131 (37.1) | ||
0–2 | 156 (44.2) | 80 (36.0) | 76 (58.0) | ||
3–5 | 141 (39.9) | 97 (43.7) | 44 (33.6) | ||
6–10 | 56 (15.9) | 45 (20.3) | 11 (8.4) | ||
Number of methylated genes, no. (%) in G3 | 4.449 | 0.108 | |||
All | 259 (100) | 119 (45.9) | 140 (54.1) | ||
0–2 | 98 (37.8) | 38 (31.9) | 60 (42.9) | ||
3–5 | 102 (39.4) | 48 (40.3) | 54 (38.6) | ||
6–10 | 59 (22.8) | 33 (27.7) | 26 (18.6) |
Oncologic outcomes
Variables | All patients (n = 612) | Renal pelvis (n = 341) | Ureter (n = 271) | |||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
UVA | MVA | UVA | MVA | UVA | MVA | |||||||||||||
HR | 95%CI | p value | HR | 95%CI | p value | HR | 95%CI | p value | HR | 95%CI | p value | HR | 95%CI | p value | HR | 95%CI | p value | |
Location (ureter vs renal pelvis) | 1.302 | 0.976–1.738 | 0.073 | |||||||||||||||
Gender (men vs women) | 1.611 | 1.206–2.152 | 0.001* | 1.45 | 1.07–1.96 | 0.016* | 1.680 | 1.117–2.527 | 0.013* | 1.46 | 0.94–2.27 | 0.091 | 1.574 | 1.039–2.383 | 0.032* | 1.43 | 0.93–2.21 | 0.103 |
Age (continuous) | 1.020 | 1.005–1.035 | 0.009* | 1.32 | 1.07–1.64 | 0.010* | 1.008 | 0.988–1.028 | 0.422 | 1.032 | 1.008–1.056 | 0.008* | 1.09 | 0.78–1.52 | 0.628 | |||
Preoperative hydronephosis | 1.595 | 1.183–2.151 | 0.002* | 1.77 | 1.28–2.45 | 0.001* | 1.766 | 1.168–2.671 | 0.007* | 1.89 | 1.20–2.98 | 0.006* | 1.191 | 0.691–2.053 | 0.529 | |||
Multifocality (presence of multiple foci vs absence) | 1.414 | 1.028–1.943 | 0.033* | 1.57 | 1.10–2.24 | 0.014* | 1.675 | 1.088–2.578 | 0.019* | 1.70 | 1.03–2.82 | 0.040* | 1.145 | 0.711–1.845 | 0.577 | |||
Preoperative renal function(eGFR, continuous) | 0.996 | 0.991–1.001 | 0.119 | 1.000 | 0.993–1.007 | 0.993 | 0.989 | 0.979–0.998 | 0.021* | 0.77 | 0.55–1.06 | 0.106 | ||||||
Previous or concomitant BT (presence vs absence) | 1.544 | 1.019–2.339 | 0.041* | 1.53 | 0.97–2.41 | 0.070 | 1.980 | 1.099–3.568 | 0.023* | 2.03 | 1.04–3.94 | 0.037* | 1.183 | 0.657–2.132 | 0.575 | |||
Gross hematuria (presence vs absence) | 0.913 | 0.650–1.282 | 0.599 | 0.625 | 0.353–1.104 | 0.105 | 1.329 | 0.845–2.090 | 0.218 | |||||||||
Smoke (presence vs absence) | 1.102 | 0.765–1.588 | 0.601 | 1.242 | 0.757–2.037 | 0.391 | 0.985 | 0.572–1.698 | 0.958 | |||||||||
Alcohol (presence vs absence) | 1.108 | 0.726–1.690 | 0.634 | 1.546 | 0.912–2.619 | 0.105 | 0.713 | 0.344–1.477 | 0.363 | |||||||||
Diabetes (presence vs absence) | 0.891 | 0.592–1.340 | 0.579 | 0.994 | 0.563–1.756 | 0.984 | 0.797 | 0.442–1.437 | 0.451 | |||||||||
Hypertension (presence vs absence) | 1.180 | 0.879–1.584 | 0.270 | 1.056 | 0.689–1.618 | 0.802 | 1.230 | 0.810–1.868 | 0.332 | |||||||||
Preoperative ureteroscopy | 0.616 | 0.383–0.992 | 0.046* | 0.72 | 0.44–1.18 | 0.194 | 0.234 | 0.058–0.951 | 0.042* | 0.24 | 0.06–1.03 | 0.055 | 0.663 | 0.387–1.137 | 0.135 | |||
Tumor stage^ (T4 vs T3 vs T2 vs T1 vs Ta) | 1.725 | 1.443–2.061 | < 0.001* | 2.42 | 1.56–3.76 | < 0.001* | 1.514 | 1.197–1.915 | 0.001* | 1.83 | 1.04–3.21 | 0.035* | 2.288 | 1.716–3.050 | < 0.001* | 2.53 | 1.46–4.38 | 0.001* |
Tumor grade^ (G3 vs G2 vs G1) | 1.593 | 1.222–2.075 | 0.001* | 0.69 | 0.36–1.34 | 0.274 | 1.284 | 0.868–1.900 | 0.211 | 1.856 | 1.271–2.710 | 0.001* | 1.30 | 0.47–3.61 | 0.611 | |||
Lymph node status (N+ vs Nx vs N-) | 2.524 | 1.583–4.023 | < 0.001* | 1.82 | 1.08–3.07 | 0.024* | 2.863 | 1.615–5.074 | < 0.001* | 2.49 | 1.26–4.92 | 0.009* | 2.356 | 1.024–5.417 | 0.044* | 1.18 | 0.49–2.84 | 0.713 |
Architecture (presence of sessile vs absence) | 1.974 | 1.437–2.713 | < 0.001* | 1.38 | 0.92–2.07 | 0.125 | 2.105 | 1.242–3.566 | 0.006* | 1.20 | 0.63–2.28 | 0.584 | 1.811 | 1.186–2.766 | 0.006* | 0.98 | 0.55–1.75 | 0.951 |
CIS (presence of sessile vs absence) | 1.027 | 0.480–2.202 | 0.994 | 1.386 | 0.424–4.535 | 0.590 | 0.808 | 0.296–2.210 | 0.678 | |||||||||
Necrosis(presence vs absence) | 1.925 | 1.302–2.846 | 0.001* | 1.36 | 0.84–2.18 | 0.207 | 1.606 | 0.905–2.850 | 0.105 | 2.352 | 1.375–4.025 | 0.002* | 1.36 | 0.69–2.70 | 0.376 | |||
Squamous metaplasia (presence vs absence) | 1.783 | 1.081–2.943 | 0.024* | 1.45 | 0.85–2.48 | 0.171 | 2.123 | 1.063–4.241 | 0.033* | 2.31 | 1.06–5.02 | 0.034* | 1.485 | 0.716–3.079 | 0.288 | |||
Sarcomatoid metaplasia (presence vs absence) | 2.595 | 1.526–4.413 | < 0.001* | 0.79 | 0.40–1.56 | 0.493 | 2.541 | 1.171–5.513 | 0.018* | 1.03 | 0.40–2.62 | 0.955 | 2.629 | 1.266–5.459 | 0.010* | 1.00 | 0.41–2.45 | 0.993 |
Gland-like differentiation (presence vs absence) | 1.963 | 0.965–3.995 | 0.063 | 3.394 | 1.239–9.296 | 0.017* | 2.08 | 0.68–6.34 | 0.197 | 1.229 | 0.449–3.362 | 0.688 | ||||||
Tumor size (continuous) | 1.172 | 1.112–1.236 | < 0.001* | 1.17 | 1.04–1.32 | 0.010* | 1.163 | 1.070–1.264 | < 0.001* | 1.16 | 0.93–1.44 | 0.188 | 1.184 | 1.110–1.264 | < 0.001* | 1.26 | 1.06–1.49 | 0.008* |
TMEFF2 (methylated vs unmethylated) | 1.812 | 1.353–2.427 | < 0.001* | 1.67 | 1.12–2.50 | 0.012* | 1.634 | 1.085–2.459 | 0.019* | 1.16 | 0.70–1.92 | 0.562 | 2.189 | 1.434–3.340 | < 0.001* | 1.84 | 0.97–3.50 | 0.061 |
HSPA2 (methylated vs unmethylated) | 1.815 | 1.349–2.442 | < 0.001* | 1.52 | 1.03–2.24 | 0.036* | 2.064 | 1.365–3.119 | 0.001* | 1.40 | 0.86–2.28 | 0.180 | 1.698 | 1.097–2.626 | 0.017* | 1.08 | 0.60–1.97 | 0.793 |
GDF15 (methylated vs unmethylated) | 1.242 | 0.930–1.660 | 0.142 | 1.575 | 1.025–2.421 | 0.038* | 1.24 | 0.73–2.12 | 0.426 | 1.152 | 0.741–1.793 | 0.530 | ||||||
RASSF1A (methylated vs unmethylated) | 1.383 | 1.002–1.908 | 0.049* | 1.15 | 0.78–1.70 | 0.477 | 1.271 | 0.824–1.961 | 0.279 | 1.796 | 1.102–2.929 | 0.019* | 1.57 | 0.87–2.82 | 0.135 | |||
SALL3 (methylated vs unmethylated) | 1.214 | 0.887–1.662 | 0.226 | 0.887 | 0.565–1.392 | 0.602 | 1.853 | 1.190–2.885 | 0.006* | 1.58 | 0.93–2.68 | 0.094 | ||||||
VIM (methylated vs unmethylated) | 1.360 | 1.002–1.847 | 0.049* | 0.99 | 0.68–1.44 | 0.941 | 1.630 | 1.041–2.550 | 0.033* | 1.37 | 0.81–2.32 | 0.243 | 1.208 | 0.786–1.857 | 0.388 | |||
ABCC6 (methylated vs unmethylated) | 1.430 | 0.928–2.203 | 0.105 | 1.206 | 0.682–2.134 | 0.519 | 2.283 | 1.165–4.476 | 0.016* | 1.51 | 0.67–3.38 | 0.317 | ||||||
CDH1 (methylated vs unmethylated) | 1.178 | 0.766–1.812 | 0.456 | 1.112 | 0.618–2.001 | 0.724 | 1.401 | 0.741–2.649 | 0.300 | |||||||||
THBS1 (methylated vs unmethylated) | 1.131 | 0.811–1.577 | 0.468 | 0.877 | 0.534–1.439 | 0.603 | 1.415 | 0.899–2.227 | 0.133 | |||||||||
BRCA1 (methylated vs unmethylated) | 0.851 | 0.565–1.280 | 0.438 | 0.678 | 0.361–1.272 | 0.226 | 1.026 | 0.596–1.765 | 0.927 | |||||||||
No. methylated genes (continuous) | 1.348 | 1.107–1.641 | 0.003* | 0.62 | 0.30–1.28 | 0.193 | 1.225 | 0.930–1.613 | 0.149 | 1.646 | 1.234–2.196 | 0.001* | 0.58 | 0.18–1.82 | 0.351 |
Variables | All patients (n = 612) | Renal pelvis (n = 341) | Ureter (n = 271) | |||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
UVA | MVA | UVA | MVA | UVA | MVA | |||||||||||||
HR | 95%CI | p value | HR | 95%CI | p value | HR | 95%CI | p value | HR | 95%CI | p value | HR | 95%CI | p value | HR | 95%CI | p value | |
Location (ureter vs renal pelvis) | 1.172 | 0.870–1.579 | 0.297 | |||||||||||||||
Gender (men vs women) | 1.150 | 0.854–1.550 | 0.357 | 1.279 | 0.850–1.924 | 0.239 | 1.035 | 0.668–1.606 | 0.876 | |||||||||
Age (continuous) | 0.987 | 0.974–1.000 | 0.050 | 0.983 | 0.966–1.000 | 0.055 | 0.989 | 0.970–1.010 | 0.989 | |||||||||
Preoperative hydronephosis | 1.173 | 0.868–1.585 | 0.298 | 1.141 | 0.745–1.748 | 0.545 | 1.050 | 0.608–1.815 | 0.861 | |||||||||
Multifocality (presence of multiple foci vs absence) | 1.732 | 1.260–2.381 | 0.001* | 1.42 | 1.01–2.01 | 0.045* | 1.833 | 1.185–2.835 | 0.006* | 1.75 | 1.13–2.72 | 0.012* | 1.610 | 1.011–2.566 | 0.045* | 1.44 | 0.86–2.43 | 0.167 |
Preoperative renal function(eGFR, continuous) | 0.999 | 0.993–1.004 | 0.671 | 0.999 | 0.993–1.006 | 0.876 | 0.999 | 0.989–1.009 | 0.887 | |||||||||
Previous or concomitant BT (presence vs absence) | 1.900 | 1.267–2.850 | 0.002* | 1.47 | 0.95–2.28 | 0.081 | 1.710 | 0.931–3.138 | 0.084 | 2.034 | 1.176–3.517 | 0.011* | 1.39 | 0.75–2.58 | 0.293 | |||
Gross hematuria (presence vs absence) | 1.108 | 0.773–1.588 | 0.577 | 1.102 | 0.572–2.125 | 0.772 | 1.268 | 0.802–2.005 | 0.310 | |||||||||
Smoke (presence vs absence) | 0.946 | 0.644–1.388 | 0.775 | 1.097 | 0.655–1.836 | 0.726 | 0.784 | 0.441–1.394 | 0.407 | |||||||||
Alcohol (presence vs absence) | 0.771 | 0.473–1.257 | 0.297 | 0.901 | 0.480–1.692 | 0.746 | 0.622 | 0.286–1.351 | 0.230 | |||||||||
Diabetes (presence vs absence) | 1.086 | 0.736–1.601 | 0.679 | 0.842 | 0.469–1.515 | 0.567 | 1.414 | 0.837–2.388 | 0.196 | |||||||||
Hypertension (presence vs absence) | 0.774 | 0.566–1.059 | 0.109 | 0.916 | 0.595–1.412 | 0.692 | 0.614 | 0.391–0.967 | 0.035* | 0.71 | 0.44–1.15 | 0.163 | ||||||
Preoperative ureteroscopy | 1.631 | 1.111–2.395 | 0.012* | 1.25 | 0.83–1.87 | 0.285 | 2.087 | 1.137–3.829 | 0.018* | 1.62 | 0.87–3.02 | 0.126 | 1.319 | 0.794–2.189 | 0.285 | |||
Tumor stage^ (T4 vs T3 vs T2 vs T1 vs Ta) | 0.861 | 0.731–1.014 | 0.074 | 0.956 | 0.772–1.185 | 0.683 | 0.744 | 0.574–0.965 | 0.026* | 0.81 | 0.54–1.20 | 0.292 | ||||||
Tumor grade^ (G3 vs G2 vs G1) | 0.655 | 0.504–0.851 | 0.002* | 0.54 | 0.31–0.93 | 0.027* | 0.515 | 0.336–0.789 | 0.002* | 0.30 | 0.13–0.71 | 0.006* | 0.777 | 0.555–1.089 | 0.143 | |||
Lymph node status (N+ vs Nx vs N-) | 0.326 | 0.121–0.879 | 0.027* | 0.45 | 0.17–1.23 | 0.120 | 0.491 | 0.180–1.338 | 0.164 | 0.046 | 0.000–5.017 | 0.199 | ||||||
Architecture (presence of sessile vs absence) | 0.718 | 0.479–1.075 | 0.108 | 0.721 | 0.349–1.490 | 0.377 | 0.644 | 0.389–1.067 | 0.087 | |||||||||
CIS (presence of sessile vs absence) | 1.604 | 0.789–3.262 | 0.192 | 1.498 | 0.369–6.086 | 0.572 | 1.555 | 0.676–3.573 | 0.299 | |||||||||
Necrosis(presence vs absence) | 1.164 | 0.750–1.806 | 0.498 | 1.532 | 0.881–2.664 | 0.131 | 0.810 | 0.390–1.682 | 0.572 | |||||||||
Squamous metaplasia(presence vs absence) | 0.626 | 0.308–1.274 | 0.196 | 0.630 | 0.231–1.720 | 0.367 | 0.609 | 0.223–1.665 | 0.334 | |||||||||
Sarcomatoid metaplasia (presence vs absence) | 0.490 | 0.182–1.321 | 0.159 | 0.465 | 0.114–1.887 | 0.284 | 0.541 | 0.133–2.204 | 0.392 | |||||||||
Gland-like differentiation (presence vs absence) | 0.576 | 0.184–1.806 | 0.344 | 0.619 | 0.086–4.452 | 0.634 | 0.509 | 0.125–2.073 | 0.346 | |||||||||
Tumor size (continuous) | 0.920 | 0.850–0.996 | 0.039* | 0.91 | 0.78–1.06 | 0.213 | 0.967 | 0.872–1.072 | 0.520 | 0.875 | 0.771–0.991 | 0.036* | 0.83 | 0.64–1.08 | 0.170 | |||
TMEFF2 (methylated vs unmethylated) | 0.714 | 0.521–0.978 | 0.036* | 0.91 | 0.60–1.38 | 0.657 | 0.839 | 0.554–1.268 | 0.404 | 0.593 | 0.358–0.984 | 0.043* | 1.00 | 0.50–2.00 | 0.999 | |||
HSPA2 (methylated vs unmethylated) | 0.704 | 0.511–0.968 | 0.031* | 0.82 | 0.55–1.24 | 0.348 | 0.792 | 0.519–1.207 | 0.278 | 0.626 | 0.380–1.033 | 0.067 | ||||||
GDF15 (methylated vs unmethylated) | 0.823 | 0.611–1.110 | 0.203 | 0.936 | 0.616–1.421 | 0.755 | 0.738 | 0.456–1.196 | 0.217 | |||||||||
RASSF1A (methylated vs unmethylated) | 0.598 | 0.407–0.878 | 0.009* | 0.69 | 0.45–1.07 | 0.095 | 0.786 | 0.499–1.237 | 0.298 | 0.318 | 0.138–0.731 | 0.007* | 0.41 | 0.17–0.97 | 0.042* | |||
SALL3 (methylated vs unmethylated) | 0.725 | 0.519–1.013 | 0.059 | 0.669 | 0.427–1.048 | 0.079 | 0.837 | 0.505–1.386 | 0.489 | |||||||||
VIM (methylated vs unmethylated) | 0.862 | 0.636–1.167 | 0.336 | 1.302 | 0.831–2.041 | 0.249 | 0.567 | 0.367–0.875 | 0.010* | 0.64 | 0.38–1.06 | 0.081 | ||||||
ABCC6 (methylated vs unmethylated) | 0.805 | 0.499–1.297 | 0.373 | 1.007 | 0.578–1.752 | 0.981 | 0.508 | 0.185–1.392 | 0.188 | |||||||||
CDH1 (methylated vs unmethylated) | 0.681 | 0.413–1.124 | 0.133 | 0.870 | 0.474–1.597 | 0.654 | 0.466 | 0.188–1.155 | 0.099 | |||||||||
THBS1 (methylated vs unmethylated) | 0.960 | 0.678–1.359 | 0.818 | 1.044 | 0.651–1.675 | 0.858 | 0.872 | 0.522–1.457 | 0.601 | |||||||||
BRCA1 (methylated vs unmethylated) | 0.977 | 0.659–1.448 | 0.908 | 0.858 | 0.485–1.515 | 0.597 | 1.131 | 0.655–1.955 | 0.659 | |||||||||
No. methylated genes(continuous) | 0.787 | 0.637–0.972 | 0.026* | 1.14 | 0.56–2.34 | 0.718 | 0.906 | 0.688–1.193 | 0.483 | 0.656 | 0.460–0.935 | 0.020* | 0.96 | 0.34–2.72 | 0.934 |
Location | Comparison between three groups | Comparison after excluding cases in both locations | ||||||
---|---|---|---|---|---|---|---|---|
All | Renal pelvis only | Ureter only | Both locations | Chi-square or Z | p value | Chi-square or Z | p value | |
Patients, no. (%) | 612 (100) | 304 (49.7) | 267 (43.6) | 41 (6.7) | ||||
Pre-operative characteristic | ||||||||
Gender, no. (%) | 1.595 | 0.450 | 0.495 | 0.501 | ||||
Male | 340 (55.6) | 163 (53.6) | 151 (56.6) | 26 (63.4) | ||||
Female | 272 (44.4) | 141 (46.4) | 116 (43.4) | 15 (36.6) | ||||
Age, no. (%) | 5.554 | 0.062 | 5.391 | 0.023* | ||||
<70 | 340 (55.6) | 182 (59.9) | 134 (50.2) | 24 (58.5) | ||||
≥ 70 | 272 (44.4) | 122 (40.1) | 133 (49.8) | 17 (41.5) | ||||
Age, mean ± SD | 65.09 ± 11.32 | 68.12 ± 10.22 | 66.52 ± 10.79 | 11.059 | 0.004* | −3.298 | 0.001* | |
Previous or concomitant bladder cancer, no. (%) | 31.791 | < 0.001* | 8.721 | 0.004* | ||||
Absent | 545 (89.1) | 286 (94.1) | 232 (86.9) | 27 (65.9) | ||||
Present | 67 (10.9) | 18 (5.9) | 35 (13.1) | 14 (34.1) | ||||
Initial complaint, no. (%) | 23.992 | < 0.001* | 23.745 | < 0.001* | ||||
Absent | 84 (13.7) | 22 (7.2) | 57 (21.3) | 5 (12.2) | ||||
Present | 528 (86.3) | 282 (92.8) | 210 (78.7) | 36 (87.8) | ||||
Gross hematuria, no. (%) | 66.717 | < 0.001* | 65.579 | < 0.001* | ||||
Absent | 148 (24.2) | 33 (10.9) | 107 (40.1) | 8 (19.5) | ||||
Present | 464 (75.8) | 271 (89.1) | 160 (59.9) | 33 (80.5) | ||||
Preoperative renal function, no. (%) | 39.081 | < 0.001* | 29.841 | < 0.001* | ||||
End-stage CKD (eGFR<15) | 34 (5.6) | 21 (6.9) | 10 (3.7) | 3 (7.3) | ||||
Moderate CKD (60>eGFR≥15) | 198 (32.4) | 64 (21.1) | 112 (41.9) | 22 (53.7) | ||||
Early CKD (eGFR≥60) | 378 (61.8) | 218 (71.7) | 144 (53.9) | 16 (39.0) | ||||
eGFR, mean ± SD | 71.30 ± 29.38 | 62.63 ± 22.32 | 55.80 ± 31.99 | 34.160 | < 0.001* | −5.108 | < 0.001* | |
Hydronephrosis, no. (%) | 156.085 | < 0.001* | 151.247 | < 0.001* | ||||
Absent | 273 (44.6) | 212 (69.7) | 49 (18.4) | 12 (29.3) | ||||
Present | 339 (55.4) | 92 (30.3) | 218 (81.6) | 29 (70.7) | ||||
Multifocality, no. (%) | 156.779 | < 0.001* | 10.618 | < 0.001* | ||||
Single | 472 (77.1) | 266 (87.5) | 206 (77.2) | 0 | ||||
Multiple | 140 (22.9) | 38 (12.5) | 61 (22.8) | 41 (100) | ||||
Pathological outcomes | ||||||||
Architecture, no. (%) | 39.792 | < 0.001* | 39.811 | < 0.001* | ||||
Papillary | 479 (78.3) | 269 (88.5) | 178 (66.7) | 32 (78.0) | ||||
Sessile | 133 (21.7) | 35 (12.5) | 89 (33.3) | 9 (22.0) | ||||
Tumor stage, no. (%) | 0.160 | 0.923 | 0.155 | 0.723 | ||||
Ta-T1 | 206 (33.7) | 100 (32.9) | 92 (34.5) | 14 (34.1) | ||||
T2–4 | 406 (66.3) | 204 (67.1) | 175 (65.5) | 27 (65.9) | ||||
Tumor grade, no. (%) | 30.572 | < 0.001* | 28.242 | < 0.001* | ||||
G1 | 19 (3.1) | 4 (1.3) | 15 (5.6) | 0 | ||||
G2 | 334 (54.6) | 214 (70.4) | 115 (43.1) | 25 (61.0) | ||||
G3 | 259 (42.3) | 106 (34.9) | 137 (51.3) | 16 (39.0) | ||||
Lymph node status, no. (%) | 3.772 | 0.152 | 3.769 | 0.064 | ||||
N0 or Nx | 571 (93.3) | 278 (91.4) | 255 (95.5) | 38 (92.7) | ||||
N+ | 41 (6.7) | 26 (8.6) | 12 (4.5) | 3 (7.3) | ||||
Non-organ-confined disease, no. (%) | 10.339 | 0.006* | 9.592 | 0.002* | ||||
No | 412 (67.3) | 186 (61.2) | 196 (73.4) | 30 (73.2) | ||||
Yes | 200 (32.7) | 118 (38.8) | 71 (26.6) | 11 (26.8) | ||||
Tumor size, mean ± SD | 3.56 ± 1.94 | 3.25 ± 2.40 | 3.89 ± 3.39 | 13.014 | 0.001* | −3.695 | < 0.001* | |
Methylation status | ||||||||
TMEFF2, no. (%) | 6.972 | 0.031* | 6.481 | 0.011* | ||||
Unmethylated | 346 (56.5) | 158 (52.0) | 167 (62.5) | 21 (51.2) | ||||
Methylated | 266 (43.5) | 146 (48.0) | 100 (37.5) | 20 (48.8) | ||||
HSPA2, no. (%) | 3.398 | 0.183 | 3.064 | 0.089 | ||||
Unmethylated | 355 (58.0) | 167 (54.9) | 166 (62.2) | 22 (53.7) | ||||
Methylated | 257 (42.0) | 137 (45.1) | 101 (37.8) | 19 (46.3) | ||||
GDF15, no. (%) | 56.507 | < 0.001* | 56.310 | < 0.001* | ||||
Unmethylated | 304 (49.7) | 107 (35.2) | 178 (66.7) | 19 (46.3) | ||||
Methylated | 308 (50.3) | 197 (64.8) | 89 (33.3) | 22 (53.7) | ||||
RASSF1A, no. (%) | 22.562 | < 0.001* | 22.341 | < 0.001* | ||||
Unmethylated | 448 (73.2) | 197 (64.8) | 220 (82.4) | 31 (75.6) | ||||
Methylated | 164 (26.8) | 107 (35.2) | 47 (17.6) | 10 (24.4) | ||||
SALL3, no. (%) | 9.797 | 0.007* | 6.982 | 0.010* | ||||
Unmethylated | 403 (65.8) | 188 (61.8) | 193 (72.3) | 22 (53.7) | ||||
Methylated | 209 (34.2) | 116 (38.2) | 74 (27.7) | 19 (46.3) | ||||
VIM, no. (%) | 3.367 | 0.186 | 1.819 | 0.192 | ||||
Unmethylated | 219 (35.8) | 103 (33.9) | 105 (39.3) | 11 (26.8) | ||||
Methylated | 393 (64.2) | 201 (66.1) | 162 (60.7) | 30 (73.2) | ||||
ABCC6, no. (%) | 6.282 | 0.043* | 6.119 | 0.016* | ||||
Unmethylated | 523 (85.5) | 250 (82.2) | 239 (89.5) | 34 (82.9) | ||||
Methylated | 89 (14.5) | 54 (17.8) | 28 (10.5) | 7 (17.1) | ||||
CDH1, no. (%) | 1.054 | 0.590 | 0.116 | 0.809 | ||||
Unmethylated | 524 (85.6) | 260 (85.5) | 231 (86.5) | 33 (80.5) | ||||
Methylated | 88 (14.4) | 44 (14.5) | 36 (13.5) | 8 (19.5) | ||||
THBS1, no. (%) | 1.041 | 0.594 | 0.096 | 0.772 | ||||
Unmethylated | 457 (74.7) | 230 (75.7) | 199 (74.5) | 28 (68.3) | ||||
Methylated | 155 (25.3) | 74 (24.3) | 68 (25.5) | 13 (31.7) | ||||
BRCA1, no. (%) | 2.219 | 0.330 | 0.863 | 0.375 | ||||
Unmethylated | 504 (82.4) | 256 (84.2) | 217 (81.3) | 31 (75.6) | ||||
Methylated | 108 (17.6) | 48 (15.8) | 50 (18.7) | 10 (24.4) | ||||
Presence of hypermethylation in any gene, no. (%) | 8.739 | 0.013* | 8.537 | 0.004* | ||||
Unmethylated | 70 (11.4) | 24 (7.9) | 42 (15.7) | 4 (9.8) | ||||
Methylated | 542 (88.6) | 28 (92.1) | 225 (84.3) | 37 (90.2) | ||||
Mean methylated genes | 3.70 ± 2.33 | 2.83 ± 2.18 | 3.85 ± 2.35 | 21.900 | < 0.001* | −4.431 | < 0.001* | |
Number of methylated genes, no. (%) | 20.046 | < 0.001* | 16.108 | < 0.001* | ||||
0–2 | 254 (41.5) | 108 (35.5) | 135 (50.6) | 11 (26.8) | ||||
3–5 | 243 (39.7) | 126 (41.4) | 97 (36.3) | 20 (48.8) | ||||
6–10 | 115 (18.8) | 70 (23.0) | 35 (13.1) | 10 (24.4) | ||||
Prognostic outcomes | ||||||||
aOverall mortality, no. (%) | 0.059 | 0.011* | 4.547 | 0.033* | ||||
Survive | 379 (66.4) | 210 (69.1) | 169 (63.3) | 23 (56.1) | ||||
Death | 192 | 94 (30.9) | 98 (36.7) | 18 (43.9) | ||||
aCancer-specific mortality, no. (%) | 0.059 | 0.011* | 4.547 | 0.033* | ||||
Survive | 425 (69.4) | 223 (73.4) | 178 (66.7) | 34 (58.5) | ||||
Death | 187 (30.6) | 81 (26.6) | 89 (33.3) | 17 (41.5) | ||||
aIntravesical recurrence, no. (%) | 6.131 | 0.047* | 2.879 | 0.090 | ||||
No recurrence | 438 (71.6) | 228 (75.0) | 185 (69.3) | 25 (61.0) | ||||
Recurrence | 174 (28.4) | 76 (25.0) | 82 (30.7) | 16 (39.0) | ||||
aContralateral recurrence, no. (%) | 6.668 | 0.036* | 0.610 | 0.435 | ||||
No recurrence | 580 (94.8) | 291 (95.7) | 253 (94.8) | 41 (87.8) | ||||
Recurrence | 32 (5.2) | 13 (4.3) | 14 (5.2) | 5 (12.2) |