3.1 Clinicopathologic characteristics
The clinicopathologic characteristics of the 1760 solitary HBV-related HCC patients are summarized in Table 1. Most of these patients were male (85.1%), and the mean age was 50.7 (SD 10.2). Over half of patients (54.5%) were detected with a positive HBVDNA (> 1000 IU/mL). Half of patients (47.3%) were diagnosis cirrhosis pathologically. There are only 583 (33.1%) had AFP levels ≥ 400 ng/mL, and MVI incidence is 23.1%. The mean tumor diameter was 5.55 cm.
Table 1
The clinicopathologic factors of solitary HBV-related HCC patients who underwent initial hepatectomy (n = 1760)
Parameter | Value |
Age, year | 50.7 ± 10.2 |
Sex | |
Male | 1497 (85.1%) |
Female | 263 (14.9%) |
α-fetoprotein, ng/mL | |
≤ 20 | 726 (41.2%) |
20–400 | 451 (25.6%) |
≥ 400 | 583 (33.1%) |
HBV DNA, IU/ml | |
≤ 1000 | 801 (45.5%) |
> 1000 | 959 (54.5%) |
White blood cells, 109/L | 5.26 ± 1.74 |
Platelet count, 109/L | 152 (23–479) |
Albumin, g/L | 41.7 ± 3.74 |
Total bilirubin, µmol/L | 13.4 (3.3–45.4) |
γ-glutamyl transferase, IU/L | 55.0 (10-1175) |
Alkaline phosphatase, IU/L | 80.0 (17-1155) |
ALBI Grade | |
≤-2.63 | 1270 (72.2%) |
> 2.63 | 490 (27.8%) |
Blood loss, mL |
< 800 | 1650 (93.8%) |
≥ 800 | 110 (6.2%) |
Tumor size, cm | 5.55 ± 3.48 |
Differentiation degree |
I/II | 295 (16.8%) |
III/IV | 1465 (83.2%) |
Microvascular invasion |
Absent | 1354 (76.9%) |
Present | 406 (23.1%) |
AJCC TNM stage | |
T1a | 121 (6.9%) |
T1b | 1250 (71.0%) |
T2 | 389 (22.1%) |
BCLC stage | |
0 | 121 (6.9%) |
A | 1639 (93.1%) |
Tumor capsule | |
Incomplete/absent | 1232 (70.0%) |
Complete | 528 (30.0%) |
Cirrhosis | |
Absent | 927 (52.7%) |
Present | 833 (47.3%) |
Values shown are mean ± SD, median (range), or n (%) |
3.2 Tumor overall survival outcomes
Among all 1760 patients, median survival time was 70 months. The 1-, 3-, and 5-year OS were 90.7%, 75.9%, and 57.8%, respectively. Patients were classified into 11 groups based on tumor size with 1-cm intervals, and the OS decreased with increasing tumor size (Fig. 1).
3.3 Tumor size cutoffs screening based on minimum p value of prognosis
To examine possible cutoffs of solitary HCC, the largest tumor diameters were subdivided by 10 dichotomy, 45 trichotomy and 120 inquartation groups and there were 10, 45 and 120 cutoffs after exhaustive search. The p values of log-rank test for OS of each cutoff were calculated and cutoffs were screened. And the threshold of minimum p value was set at p < 0.05, p < 0.01, p < 0.001 or p < 0.0001.
As much as 8 from 10 cutoffs were screened when classifying tumor diameters by dichotomy and minimum p value was set at p < 0.0001 (Table 2). The HR values of tumor size at these cutoffs for OS were compared and the highest is 9 cm. Similarly, there were 8 from 45 cutoffs were screened when classifying tumor size by trichotomy and minimum p value was set at p < 0.0001 (Table 3). The HR values of tumor size at these cutoffs for OS were compared, the highest is 3/9 cm.
Table 2
The p values of log-rank test and HR values for OS of each dichotomy size cutoff
Cutoffs | Log-rank OS | Cox |
P-value | HR-OS (95%CI) |
1 cm | 0.40435 | 2.187 (0.301–15.887) |
2 cm | 0.00016 | 1.927 (1.358–2.734) |
3cm* | 0.00000 | 1.702 (1.408–2.059) |
4cm* | 0.00000 | 1.881 (1.613–2.194) |
5cm* | 0.00000 | 1.87 (1.615–2.164) |
6cm* | 0.00000 | 2.049 (1.766–2.377) |
7cm* | 0.00000 | 1.968 (1.683–2.302) |
8cm* | 0.00000 | 1.948 (1.650–2.299) |
9cm* | 0.00000 | 2.074 (1.737–2.476) |
10cm* | 0.00000 | 2.013 (1.662–2.439) |
*means the p values of log-rank test for OS of size cutoff were significant statistical difference (p < 0.0001). |
OS, overall survival; HR, hazard ratio; CI, confidence interval. |
Table 3
The p values of log-rank test and HR values for OS of each trichotomy size cutoff
Cutoffs (cm) | P-value of Log-rank | Cox |
A | B | ≤A vs. A ~ B | ≤A vs. >B | A ~ B vs. >B | HR (95%CI) |
1 | 2 | 0.611280 | 0.417322 | 0.000224 | 1.874 (1.337–2.628) |
1 | 3 | 0.401394 | 0.424487 | 0.000000 | 1.692 (1.402–2.042) |
1 | 4 | 0.588828 | 0.327959 | 0.000000 | 1.875 (1.609–2.184) |
1 | 5 | 0.566227 | 0.277350 | 0.000000 | 1.866 (1.613–2.159) |
1 | 6 | 0.545619 | 0.222792 | 0.000000 | 2.045 (1.763–2.371) |
1 | 7 | 0.493309 | 0.263552 | 0.000000 | 1.965 (1.682–2.297) |
1 | 8 | 0.482870 | 0.257788 | 0.000000 | 1.945 (1.649–2.294) |
1 | 9 | 0.460243 | 0.289755 | 0.000000 | 2.07 (1.735–2.469) |
1 | 10 | 0.444595 | 0.325466 | 0.000000 | 2.01 (1.661–2.433) |
2 | 3 | 0.083743 | 0.000028 | 0.000025 | 1.494 (1.295–1.725) |
2 | 4 | 0.103040 | 0.000001 | 0.000000 | 1.693 (1.486–1.928) |
2 | 5 | 0.029683 | 0.000000 | 0.000000 | 1.728 (1.521–1.963) |
2 | 6 | 0.018186 | 0.000000 | 0.000000 | 1.882 (1.649–2.147) |
2 | 7 | 0.005548 | 0.000000 | 0.000000 | 1.837 (1.601–2.109) |
2 | 8 | 0.002914 | 0.000000 | 0.000000 | 1.831 (1.584–2.116) |
2 | 9 | 0.001960 | 0.000000 | 0.000000 | 1.927 (1.652–2.249) |
2 | 10 | 0.001138 | 0.000000 | 0.000000 | 1.889 (1.604–2.226) |
3 | 4 | 0.451643 | 0.000000 | 0.000000 | 1.452 (1.319–1.599) |
3 | 5 | 0.028445 | 0.000000 | 0.000000 | 1.51 (1.369–1.666) |
3 | 6 | 0.009799 | 0.000000 | 0.000000 | 1.62 (1.460–1.797) |
3 | 7 | 0.000557 | 0.000000 | 0.000000 | 1.613 (1.447–1.798) |
3 | 8* | 0.000096 | 0.000000 | 0.000000 | 1.62 (1.446–1.814) |
3 | 9* | 0.000040 | 0.000000 | 0.000000 | 1.681 (1.491–1.896) |
3 | 10* | 0.000009 | 0.000000 | 0.000000 | 1.667 (1.470–1.890) |
4 | 5 | 0.000843 | 0.000000 | 0.001334 | 1.436 (1.325–1.557) |
4 | 6 | 0.000214 | 0.000000 | 0.000000 | 1.533 (1.408–1.670) |
4 | 7* | 0.000000 | 0.000000 | 0.000002 | 1.551 (1.418–1.697) |
4 | 8* | 0.000000 | 0.000000 | 0.000008 | 1.573 (1.432–1.727) |
4 | 9* | 0.000000 | 0.000000 | 0.000001 | 1.635 (1.481–1.805) |
4 | 10* | 0.000000 | 0.000000 | 0.000014 | 1.643 (1.481–1.822) |
5 | 6 | 0.074289 | 0.000000 | 0.000048 | 1.455 (1.346–1.573) |
5 | 7 | 0.000024 | 0.000000 | 0.000524 | 1.478 (1.360–1.605) |
5 | 8 | 0.000000 | 0.000000 | 0.001047 | 1.502 (1.377–1.638) |
5 | 9* | 0.000000 | 0.000000 | 0.000075 | 1.561 (1.425–1.711) |
5 | 10 | 0.000000 | 0.000000 | 0.000794 | 1.574 (1.430–1.732) |
6 | 7 | 0.000001 | 0.000000 | 0.381256 | 1.46 (1.349–1.580) |
6 | 8 | 0.000000 | 0.000000 | 0.255359 | 1.49 (1.371–1.619) |
6 | 9 | 0.000000 | 0.000000 | 0.025411 | 1.554 (1.423–1.697) |
6 | 10 | 0.000000 | 0.000000 | 0.069108 | 1.575 (1.436–1.727) |
7 | 8 | 0.000275 | 0.000000 | 0.449406 | 1.429 (1.316–1.553) |
7 | 9 | 0.000057 | 0.000000 | 0.037663 | 1.488 (1.363–1.625) |
7 | 10 | 0.000000 | 0.000000 | 0.109361 | 1.506 (1.372–1.652) |
8 | 9 | 0.044308 | 0.000000 | 0.042670 | 1.452 (1.329–1.586) |
8 | 10 | 0.000053 | 0.000000 | 0.166143 | 1.468 (1.337–1.612) |
9 | 10 | 0.000044 | 0.000000 | 0.944208 | 1.458 (1.327–1.601) |
*means the p values of log-rank test for OS of size cutoff were significant statistical difference (p < 0.0001). |
OS, overall survival; HR, hazard ratio; CI, confidence interval. |
Besides, there are no cutoffs were screened when classifying tumor size by inquartation until minimum p value was set at p < 0.05 (Table 4). There are 14 cutoffs and the HR values of tumor size at these cutoffs for OS were compared, the highest is 2/5/10 cm.
Table 4
The p values of log-rank test and HR for OS of each inquartation size cutoff
Cutoffs (cm) | P-value of Log-rank test | Cox |
A | B | C | ≤A vs. A ~ B | ≤A vs. B ~ C | ≤A vs. >C | A ~ B vs. B ~ C | A ~ B vs. >C | B ~ C vs. >C | HR (95%CI) |
1 | 2 | 3 | 0.611 | 0.488 | 0.424 | 0.091 | 0.000 | 0.000 | 1.487 (1.290–1.714) |
1 | 2 | 4 | 0.611 | 0.657 | 0.328 | 0.120 | 0.000 | 0.000 | 1.685 (1.480–1.918) |
1 | 2 | 5 | 0.611 | 0.610 | 0.277 | 0.035 | 0.000 | 0.000 | 1.721 (1.516–1.954) |
1 | 2 | 6 | 0.611 | 0.585 | 0.223 | 0.022 | 0.000 | 0.000 | 1.873 (1.642–2.136) |
1 | 2 | 7 | 0.611 | 0.522 | 0.264 | 0.007 | 0.000 | 0.000 | 1.829 (1.594–2.098) |
1 | 2 | 8 | 0.611 | 0.510 | 0.258 | 0.004 | 0.000 | 0.000 | 1.821 (1.576–2.104) |
1 | 2 | 9 | 0.611 | 0.483 | 0.290 | 0.003 | 0.000 | 0.000 | 1.915 (1.642–2.234) |
1 | 2 | 10 | 0.611 | 0.464 | 0.325 | 0.002 | 0.000 | 0.000 | 1.877 (1.594–2.209) |
1 | 3 | 4 | 0.401 | 0.802 | 0.328 | 0.499 | 0.000 | 0.000 | 1.45 (1.318–1.596) |
1 | 3 | 5 | 0.401 | 0.679 | 0.277 | 0.033 | 0.000 | 0.000 | 1.508 (1.367–1.663) |
1 | 3 | 6 | 0.401 | 0.641 | 0.223 | 0.012 | 0.000 | 0.000 | 1.616 (1.458–1.792) |
1 | 3 | 7 | 0.401 | 0.554 | 0.264 | 0.001 | 0.000 | 0.000 | 1.609 (1.444–1.793) |
1 | 3 | 8 | 0.401 | 0.539 | 0.258 | 0.000 | 0.000 | 0.000 | 1.616 (1.443–1.809) |
1 | 3 | 9 | 0.401 | 0.506 | 0.290 | 0.000 | 0.000 | 0.000 | 1.677 (1.487–1.890) |
1 | 3 | 10 | 0.401 | 0.484 | 0.325 | 0.000 | 0.000 | 0.000 | 1.662 (1.466–1.883) |
1 | 4 | 5 | 0.589 | 0.625 | 0.277 | 0.001 | 0.000 | 0.001 | 1.435 (1.325–1.555) |
1 | 4 | 6 | 0.589 | 0.583 | 0.223 | 0.000 | 0.000 | 0.000 | 1.532 (1.407–1.668) |
1 | 4 | 7 | 0.589 | 0.459 | 0.264 | 0.000 | 0.000 | 0.000 | 1.55 (1.417–1.695) |
1 | 4 | 8 | 0.589 | 0.444 | 0.258 | 0.000 | 0.000 | 0.000 | 1.571 (1.431–1.725) |
1 | 4 | 9 | 0.589 | 0.400 | 0.290 | 0.000 | 0.000 | 0.000 | 1.633 (1.480–1.803) |
1 | 4 | 10 | 0.589 | 0.372 | 0.325 | 0.000 | 0.000 | 0.000 | 1.641 (1.480–1.819) |
1 | 5 | 6 | 0.566 | 0.685 | 0.223 | 0.074 | 0.000 | 0.000 | 1.455 (1.346–1.572) |
1 | 5 | 7 | 0.566 | 0.406 | 0.264 | 0.000 | 0.000 | 0.001 | 1.477 (1.360–1.604) |
1 | 5 | 8 | 0.566 | 0.389 | 0.258 | 0.000 | 0.000 | 0.001 | 1.502 (1.377–1.637) |
1 | 5 | 9 | 0.566 | 0.317 | 0.290 | 0.000 | 0.000 | 0.000 | 1.561 (1.424–1.710) |
1 | 5 | 10 | 0.566 | 0.276 | 0.325 | 0.000 | 0.000 | 0.001 | 1.573 (1.430–1.731) |
1 | 6 | 7 | 0.546 | 0.297 | 0.264 | 0.000 | 0.000 | 0.381 | 1.46 (1.349–1.580) |
1 | 6 | 8 | 0.546 | 0.304 | 0.258 | 0.000 | 0.000 | 0.255 | 1.49 (1.371–1.619) |
1 | 6 | 9 | 0.546 | 0.233 | 0.290 | 0.000 | 0.000 | 0.025 | 1.554 (1.423–1.696) |
1 | 6 | 10 | 0.546 | 0.204 | 0.325 | 0.000 | 0.000 | 0.069 | 1.574 (1.436–1.726) |
1 | 7 | 8 | 0.493 | 0.768 | 0.258 | 0.000 | 0.000 | 0.449 | 1.43 (1.316–1.553) |
1 | 7 | 9 | 0.493 | 0.391 | 0.290 | 0.000 | 0.000 | 0.038 | 1.488 (1.363–1.625) |
1 | 7 | 10 | 0.493 | 0.330 | 0.325 | 0.000 | 0.000 | 0.109 | 1.506 (1.373–1.652) |
1 | 8 | 9 | 0.483 | 0.427 | 0.290 | 0.044 | 0.000 | 0.043 | 1.452 (1.330–1.586) |
1 | 8 | 10 | 0.483 | 0.334 | 0.325 | 0.000 | 0.000 | 0.166 | 1.468 (1.337–1.612) |
1 | 9 | 10 | 0.460 | 0.443 | 0.325 | 0.000 | 0.000 | 0.944 | 1.458 (1.327–1.601) |
2 | 3 | 4 | 0.084 | 0.122 | 0.000 | 0.887 | 0.000 | 0.000 | 1.385 (1.272–1.508) |
2 | 3 | 5 | 0.084 | 0.018 | 0.000 | 0.172 | 0.000 | 0.000 | 1.434 (1.313–1.567) |
2 | 3 | 6 | 0.084 | 0.010 | 0.000 | 0.095 | 0.000 | 0.000 | 1.519 (1.384–1.669) |
2 | 3 | 7 | 0.084 | 0.002 | 0.000 | 0.017 | 0.000 | 0.000 | 1.512 (1.371–1.667) |
2 | 3 | 8 | 0.084 | 0.001 | 0.000 | 0.005 | 0.000 | 0.000 | 1.514 (1.368–1.675) |
2 | 3 | 9 | 0.084 | 0.001 | 0.000 | 0.003 | 0.000 | 0.000 | 1.553 (1.396–1.728) |
2 | 3 | 10 | 0.084 | 0.000 | 0.000 | 0.001 | 0.000 | 0.000 | 1.537 (1.376–1.717) |
2 | 4 | 5 | 0.103 | 0.002 | 0.000 | 0.004 | 0.000 | 0.001 | 1.399 (1.299–1.507) |
2 | 4 | 6 | 0.103 | 0.002 | 0.000 | 0.002 | 0.000 | 0.000 | 1.482 (1.369–1.604) |
2 | 4 | 7 | 0.103 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 1.497 (1.377–1.626) |
2 | 4 | 8 | 0.103 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 1.514 (1.388–1.651) |
2 | 4 | 9 | 0.103 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 1.563 (1.427–1.712) |
2 | 4 | 10 | 0.103 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 1.566 (1.425–1.722) |
2 | 5 | 6 | 0.030 | 0.005 | 0.000 | 0.154 | 0.000 | 0.000 | 1.427 (1.327–1.535) |
2 | 5 | 7* | 0.030 | 0.000 | 0.000 | 0.000 | 0.000 | 0.001 | 1.448 (1.341–1.564) |
2 | 5 | 8* | 0.030 | 0.000 | 0.000 | 0.000 | 0.000 | 0.001 | 1.47 (1.356–1.593) |
2 | 5 | 9* | 0.030 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 1.52 (1.396–1.655) |
2 | 5 | 10* | 0.030 | 0.000 | 0.000 | 0.000 | 0.000 | 0.001 | 1.53 (1.400-1.672) |
2 | 6 | 7 | 0.018 | 0.000 | 0.000 | 0.000 | 0.000 | 0.381 | 1.44 (1.337–1.551) |
2 | 6 | 8 | 0.018 | 0.000 | 0.000 | 0.000 | 0.000 | 0.255 | 1.467 (1.357–1.586) |
2 | 6 | 9* | 0.018 | 0.000 | 0.000 | 0.000 | 0.000 | 0.025 | 1.523 (1.403–1.654) |
2 | 6 | 10 | 0.018 | 0.000 | 0.000 | 0.000 | 0.000 | 0.069 | 1.541 (1.414–1.680) |
2 | 7 | 8 | 0.006 | 0.000 | 0.000 | 0.001 | 0.000 | 0.449 | 1.419 (1.313–1.533) |
2 | 7 | 9* | 0.006 | 0.000 | 0.000 | 0.000 | 0.000 | 0.038 | 1.472 (1.356–1.598) |
2 | 7 | 10 | 0.006 | 0.000 | 0.000 | 0.000 | 0.000 | 0.109 | 1.488 (1.366–1.622) |
2 | 8 | 9 | 0.003 | 0.000 | 0.000 | 0.076 | 0.000 | 0.043 | 1.443 (1.329–1.567) |
2 | 8 | 10 | 0.003 | 0.000 | 0.000 | 0.000 | 0.000 | 0.166 | 1.459 (1.338–1.592) |
2 | 9 | 10 | 0.002 | 0.000 | 0.000 | 0.000 | 0.000 | 0.944 | 1.454 (1.333–1.586) |
3 | 4 | 5 | 0.452 | 0.001 | 0.000 | 0.013 | 0.000 | 0.001 | 1.318 (1.237–1.403) |
3 | 4 | 6 | 0.452 | 0.001 | 0.000 | 0.010 | 0.000 | 0.000 | 1.375 (1.286–1.471) |
3 | 4 | 7 | 0.452 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 1.385 (1.291–1.485) |
3 | 4 | 8 | 0.452 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 1.395 (1.297-1.500) |
3 | 4 | 9 | 0.452 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 1.423 (1.319–1.535) |
3 | 4 | 10 | 0.452 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 1.423 (1.315–1.538) |
3 | 5 | 6 | 0.028 | 0.011 | 0.000 | 0.350 | 0.000 | 0.000 | 1.356 (1.272–1.445) |
3 | 5 | 7* | 0.028 | 0.000 | 0.000 | 0.003 | 0.000 | 0.001 | 1.372 (1.283–1.467) |
3 | 5 | 8* | 0.028 | 0.000 | 0.000 | 0.000 | 0.000 | 0.001 | 1.387 (1.293–1.487) |
3 | 5 | 9* | 0.028 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 1.421 (1.320–1.528) |
3 | 5 | 10* | 0.028 | 0.000 | 0.000 | 0.000 | 0.000 | 0.001 | 1.426 (1.322–1.538) |
3 | 6 | 7 | 0.010 | 0.000 | 0.000 | 0.000 | 0.000 | 0.381 | 1.378 (1.291–1.471) |
3 | 6 | 8 | 0.010 | 0.000 | 0.000 | 0.000 | 0.000 | 0.255 | 1.399 (1.306–1.497) |
3 | 6 | 9* | 0.010 | 0.000 | 0.000 | 0.000 | 0.000 | 0.025 | 1.44 (1.340–1.547) |
3 | 6 | 10 | 0.010 | 0.000 | 0.000 | 0.000 | 0.000 | 0.069 | 1.451 (1.347–1.564) |
3 | 7 | 8 | 0.001 | 0.000 | 0.000 | 0.005 | 0.000 | 0.449 | 1.37 (1.280–1.467) |
3 | 7 | 9* | 0.001 | 0.000 | 0.000 | 0.003 | 0.000 | 0.038 | 1.411 (1.313–1.516) |
3 | 7 | 10 | 0.001 | 0.000 | 0.000 | 0.000 | 0.000 | 0.109 | 1.423 (1.320–1.535) |
3 | 8 | 9 | 0.000 | 0.001 | 0.000 | 0.174 | 0.000 | 0.043 | 1.395 (1.298-1.500) |
3 | 8 | 10 | 0.000 | 0.000 | 0.000 | 0.002 | 0.000 | 0.166 | 1.408 (1.305–1.519) |
3 | 9 | 10 | 0.000 | 0.000 | 0.000 | 0.001 | 0.000 | 0.944 | 1.41 (1.306–1.522) |
4 | 5 | 6 | 0.001 | 0.011 | 0.000 | 0.712 | 0.000 | 0.000 | 1.314 (1.243–1.389) |
4 | 5 | 7 | 0.001 | 0.000 | 0.000 | 0.294 | 0.000 | 0.001 | 1.329 (1.254–1.409) |
4 | 5 | 8 | 0.001 | 0.000 | 0.000 | 0.123 | 0.000 | 0.001 | 1.342 (1.263–1.426) |
4 | 5 | 9 | 0.001 | 0.000 | 0.000 | 0.096 | 0.000 | 0.000 | 1.369 (1.285–1.458) |
4 | 5 | 10* | 0.001 | 0.000 | 0.000 | 0.037 | 0.000 | 0.001 | 1.374 (1.287–1.467) |
4 | 6 | 7 | 0.000 | 0.000 | 0.000 | 0.004 | 0.000 | 0.381 | 1.343 (1.268–1.423) |
4 | 6 | 8 | 0.000 | 0.000 | 0.000 | 0.001 | 0.000 | 0.255 | 1.362 (1.282–1.446) |
4 | 6 | 9* | 0.000 | 0.000 | 0.000 | 0.001 | 0.000 | 0.025 | 1.396 (1.310–1.487) |
4 | 6 | 10 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.069 | 1.407 (1.317–1.502) |
4 | 7 | 8 | 0.000 | 0.000 | 0.000 | 0.058 | 0.000 | 0.449 | 1.347 (1.267–1.430) |
4 | 7 | 9 | 0.000 | 0.000 | 0.000 | 0.067 | 0.000 | 0.038 | 1.382 (1.297–1.473) |
4 | 7 | 10 | 0.000 | 0.000 | 0.000 | 0.006 | 0.000 | 0.109 | 1.395 (1.305–1.490) |
4 | 8 | 9 | 0.000 | 0.001 | 0.000 | 0.570 | 0.000 | 0.043 | 1.375 (1.290–1.466) |
4 | 8 | 10 | 0.000 | 0.000 | 0.000 | 0.046 | 0.000 | 0.166 | 1.389 (1.299–1.485) |
4 | 9 | 10 | 0.000 | 0.000 | 0.000 | 0.008 | 0.000 | 0.944 | 1.396 (1.305–1.493) |
5 | 6 | 7 | 0.074 | 0.000 | 0.000 | 0.010 | 0.000 | 0.381 | 1.304 (1.235–1.377) |
5 | 6 | 8 | 0.074 | 0.000 | 0.000 | 0.003 | 0.000 | 0.255 | 1.32 (1.247–1.397) |
5 | 6 | 9 | 0.074 | 0.000 | 0.000 | 0.004 | 0.000 | 0.025 | 1.349 (1.271–1.431) |
5 | 6 | 10 | 0.074 | 0.000 | 0.000 | 0.001 | 0.000 | 0.069 | 1.358 (1.277–1.443) |
5 | 7 | 8 | 0.000 | 0.000 | 0.000 | 0.121 | 0.000 | 0.449 | 1.311 (1.238–1.388) |
5 | 7 | 9 | 0.000 | 0.000 | 0.000 | 0.173 | 0.000 | 0.038 | 1.342 (1.263–1.424) |
5 | 7 | 10 | 0.000 | 0.000 | 0.000 | 0.035 | 0.000 | 0.109 | 1.352 (1.271–1.439) |
5 | 8 | 9 | 0.000 | 0.006 | 0.000 | 0.849 | 0.000 | 0.043 | 1.338 (1.259–1.422) |
5 | 8 | 10 | 0.000 | 0.000 | 0.000 | 0.156 | 0.000 | 0.166 | 1.35 (1.268–1.438) |
5 | 9 | 10 | 0.000 | 0.000 | 0.000 | 0.024 | 0.000 | 0.944 | 1.36 (1.275–1.449) |
6 | 7 | 8 | 0.000 | 0.000 | 0.000 | 0.827 | 0.309 | 0.449 | 1.297 (1.228–1.371) |
6 | 7 | 9 | 0.000 | 0.000 | 0.000 | 0.771 | 0.121 | 0.038 | 1.327 (1.252–1.406) |
6 | 7 | 10 | 0.000 | 0.000 | 0.000 | 0.884 | 0.136 | 0.109 | 1.338 (1.260–1.421) |
6 | 8 | 9 | 0.000 | 0.010 | 0.000 | 0.369 | 0.077 | 0.043 | 1.326 (1.250–1.406) |
6 | 8 | 10 | 0.000 | 0.000 | 0.000 | 0.967 | 0.093 | 0.166 | 1.338 (1.259–1.423) |
6 | 9 | 10 | 0.000 | 0.000 | 0.000 | 0.179 | 0.036 | 0.944 | 1.349 (1.268–1.435) |
7 | 8 | 9 | 0.000 | 0.027 | 0.000 | 0.343 | 0.212 | 0.043 | 1.294 (1.221–1.372) |
7 | 8 | 10 | 0.000 | 0.000 | 0.000 | 0.861 | 0.222 | 0.166 | 1.304 (1.227–1.386) |
7 | 9 | 10 | 0.000 | 0.000 | 0.000 | 0.178 | 0.047 | 0.944 | 1.315 (1.236–1.399) |
8 | 9 | 10 | 0.044 | 0.000 | 0.000 | 0.107 | 0.049 | 0.944 | 1.295 (1.217–1.378) |
*means the p values of log-rank test for OS of size cutoff were significant statistical difference (p < 0.05). |
OS, overall survival; HR, hazard ratio; CI, confidence interval. |
3.4 Redefinition of tumor size groups and their characteristics
We reclassified patients into three new categories: ≤ 3 cm (n = 422), > 3 and ≤ 9 cm (n = 1072), and > 9 cm (n = 266). The comparison of clinicopathologic characteristics among these three new classifications (Table 5) showed that the increase of tumor size was associated with the increase of AFP, white blood cell count (WBC), platelet count (PLT), γ-glutamyl transferase (GGT), Alkaline phosphatase (ALP), volume of blood loss, MVI, tumor differentiation, and liver cirrhosis.
Table 5
Comparison of clinicopathologic characteristics among three new classifications
Parameter | ≤ 3 cm | 3 ~ 9 cm | > 9 cm | | P-value | |
(n = 422) | (n = 1072) | (n = 266) | ≤ 3 vs. 3 ~ 9 | 3 ~ 9 vs. >9 | ≤ 3 vs. >9 |
Age, year | | | | | | |
≤ 50 | 212 (50.2%) | 534 (49.8%) | 139 (52.3%) | 0.928 | 0.519 | 0.662 |
> 50 | 210 (49.8%) | 538 (50.2%) | 127 (47.7%) | | | |
Sex | | | | | | |
Male | 346 (82.0%) | 928 (86.6%) | 223 (83.8%) | 0.0303 | 0.293 | 0.604 |
Female | 76 (18.0%) | 144 (13.4%) | 43 (16.2%) | | | |
AFP, ng/mL | | | | | | |
≤ 20 | 183 (43.4%) | 471 (43.9%) | 72 (27.1%) | < 0.001 | < 0.001 | < 0.001 |
20–400 | 140 (33.2%) | 249 (23.2%) | 62 (23.3%) | | | |
≥ 400 | 99 (23.5%) | 352 (32.8%) | 132 (49.6%) | | | |
HBV DNA, IU/ml | | | | | |
≤ 1000 | 213 (50.5%) | 488 (45.5%) | 100 (37.6%) | 0.0951 | 0.0236 | 0.00126 |
> 1000 | 209 (49.5%) | 584 (54.5%) | 166 (62.4%) | | | |
White blood cells, 109/L | | | | | |
< 4 | 131 (31.0%) | 236 (22.0%) | 41 (15.4%) | < 0.001 | 0.0218 | < 0.001 |
≥ 4 | 291 (69.0%) | 836 (78.0%) | 225 (84.6%) | | | |
Platelet count, 109/L | | | | | |
< 100 | 115 (27.3%) | 193 (18.0%) | 15 (5.6%) | < 0.001 | < 0.001 | < 0.001 |
≥ 100 | 307 (72.7%) | 879 (82.0%) | 251 (94.4%) | | | |
Albumin, g/L | | | | | |
< 35 | 10 (2.4%) | 29 (2.7%) | 14 (5.3%) | 0.852 | 0.0545 | 0.0717 |
≥ 35 | 412 (97.6%) | 1043 (97.3%) | 252 (94.7%) | | | |
Total bilirubin, µmol/L | | | | | |
≤ 17.1 | 314 (74.4%) | 822 (76.7%) | 205 (77.1%) | 0.391 | 0.958 | 0.485 |
> 17.1 | 108 (25.6%) | 250 (23.3%) | 61 (22.9%) | | | |
γ-glutamyl transferase, IU/L | | | | | |
≤ 64 | 300 (71.1%) | 663 (61.8%) | 62 (23.3%) | < 0.001 | < 0.001 | < 0.001 |
> 64 | 122 (28.9%) | 409 (38.2%) | 204 (76.7%) | | | |
Alkaline phosphatase, IU/L | | | | | |
≤ 129 | 410 (97.2%) | 998 (93.1%) | 181 (68.0%) | 0.00362 | < 0.001 | < 0.001 |
> 129 | 12 (2.8%) | 74 (6.9%) | 85 (32.0%) | | | |
ALBI Grade | | | | | | |
≤-2.63 | 321 (76.1%) | 795 (74.2%) | 154 (57.9%) | 0.486 | < 0.001 | < 0.001 |
> 2.63 | 101 (23.9%) | 277 (25.8%) | 112 (42.1%) | | | |
Blood loss, mL | | | | | |
< 800 | 417 (98.8%) | 1024 (95.5%) | 209 (78.6%) | 0.00326 | < 0.001 | < 0.001 |
≥ 800 | 5 (1.2%) | 48 (4.5%) | 57 (21.4%) | | | |
Differentiation degree | | | | | |
I/II | 105 (24.9%) | 174 (16.2%) | 16 (6.0%) | < 0.001 | < 0.001 | < 0.001 |
III/IV | 317 (75.1%) | 898 (83.8%) | 250 (94.0%) | | | |
Microvascular invasion | | | | | |
Negative | 349 (82.7%) | 830 (77.4%) | 175 (65.8%) | 0.0292 | < 0.001 | < 0.001 |
Positive | 73 (17.3%) | 242 (22.6%) | 91 (34.2%) | | | |
Tumor capsule | | | | | |
Incomplete/absent | 292 (69.2%) | 735 (68.6%) | 205 (77.1%) | 0.861 | 0.00827 | 0.0309 |
Complete | 130 (30.8%) | 337 (31.4%) | 61 (22.9%) | | | |
Cirrhosis | | | | | | |
Absent | 157 (37.2%) | 588 (54.9%) | 182 (68.4%) | < 0.001 | < 0.001 | < 0.001 |
Present | 265 (62.8%) | 484 (45.1%) | 84 (31.6%) | | | |
In addition, we divided patients into four new categories: ≤ 2 cm (n = 121), > 2 and ≤ 5 cm (n = 907), > 5 and ≤ 10 cm (n = 518), and > 10 cm (n = 214). And the comparison of clinicopathologic characteristics among these four classifications (Table 6) showed that the increase of tumor size was associated with only AFP and PLT.
Table 6
Comparison of clinicopathologic characteristics among four new classifications
| ≤ 2 cm | 2 ~ 5 cm | 5 ~ 10 cm | > 10 cm | P-value |
(n = 121) | (n = 907) | (n = 518) | (n = 214) | ≤ 2 vs. 2 ~ 5 | ≤ 2 vs. 5 ~ 10 | ≤ 2 vs. >10 | 2 ~ 5 vs. 5 ~ 10 | 2 ~ 5 vs. >10 | 5 ~ 10 vs. >10 |
Age, year | | | | | | | | | | |
≤ 50 | 65 (53.7%) | 444 (49.0%) | 258 (49.8%) | 118 (55.1%) | 0.374 | 0.5 | 0.891 | 0.799 | 0.121 | 0.218 |
> 50 | 56 (46.3%) | 463 (51.0%) | 260 (50.2%) | 96 (44.9%) | | | | | | |
Sex | | | | | | | | | | |
Male | 98 (81.0%) | 770 (84.9%) | 448 (86.5%) | 181 (84.6%) | 0.328 | 0.162 | 0.488 | 0.458 | 0.992 | 0.577 |
Female | 23 (19.0%) | 137 (15.1%) | 70 (13.5%) | 33 (15.4%) | | | | | | |
AFP, ng/mL | | | | | | | | | | |
≤ 20 | 51 (42.1%) | 431 (47.5%) | 189 (36.5%) | 55 (25.7%) | < 0.001 | < 0.001 | < 0.001 | < 0.001 | < 0.001 | 0.00871 |
20–400 | 52 (43.0%) | 224 (24.7%) | 124 (23.9%) | 51 (23.8%) | | | | | | |
≥ 400 | 18 (14.9%) | 252 (27.8%) | 205 (39.6%) | 108 (50.5%) | | | | | | |
HBV DNA, IU/ml | | | | | | | | | |
≤ 1000 | 67 (55.4%) | 431 (47.5%) | 220 (42.5%) | 83 (38.8%) | 0.127 | 0.0136 | 0.00483 | 0.0743 | 0.0257 | 0.402 |
> 1000 | 54 (44.6%) | 476 (52.5%) | 298 (57.5%) | 131 (61.2%) | | | | | | |
White blood cells, 109/L | | | | | | | | | |
< 4 | 39 (32.2%) | 245 (27.0%) | 93 (18.0%) | 31 (14.5%) | 0.272 | < 0.001 | < 0.001 | < 0.001 | < 0.001 | 0.303 |
≥ 4 | 82 (67.8%) | 662 (73.0%) | 425 (82.0%) | 183 (85.5%) | | | | | | |
Platelet count, 109/L | | | | | | | | | |
< 100 | 36 (29.8%) | 211 (23.3%) | 67 (12.9%) | 9 (4.2%) | 0.145 | < 0.001 | < 0.001 | < 0.001 | < 0.001 | < 0.001 |
≥ 100 | 85 (70.2%) | 696 (76.7%) | 451 (87.1%) | 205 (95.8%) | | | | | | |
Albumin, g/L | | | | | | | | | |
< 35 | 3 (2.5%) | 24 (2.6%) | 16 (3.1%) | 10 (4.7%) | 1 | 0.954 | 0.481 | 0.749 | 0.182 | 0.404 |
≥ 35 | 118 (97.5%) | 883 (97.4%) | 502 (96.9%) | 204 (95.3%) | | | | | | |
Total bilirubin, µmol/L | | | | | | | | | |
≤ 17.1 | 94 (77.7%) | 669 (73.8%) | 411 (79.3%) | 167 (78.0%) | 0.414 | 0.78 | 1 | 0.0213 | 0.228 | 0.768 |
> 17.1 | 27 (22.3%) | 238 (26.2%) | 107 (20.7%) | 47 (22.0%) | | | | | | |
γ-glutamyl transferase, IU/L | | | | | | | | | |
≤ 64 | 88 (72.7%) | 637 (70.2%) | 255 (49.2%) | 45 (21.0%) | 0.646 | < 0.001 | < 0.001 | < 0.001 | < 0.001 | < 0.001 |
> 64 | 33 (27.3%) | 270 (29.8%) | 263 (50.8%) | 169 (79.0%) | | | | | | |
Alkaline phosphatase, IU/L | | | | | | | | | |
≤ 129 | 120 (99.2%) | 864 (95.3%) | 467 (90.2%) | 138 (64.5%) | 0.0786 | 0.00205 | < 0.001 | < 0.001 | < 0.001 | < 0.001 |
> 129 | 1 (0.8%) | 43 (4.7%) | 51 (9.8%) | 76 (35.5%) | | | | | | |
ALBI Grade | | | | | | | | | | |
≤-2.63 | 101 (83.5%) | 688 (75.9%) | 355 (68.5%) | 126 (58.9%) | 0.0804 | 0.00157 | < 0.001 | 0.00329 | < 0.001 | 0.0156 |
> 2.63 | 20 (16.5%) | 219 (24.1%) | 163 (31.5%) | 88 (41.1%) | | | | | | |
Blood loss, mL | | | | | | | | | |
< 800 | 120 (99.2%) | 890 (98.1%) | 476 (91.9%) | 164 (76.6%) | 0.648 | 0.00743 | < 0.001 | < 0.001 | < 0.001 | < 0.001 |
≥ 800 | 1 (0.8%) | 17 (1.9%) | 42 (8.1%) | 50 (23.4%) | | | | | | |
Differentiation degree | | | | | | | | | |
I/II | 39 (32.2%) | 190 (20.9%) | 54 (10.4%) | 12 (5.6%) | 0.00724 | < 0.001 | < 0.001 | < 0.001 | < 0.001 | 0.0539 |
III/IV | 82 (67.8%) | 717 (79.1%) | 464 (89.6%) | 202 (94.4%) | | | | | | |
Microvascular invasion | | | | | | | | | |
Negative | 104 (86.0%) | 715 (78.8%) | 395 (76.3%) | 140 (65.4%) | 0.0877 | 0.0278 | < 0.001 | 0.289 | < 0.001 | 0.00356 |
Positive | 17 (14.0%) | 192 (21.2%) | 123 (23.7%) | 74 (34.6%) | | | | | | |
Tumor capsule | | | | | | | | | |
Incomplete/absent | 76 (62.8%) | 631 (69.6%) | 362 (69.9%) | 163 (76.2%) | 0.161 | 0.161 | 0.0135 | 0.949 | 0.0678 | 0.104 |
Complete | 45 (37.2%) | 276 (30.4%) | 156 (30.1%) | 51 (23.8%) | | | | | | |
Cirrhosis | | | | | | | | | | |
Absent | 44 (36.4%) | 415 (45.8%) | 317 (61.2%) | 151 (70.6%) | 0.0637 | < 0.001 | < 0.001 | < 0.001 | < 0.001 | 0.0206 |
Present | 77 (63.6%) | 492 (54.2%) | 201 (38.8%) | 63 (29.4%) | | | | | | |
3.5 Overall survival of the new three groups
Based on these biological characteristics and prognostic findings, we suggested 3/9 cm could be appropriate cutoff for tumor size of solitary HBV related HCC. The overall 1-, 3-, and 5-year survival rates were 94.5%, 84.5%, and 69.0% in patients with HCC ≤ 3 cm, 92.0%, 76.3%, and 58.3% in patients with HCC > 3 and ≤ 9 cm, and 79.3%, 60.5%, and 37.4% in patients with HCC > 9 cm, respectively. The comparison of the overall survival rates between any two subgroups showed statistical differences (all p = 0.000) (Fig. 2).
4.Discussion
Tumor size is a key characteristic of HCC and its classification is one of the most important issues for HCC treatment and prognosis. However, there is currently no uniform cutoff criteria for size of HCC. A systematic review showed there are three kinds of criteria for small HCC alone [19]. Even in different stage systems, the criteria for size of solitary HCC are inconsistent. In this study, we subdivided tumor size by 1 cm intervals and analyzed the relationship between tumor size and the overall survival of 1760 patients with solitary HBV-related HCC. Our results revealed a stepwise incremental deterioration in OS outcomes with increased tumor size, which is consistent with other studies [10, 11]. Then we employed minimum p value method to screen the appropriate size cutoffs that could divided HCC tumor OS well.
Many previous studies showed that multiple dichotomy can divide tumor size well based on prognosis. The BCLC, TNM, Japan Integrated Staging Score (JIS) employ 2 cm as the cutoff for single HCC [17, 18, 20], while the Hong Kong Liver Cancer staging system and Chinese staging system use a cutoff with 5 cm [21, 22]. One previous study suggested multiple size cutoffs such as 2 cm, 3 cm, 4 cm, 5 cm, 8 cm, and 10 cm have good discrimination for HCC prognosis [23]. In this study, similarly, dichotomy results of minimum p value of OS showed that 8 among 10 cutoffs can divide tumor size into 2 groups well. These evidences indicated dichotomy of HCC tumor size might not reflect the biological nature of HCC. Among these cutoffs, the HR values of OS are compared, 9 cm has the highest HR for OS. This is inconsistent with the result of a multi-center study indicating 2 cm has the highest HR for OS [12], which may be caused by different study population and treatment decisions in different countries or regions.
Then, we divided HCC tumors into 45 trichotomy groups. There are 8 cutoffs of size discriminated OS well when minimum p value was set at p < 0.0001. With the comparison of HR of these groups, we found that 3/9 cm cutoff groups have the highest HR value for OS. When we tried inquartation of tumor size, there were no cutoffs were screened until minimum p value was set at p < 0.05 and 2/5/10 cm cutoff groups have the highest HR value for OS. Furthermore, the comparison of clinicopathologic characteristics of new classifications showed that the increase of tumor size was associated with more biological characteristics. On the basis of these results, 3/9 cm could be an appropriate size cutoff for HCC tumor.
There are some similarities and differences with other studies. In one study of 857 patients with single HCC, 5/8 cm were suggested to be cutoff of size after dividing HCC into 5 groups with 2 cm intervals and combining the adjacent groups with similar OS [10]. Another large retrospective study chose the controversial cutoff of 5 cm as the boundary of small and large HCC after similar method [11]. As the initial criteria of small HCC, 5 cm were raised since the mid to late 1970s [24]. Along with the advances in radiographic diagnostic techniques and pathophysiology, smaller criteria such as 3 cm and 2 cm were proposed to replace the criteria of SHCC by many East-West study groups. The size cutoff of 2 cm was raised from BCLC system in 2003 based on the LCSGJ’s data and has been adopted in the BCLC and TNM staging system (Eight Edition). However, many studies showed tumor up to 2 cm are accounted for a very small proportion of HCC and hard to analyze their pathobiological characteristics [25]. Moreover, studies based on pathobiological characteristics indicated that 3 cm in diameter is an important turning point of HCC development, where HCC transformed from relatively benign behavior to a more aggressive progression [6]. From a clinical standpoint, single HCC tumors up to 3 cm had a similar 3-years OS rate when treated by radiofrequency ablation (RFA), percutaneous ethanol injection (PEI) and surgical resection [26]. Thus, 3 cm as a cutoff of small HCC had a pathobiological and treatment significance.
With the development of research, the cutoff of large HCC tumor size was no longer confined to 5 cm, which can be reflected in changes in criteria for liver transplantation. University of California, San Francisco (UCSF) criteria [27] and Up-to-Seven criteria [28] implied single tumors ≤ 6.5 or ≤ 6 cm had a same prognosis with Milan criteria. Hangzhou criteria [29] and Fudan criteria [30] further broadened the size cutoff of single HCC tumor to 8 cm and 9 cm. In this study, we reclassified patients into three new classifications: ≤ 3 cm, > 3 and ≤ 9 cm, and > 9 cm according to the results of minimum p value of OS. The comparison of clinicopathologic characteristics among these three groups showed that increase of tumor size was associated with multiple pathobiological features such as AFP, MVI, tumor differentiation, and liver cirrhosis. In addition, the comparison of the overall survival between any two subgroups showed a statistical difference (all p = 0.000). These indicated that 3/9 cm as the boundary of small HCC and large HCC had a biological meaning and prognostic significance.
There are a few limitations to this study. Firstly, although the study population is large enough, this is a retrospective, single-center study and thus the results may not be generalized. A multicenter prospective study may be necessary to perform to validate our results. Secondly, all of the study population was HBV related HCC since their characteristics are different from non-HBV related HCC. Thirdly, insufficient patient volume of HCC ≤ 1 cm may lead to be hard to work out further subclassification of HCC tumor size.
In conclusion, this study suggested that the tumor size with a cutoff of 3 cm and 9 cm in solitary HBV related HCC patients were appropriate based on biological characteristics and prognostic significance.
2.1 Study cohort
This study was conducted under the guideline of the 1975 Declaration of Helsinki and was approved by the Institutional Ethics Committee of the Mengchao Hepatobiliary Hospital of Fujian medical University. Informed consent obtained from all patients were written before LR operation. Medical records of HCC patients from June 2008 to December 2014 were extracted from primary liver cancer big data (PLCBD) [15]. Data were extracted by an engineer and were verified by five researchers in this study.
The inclusion criteria were as follows: (1) solitary HCC tumor, (2) Child-Pugh A or B liver function, (3) seropositive for HBV surface antigen (HBsAg) and seronegative for hepatitis C virus anti-body (HCV-Ab), (4) underwent curative hepatectomy. Exclusion criteria were as follows: (1) having received any preoperative anticancer treatments, (2) had a history of other cancers, (3) pathological and clinical data are incomplete. Finally, 1760 patients were selected as the study cohort.
2.2 Study design
To examine possible subclassification of solitary HCC, HCCs with the largest tumor diameters ≤ 10 cm were divided into ten groups with 1-cm intervals, and HCCs with the largest tumor diameters > 10 cm were selected as one group. There were 10, 45 and 120 cutoffs of size when classifying our patients into dichotomy, trichotomy and inquartation groups respectively. The rationale for adopting the appropriate cutoff value for solitary HBV-related HCC was confirmed by the minimum p value approach to predict OS after LR.
The OS rates were generated by using the Kaplan-Meier method and the differences were compared by log-rank test. There was one p value when comparing OS of tumor size dichotomy, while three and six p values when comparing tumor size trichotomy and inquartation. The threshold of minimum p value was set at p < 0.05, p < 0.01, p < 0.001 or p < 0.0001. And if multiple cutoffs fulfill the standard, hazard ratio (HR) values of tumor size cutoffs for OS were compared and the highest ones were screened according to the previous study [12].
2.3 Clinicopathologic variables
The tumor size was based on the largest dimension of the tumor in the resected specimen. MVI was defined as the presence of tumor cell clusters within the blood vessels lined by endothelium including branch of the portal vein, hepatic vein, or capsular vessel [16]. Tumor differentiation was assessed according to the Edmondson-Steiner grade. Tumor stage was determined according to the BCLC staging system and TNM staging system (8th edition) [17, 18].
2.4 Follow-up
Patients were followed up by the serum levels of AFP, ultrasonography and computed tomography / magnetic resonance imaging at 1 month after LR operation, then every two months in the first 6 months and every three months at a later time. The OS was defined as the time interval between the day of the operation and death. The last follow-up data were collected until December 31, 2018.
2.5 Statistical analysis
Continuous values were expressed as mean ± standard deviation (SD) or as median (range) and compared by using the t test or Mann-Whitney U test. Categorical variables were expressed as number (%) and compared by using the Chi-square or Fisher’s exact test. The OS rates were generated by using the Kaplan-Meier method and the differences were compared by log-rank test. Univariate and multivariate analyses were performed by employing the Cox proportional hazards regression model. Statistical analyses were performed by using IBM SPSS software (version 19.0, SPSS Inc., Chicago, IL). A p < 0.05 (two-tailed) was considered as the threshold of significance.
3.Results
3.1 Clinicopathologic characteristics
The clinicopathologic characteristics of the 1760 solitary HBV-related HCC patients are summarized in Table 1. Most of these patients were male (85.1%), and the mean age was 50.7 (SD 10.2). Over half of patients (54.5%) were detected with a positive HBVDNA (> 1000 IU/mL). Half of patients (47.3%) were diagnosis cirrhosis pathologically. There are only 583 (33.1%) had AFP levels ≥ 400 ng/mL, and MVI incidence is 23.1%. The mean tumor diameter was 5.55 cm.
Table 1
The clinicopathologic factors of solitary HBV-related HCC patients who underwent initial hepatectomy (n = 1760)
Parameter | Value |
Age, year | 50.7 ± 10.2 |
Sex | |
Male | 1497 (85.1%) |
Female | 263 (14.9%) |
α-fetoprotein, ng/mL | |
≤ 20 | 726 (41.2%) |
20–400 | 451 (25.6%) |
≥ 400 | 583 (33.1%) |
HBV DNA, IU/ml | |
≤ 1000 | 801 (45.5%) |
> 1000 | 959 (54.5%) |
White blood cells, 109/L | 5.26 ± 1.74 |
Platelet count, 109/L | 152 (23–479) |
Albumin, g/L | 41.7 ± 3.74 |
Total bilirubin, µmol/L | 13.4 (3.3–45.4) |
γ-glutamyl transferase, IU/L | 55.0 (10-1175) |
Alkaline phosphatase, IU/L | 80.0 (17-1155) |
ALBI Grade | |
≤-2.63 | 1270 (72.2%) |
> 2.63 | 490 (27.8%) |
Blood loss, mL |
< 800 | 1650 (93.8%) |
≥ 800 | 110 (6.2%) |
Tumor size, cm | 5.55 ± 3.48 |
Differentiation degree |
I/II | 295 (16.8%) |
III/IV | 1465 (83.2%) |
Microvascular invasion |
Absent | 1354 (76.9%) |
Present | 406 (23.1%) |
AJCC TNM stage | |
T1a | 121 (6.9%) |
T1b | 1250 (71.0%) |
T2 | 389 (22.1%) |
BCLC stage | |
0 | 121 (6.9%) |
A | 1639 (93.1%) |
Tumor capsule | |
Incomplete/absent | 1232 (70.0%) |
Complete | 528 (30.0%) |
Cirrhosis | |
Absent | 927 (52.7%) |
Present | 833 (47.3%) |
Values shown are mean ± SD, median (range), or n (%) |
3.2 Tumor overall survival outcomes
Among all 1760 patients, median survival time was 70 months. The 1-, 3-, and 5-year OS were 90.7%, 75.9%, and 57.8%, respectively. Patients were classified into 11 groups based on tumor size with 1-cm intervals, and the OS decreased with increasing tumor size (Fig. 1).
3.3 Tumor size cutoffs screening based on minimum p value of prognosis
To examine possible cutoffs of solitary HCC, the largest tumor diameters were subdivided by 10 dichotomy, 45 trichotomy and 120 inquartation groups and there were 10, 45 and 120 cutoffs after exhaustive search. The p values of log-rank test for OS of each cutoff were calculated and cutoffs were screened. And the threshold of minimum p value was set at p < 0.05, p < 0.01, p < 0.001 or p < 0.0001.
As much as 8 from 10 cutoffs were screened when classifying tumor diameters by dichotomy and minimum p value was set at p < 0.0001 (Table 2). The HR values of tumor size at these cutoffs for OS were compared and the highest is 9 cm. Similarly, there were 8 from 45 cutoffs were screened when classifying tumor size by trichotomy and minimum p value was set at p < 0.0001 (Table 3). The HR values of tumor size at these cutoffs for OS were compared, the highest is 3/9 cm.
Table 2
The p values of log-rank test and HR values for OS of each dichotomy size cutoff
Cutoffs | Log-rank OS | Cox |
P-value | HR-OS (95%CI) |
1 cm | 0.40435 | 2.187 (0.301–15.887) |
2 cm | 0.00016 | 1.927 (1.358–2.734) |
3cm* | 0.00000 | 1.702 (1.408–2.059) |
4cm* | 0.00000 | 1.881 (1.613–2.194) |
5cm* | 0.00000 | 1.87 (1.615–2.164) |
6cm* | 0.00000 | 2.049 (1.766–2.377) |
7cm* | 0.00000 | 1.968 (1.683–2.302) |
8cm* | 0.00000 | 1.948 (1.650–2.299) |
9cm* | 0.00000 | 2.074 (1.737–2.476) |
10cm* | 0.00000 | 2.013 (1.662–2.439) |
*means the p values of log-rank test for OS of size cutoff were significant statistical difference (p < 0.0001). |
OS, overall survival; HR, hazard ratio; CI, confidence interval. |
Table 3
The p values of log-rank test and HR values for OS of each trichotomy size cutoff
Cutoffs (cm) | P-value of Log-rank | Cox |
A | B | ≤A vs. A ~ B | ≤A vs. >B | A ~ B vs. >B | HR (95%CI) |
1 | 2 | 0.611280 | 0.417322 | 0.000224 | 1.874 (1.337–2.628) |
1 | 3 | 0.401394 | 0.424487 | 0.000000 | 1.692 (1.402–2.042) |
1 | 4 | 0.588828 | 0.327959 | 0.000000 | 1.875 (1.609–2.184) |
1 | 5 | 0.566227 | 0.277350 | 0.000000 | 1.866 (1.613–2.159) |
1 | 6 | 0.545619 | 0.222792 | 0.000000 | 2.045 (1.763–2.371) |
1 | 7 | 0.493309 | 0.263552 | 0.000000 | 1.965 (1.682–2.297) |
1 | 8 | 0.482870 | 0.257788 | 0.000000 | 1.945 (1.649–2.294) |
1 | 9 | 0.460243 | 0.289755 | 0.000000 | 2.07 (1.735–2.469) |
1 | 10 | 0.444595 | 0.325466 | 0.000000 | 2.01 (1.661–2.433) |
2 | 3 | 0.083743 | 0.000028 | 0.000025 | 1.494 (1.295–1.725) |
2 | 4 | 0.103040 | 0.000001 | 0.000000 | 1.693 (1.486–1.928) |
2 | 5 | 0.029683 | 0.000000 | 0.000000 | 1.728 (1.521–1.963) |
2 | 6 | 0.018186 | 0.000000 | 0.000000 | 1.882 (1.649–2.147) |
2 | 7 | 0.005548 | 0.000000 | 0.000000 | 1.837 (1.601–2.109) |
2 | 8 | 0.002914 | 0.000000 | 0.000000 | 1.831 (1.584–2.116) |
2 | 9 | 0.001960 | 0.000000 | 0.000000 | 1.927 (1.652–2.249) |
2 | 10 | 0.001138 | 0.000000 | 0.000000 | 1.889 (1.604–2.226) |
3 | 4 | 0.451643 | 0.000000 | 0.000000 | 1.452 (1.319–1.599) |
3 | 5 | 0.028445 | 0.000000 | 0.000000 | 1.51 (1.369–1.666) |
3 | 6 | 0.009799 | 0.000000 | 0.000000 | 1.62 (1.460–1.797) |
3 | 7 | 0.000557 | 0.000000 | 0.000000 | 1.613 (1.447–1.798) |
3 | 8* | 0.000096 | 0.000000 | 0.000000 | 1.62 (1.446–1.814) |
3 | 9* | 0.000040 | 0.000000 | 0.000000 | 1.681 (1.491–1.896) |
3 | 10* | 0.000009 | 0.000000 | 0.000000 | 1.667 (1.470–1.890) |
4 | 5 | 0.000843 | 0.000000 | 0.001334 | 1.436 (1.325–1.557) |
4 | 6 | 0.000214 | 0.000000 | 0.000000 | 1.533 (1.408–1.670) |
4 | 7* | 0.000000 | 0.000000 | 0.000002 | 1.551 (1.418–1.697) |
4 | 8* | 0.000000 | 0.000000 | 0.000008 | 1.573 (1.432–1.727) |
4 | 9* | 0.000000 | 0.000000 | 0.000001 | 1.635 (1.481–1.805) |
4 | 10* | 0.000000 | 0.000000 | 0.000014 | 1.643 (1.481–1.822) |
5 | 6 | 0.074289 | 0.000000 | 0.000048 | 1.455 (1.346–1.573) |
5 | 7 | 0.000024 | 0.000000 | 0.000524 | 1.478 (1.360–1.605) |
5 | 8 | 0.000000 | 0.000000 | 0.001047 | 1.502 (1.377–1.638) |
5 | 9* | 0.000000 | 0.000000 | 0.000075 | 1.561 (1.425–1.711) |
5 | 10 | 0.000000 | 0.000000 | 0.000794 | 1.574 (1.430–1.732) |
6 | 7 | 0.000001 | 0.000000 | 0.381256 | 1.46 (1.349–1.580) |
6 | 8 | 0.000000 | 0.000000 | 0.255359 | 1.49 (1.371–1.619) |
6 | 9 | 0.000000 | 0.000000 | 0.025411 | 1.554 (1.423–1.697) |
6 | 10 | 0.000000 | 0.000000 | 0.069108 | 1.575 (1.436–1.727) |
7 | 8 | 0.000275 | 0.000000 | 0.449406 | 1.429 (1.316–1.553) |
7 | 9 | 0.000057 | 0.000000 | 0.037663 | 1.488 (1.363–1.625) |
7 | 10 | 0.000000 | 0.000000 | 0.109361 | 1.506 (1.372–1.652) |
8 | 9 | 0.044308 | 0.000000 | 0.042670 | 1.452 (1.329–1.586) |
8 | 10 | 0.000053 | 0.000000 | 0.166143 | 1.468 (1.337–1.612) |
9 | 10 | 0.000044 | 0.000000 | 0.944208 | 1.458 (1.327–1.601) |
*means the p values of log-rank test for OS of size cutoff were significant statistical difference (p < 0.0001). |
OS, overall survival; HR, hazard ratio; CI, confidence interval. |
Besides, there are no cutoffs were screened when classifying tumor size by inquartation until minimum p value was set at p < 0.05 (Table 4). There are 14 cutoffs and the HR values of tumor size at these cutoffs for OS were compared, the highest is 2/5/10 cm.
Table 4
The p values of log-rank test and HR for OS of each inquartation size cutoff
Cutoffs (cm) | P-value of Log-rank test | Cox |
A | B | C | ≤A vs. A ~ B | ≤A vs. B ~ C | ≤A vs. >C | A ~ B vs. B ~ C | A ~ B vs. >C | B ~ C vs. >C | HR (95%CI) |
1 | 2 | 3 | 0.611 | 0.488 | 0.424 | 0.091 | 0.000 | 0.000 | 1.487 (1.290–1.714) |
1 | 2 | 4 | 0.611 | 0.657 | 0.328 | 0.120 | 0.000 | 0.000 | 1.685 (1.480–1.918) |
1 | 2 | 5 | 0.611 | 0.610 | 0.277 | 0.035 | 0.000 | 0.000 | 1.721 (1.516–1.954) |
1 | 2 | 6 | 0.611 | 0.585 | 0.223 | 0.022 | 0.000 | 0.000 | 1.873 (1.642–2.136) |
1 | 2 | 7 | 0.611 | 0.522 | 0.264 | 0.007 | 0.000 | 0.000 | 1.829 (1.594–2.098) |
1 | 2 | 8 | 0.611 | 0.510 | 0.258 | 0.004 | 0.000 | 0.000 | 1.821 (1.576–2.104) |
1 | 2 | 9 | 0.611 | 0.483 | 0.290 | 0.003 | 0.000 | 0.000 | 1.915 (1.642–2.234) |
1 | 2 | 10 | 0.611 | 0.464 | 0.325 | 0.002 | 0.000 | 0.000 | 1.877 (1.594–2.209) |
1 | 3 | 4 | 0.401 | 0.802 | 0.328 | 0.499 | 0.000 | 0.000 | 1.45 (1.318–1.596) |
1 | 3 | 5 | 0.401 | 0.679 | 0.277 | 0.033 | 0.000 | 0.000 | 1.508 (1.367–1.663) |
1 | 3 | 6 | 0.401 | 0.641 | 0.223 | 0.012 | 0.000 | 0.000 | 1.616 (1.458–1.792) |
1 | 3 | 7 | 0.401 | 0.554 | 0.264 | 0.001 | 0.000 | 0.000 | 1.609 (1.444–1.793) |
1 | 3 | 8 | 0.401 | 0.539 | 0.258 | 0.000 | 0.000 | 0.000 | 1.616 (1.443–1.809) |
1 | 3 | 9 | 0.401 | 0.506 | 0.290 | 0.000 | 0.000 | 0.000 | 1.677 (1.487–1.890) |
1 | 3 | 10 | 0.401 | 0.484 | 0.325 | 0.000 | 0.000 | 0.000 | 1.662 (1.466–1.883) |
1 | 4 | 5 | 0.589 | 0.625 | 0.277 | 0.001 | 0.000 | 0.001 | 1.435 (1.325–1.555) |
1 | 4 | 6 | 0.589 | 0.583 | 0.223 | 0.000 | 0.000 | 0.000 | 1.532 (1.407–1.668) |
1 | 4 | 7 | 0.589 | 0.459 | 0.264 | 0.000 | 0.000 | 0.000 | 1.55 (1.417–1.695) |
1 | 4 | 8 | 0.589 | 0.444 | 0.258 | 0.000 | 0.000 | 0.000 | 1.571 (1.431–1.725) |
1 | 4 | 9 | 0.589 | 0.400 | 0.290 | 0.000 | 0.000 | 0.000 | 1.633 (1.480–1.803) |
1 | 4 | 10 | 0.589 | 0.372 | 0.325 | 0.000 | 0.000 | 0.000 | 1.641 (1.480–1.819) |
1 | 5 | 6 | 0.566 | 0.685 | 0.223 | 0.074 | 0.000 | 0.000 | 1.455 (1.346–1.572) |
1 | 5 | 7 | 0.566 | 0.406 | 0.264 | 0.000 | 0.000 | 0.001 | 1.477 (1.360–1.604) |
1 | 5 | 8 | 0.566 | 0.389 | 0.258 | 0.000 | 0.000 | 0.001 | 1.502 (1.377–1.637) |
1 | 5 | 9 | 0.566 | 0.317 | 0.290 | 0.000 | 0.000 | 0.000 | 1.561 (1.424–1.710) |
1 | 5 | 10 | 0.566 | 0.276 | 0.325 | 0.000 | 0.000 | 0.001 | 1.573 (1.430–1.731) |
1 | 6 | 7 | 0.546 | 0.297 | 0.264 | 0.000 | 0.000 | 0.381 | 1.46 (1.349–1.580) |
1 | 6 | 8 | 0.546 | 0.304 | 0.258 | 0.000 | 0.000 | 0.255 | 1.49 (1.371–1.619) |
1 | 6 | 9 | 0.546 | 0.233 | 0.290 | 0.000 | 0.000 | 0.025 | 1.554 (1.423–1.696) |
1 | 6 | 10 | 0.546 | 0.204 | 0.325 | 0.000 | 0.000 | 0.069 | 1.574 (1.436–1.726) |
1 | 7 | 8 | 0.493 | 0.768 | 0.258 | 0.000 | 0.000 | 0.449 | 1.43 (1.316–1.553) |
1 | 7 | 9 | 0.493 | 0.391 | 0.290 | 0.000 | 0.000 | 0.038 | 1.488 (1.363–1.625) |
1 | 7 | 10 | 0.493 | 0.330 | 0.325 | 0.000 | 0.000 | 0.109 | 1.506 (1.373–1.652) |
1 | 8 | 9 | 0.483 | 0.427 | 0.290 | 0.044 | 0.000 | 0.043 | 1.452 (1.330–1.586) |
1 | 8 | 10 | 0.483 | 0.334 | 0.325 | 0.000 | 0.000 | 0.166 | 1.468 (1.337–1.612) |
1 | 9 | 10 | 0.460 | 0.443 | 0.325 | 0.000 | 0.000 | 0.944 | 1.458 (1.327–1.601) |
2 | 3 | 4 | 0.084 | 0.122 | 0.000 | 0.887 | 0.000 | 0.000 | 1.385 (1.272–1.508) |
2 | 3 | 5 | 0.084 | 0.018 | 0.000 | 0.172 | 0.000 | 0.000 | 1.434 (1.313–1.567) |
2 | 3 | 6 | 0.084 | 0.010 | 0.000 | 0.095 | 0.000 | 0.000 | 1.519 (1.384–1.669) |
2 | 3 | 7 | 0.084 | 0.002 | 0.000 | 0.017 | 0.000 | 0.000 | 1.512 (1.371–1.667) |
2 | 3 | 8 | 0.084 | 0.001 | 0.000 | 0.005 | 0.000 | 0.000 | 1.514 (1.368–1.675) |
2 | 3 | 9 | 0.084 | 0.001 | 0.000 | 0.003 | 0.000 | 0.000 | 1.553 (1.396–1.728) |
2 | 3 | 10 | 0.084 | 0.000 | 0.000 | 0.001 | 0.000 | 0.000 | 1.537 (1.376–1.717) |
2 | 4 | 5 | 0.103 | 0.002 | 0.000 | 0.004 | 0.000 | 0.001 | 1.399 (1.299–1.507) |
2 | 4 | 6 | 0.103 | 0.002 | 0.000 | 0.002 | 0.000 | 0.000 | 1.482 (1.369–1.604) |
2 | 4 | 7 | 0.103 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 1.497 (1.377–1.626) |
2 | 4 | 8 | 0.103 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 1.514 (1.388–1.651) |
2 | 4 | 9 | 0.103 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 1.563 (1.427–1.712) |
2 | 4 | 10 | 0.103 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 1.566 (1.425–1.722) |
2 | 5 | 6 | 0.030 | 0.005 | 0.000 | 0.154 | 0.000 | 0.000 | 1.427 (1.327–1.535) |
2 | 5 | 7* | 0.030 | 0.000 | 0.000 | 0.000 | 0.000 | 0.001 | 1.448 (1.341–1.564) |
2 | 5 | 8* | 0.030 | 0.000 | 0.000 | 0.000 | 0.000 | 0.001 | 1.47 (1.356–1.593) |
2 | 5 | 9* | 0.030 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 1.52 (1.396–1.655) |
2 | 5 | 10* | 0.030 | 0.000 | 0.000 | 0.000 | 0.000 | 0.001 | 1.53 (1.400-1.672) |
2 | 6 | 7 | 0.018 | 0.000 | 0.000 | 0.000 | 0.000 | 0.381 | 1.44 (1.337–1.551) |
2 | 6 | 8 | 0.018 | 0.000 | 0.000 | 0.000 | 0.000 | 0.255 | 1.467 (1.357–1.586) |
2 | 6 | 9* | 0.018 | 0.000 | 0.000 | 0.000 | 0.000 | 0.025 | 1.523 (1.403–1.654) |
2 | 6 | 10 | 0.018 | 0.000 | 0.000 | 0.000 | 0.000 | 0.069 | 1.541 (1.414–1.680) |
2 | 7 | 8 | 0.006 | 0.000 | 0.000 | 0.001 | 0.000 | 0.449 | 1.419 (1.313–1.533) |
2 | 7 | 9* | 0.006 | 0.000 | 0.000 | 0.000 | 0.000 | 0.038 | 1.472 (1.356–1.598) |
2 | 7 | 10 | 0.006 | 0.000 | 0.000 | 0.000 | 0.000 | 0.109 | 1.488 (1.366–1.622) |
2 | 8 | 9 | 0.003 | 0.000 | 0.000 | 0.076 | 0.000 | 0.043 | 1.443 (1.329–1.567) |
2 | 8 | 10 | 0.003 | 0.000 | 0.000 | 0.000 | 0.000 | 0.166 | 1.459 (1.338–1.592) |
2 | 9 | 10 | 0.002 | 0.000 | 0.000 | 0.000 | 0.000 | 0.944 | 1.454 (1.333–1.586) |
3 | 4 | 5 | 0.452 | 0.001 | 0.000 | 0.013 | 0.000 | 0.001 | 1.318 (1.237–1.403) |
3 | 4 | 6 | 0.452 | 0.001 | 0.000 | 0.010 | 0.000 | 0.000 | 1.375 (1.286–1.471) |
3 | 4 | 7 | 0.452 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 1.385 (1.291–1.485) |
3 | 4 | 8 | 0.452 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 1.395 (1.297-1.500) |
3 | 4 | 9 | 0.452 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 1.423 (1.319–1.535) |
3 | 4 | 10 | 0.452 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 1.423 (1.315–1.538) |
3 | 5 | 6 | 0.028 | 0.011 | 0.000 | 0.350 | 0.000 | 0.000 | 1.356 (1.272–1.445) |
3 | 5 | 7* | 0.028 | 0.000 | 0.000 | 0.003 | 0.000 | 0.001 | 1.372 (1.283–1.467) |
3 | 5 | 8* | 0.028 | 0.000 | 0.000 | 0.000 | 0.000 | 0.001 | 1.387 (1.293–1.487) |
3 | 5 | 9* | 0.028 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 1.421 (1.320–1.528) |
3 | 5 | 10* | 0.028 | 0.000 | 0.000 | 0.000 | 0.000 | 0.001 | 1.426 (1.322–1.538) |
3 | 6 | 7 | 0.010 | 0.000 | 0.000 | 0.000 | 0.000 | 0.381 | 1.378 (1.291–1.471) |
3 | 6 | 8 | 0.010 | 0.000 | 0.000 | 0.000 | 0.000 | 0.255 | 1.399 (1.306–1.497) |
3 | 6 | 9* | 0.010 | 0.000 | 0.000 | 0.000 | 0.000 | 0.025 | 1.44 (1.340–1.547) |
3 | 6 | 10 | 0.010 | 0.000 | 0.000 | 0.000 | 0.000 | 0.069 | 1.451 (1.347–1.564) |
3 | 7 | 8 | 0.001 | 0.000 | 0.000 | 0.005 | 0.000 | 0.449 | 1.37 (1.280–1.467) |
3 | 7 | 9* | 0.001 | 0.000 | 0.000 | 0.003 | 0.000 | 0.038 | 1.411 (1.313–1.516) |
3 | 7 | 10 | 0.001 | 0.000 | 0.000 | 0.000 | 0.000 | 0.109 | 1.423 (1.320–1.535) |
3 | 8 | 9 | 0.000 | 0.001 | 0.000 | 0.174 | 0.000 | 0.043 | 1.395 (1.298-1.500) |
3 | 8 | 10 | 0.000 | 0.000 | 0.000 | 0.002 | 0.000 | 0.166 | 1.408 (1.305–1.519) |
3 | 9 | 10 | 0.000 | 0.000 | 0.000 | 0.001 | 0.000 | 0.944 | 1.41 (1.306–1.522) |
4 | 5 | 6 | 0.001 | 0.011 | 0.000 | 0.712 | 0.000 | 0.000 | 1.314 (1.243–1.389) |
4 | 5 | 7 | 0.001 | 0.000 | 0.000 | 0.294 | 0.000 | 0.001 | 1.329 (1.254–1.409) |
4 | 5 | 8 | 0.001 | 0.000 | 0.000 | 0.123 | 0.000 | 0.001 | 1.342 (1.263–1.426) |
4 | 5 | 9 | 0.001 | 0.000 | 0.000 | 0.096 | 0.000 | 0.000 | 1.369 (1.285–1.458) |
4 | 5 | 10* | 0.001 | 0.000 | 0.000 | 0.037 | 0.000 | 0.001 | 1.374 (1.287–1.467) |
4 | 6 | 7 | 0.000 | 0.000 | 0.000 | 0.004 | 0.000 | 0.381 | 1.343 (1.268–1.423) |
4 | 6 | 8 | 0.000 | 0.000 | 0.000 | 0.001 | 0.000 | 0.255 | 1.362 (1.282–1.446) |
4 | 6 | 9* | 0.000 | 0.000 | 0.000 | 0.001 | 0.000 | 0.025 | 1.396 (1.310–1.487) |
4 | 6 | 10 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.069 | 1.407 (1.317–1.502) |
4 | 7 | 8 | 0.000 | 0.000 | 0.000 | 0.058 | 0.000 | 0.449 | 1.347 (1.267–1.430) |
4 | 7 | 9 | 0.000 | 0.000 | 0.000 | 0.067 | 0.000 | 0.038 | 1.382 (1.297–1.473) |
4 | 7 | 10 | 0.000 | 0.000 | 0.000 | 0.006 | 0.000 | 0.109 | 1.395 (1.305–1.490) |
4 | 8 | 9 | 0.000 | 0.001 | 0.000 | 0.570 | 0.000 | 0.043 | 1.375 (1.290–1.466) |
4 | 8 | 10 | 0.000 | 0.000 | 0.000 | 0.046 | 0.000 | 0.166 | 1.389 (1.299–1.485) |
4 | 9 | 10 | 0.000 | 0.000 | 0.000 | 0.008 | 0.000 | 0.944 | 1.396 (1.305–1.493) |
5 | 6 | 7 | 0.074 | 0.000 | 0.000 | 0.010 | 0.000 | 0.381 | 1.304 (1.235–1.377) |
5 | 6 | 8 | 0.074 | 0.000 | 0.000 | 0.003 | 0.000 | 0.255 | 1.32 (1.247–1.397) |
5 | 6 | 9 | 0.074 | 0.000 | 0.000 | 0.004 | 0.000 | 0.025 | 1.349 (1.271–1.431) |
5 | 6 | 10 | 0.074 | 0.000 | 0.000 | 0.001 | 0.000 | 0.069 | 1.358 (1.277–1.443) |
5 | 7 | 8 | 0.000 | 0.000 | 0.000 | 0.121 | 0.000 | 0.449 | 1.311 (1.238–1.388) |
5 | 7 | 9 | 0.000 | 0.000 | 0.000 | 0.173 | 0.000 | 0.038 | 1.342 (1.263–1.424) |
5 | 7 | 10 | 0.000 | 0.000 | 0.000 | 0.035 | 0.000 | 0.109 | 1.352 (1.271–1.439) |
5 | 8 | 9 | 0.000 | 0.006 | 0.000 | 0.849 | 0.000 | 0.043 | 1.338 (1.259–1.422) |
5 | 8 | 10 | 0.000 | 0.000 | 0.000 | 0.156 | 0.000 | 0.166 | 1.35 (1.268–1.438) |
5 | 9 | 10 | 0.000 | 0.000 | 0.000 | 0.024 | 0.000 | 0.944 | 1.36 (1.275–1.449) |
6 | 7 | 8 | 0.000 | 0.000 | 0.000 | 0.827 | 0.309 | 0.449 | 1.297 (1.228–1.371) |
6 | 7 | 9 | 0.000 | 0.000 | 0.000 | 0.771 | 0.121 | 0.038 | 1.327 (1.252–1.406) |
6 | 7 | 10 | 0.000 | 0.000 | 0.000 | 0.884 | 0.136 | 0.109 | 1.338 (1.260–1.421) |
6 | 8 | 9 | 0.000 | 0.010 | 0.000 | 0.369 | 0.077 | 0.043 | 1.326 (1.250–1.406) |
6 | 8 | 10 | 0.000 | 0.000 | 0.000 | 0.967 | 0.093 | 0.166 | 1.338 (1.259–1.423) |
6 | 9 | 10 | 0.000 | 0.000 | 0.000 | 0.179 | 0.036 | 0.944 | 1.349 (1.268–1.435) |
7 | 8 | 9 | 0.000 | 0.027 | 0.000 | 0.343 | 0.212 | 0.043 | 1.294 (1.221–1.372) |
7 | 8 | 10 | 0.000 | 0.000 | 0.000 | 0.861 | 0.222 | 0.166 | 1.304 (1.227–1.386) |
7 | 9 | 10 | 0.000 | 0.000 | 0.000 | 0.178 | 0.047 | 0.944 | 1.315 (1.236–1.399) |
8 | 9 | 10 | 0.044 | 0.000 | 0.000 | 0.107 | 0.049 | 0.944 | 1.295 (1.217–1.378) |
*means the p values of log-rank test for OS of size cutoff were significant statistical difference (p < 0.05). |
OS, overall survival; HR, hazard ratio; CI, confidence interval. |
3.4 Redefinition of tumor size groups and their characteristics
We reclassified patients into three new categories: ≤ 3 cm (n = 422), > 3 and ≤ 9 cm (n = 1072), and > 9 cm (n = 266). The comparison of clinicopathologic characteristics among these three new classifications (Table 5) showed that the increase of tumor size was associated with the increase of AFP, white blood cell count (WBC), platelet count (PLT), γ-glutamyl transferase (GGT), Alkaline phosphatase (ALP), volume of blood loss, MVI, tumor differentiation, and liver cirrhosis.
Table 5
Comparison of clinicopathologic characteristics among three new classifications
Parameter | ≤ 3 cm | 3 ~ 9 cm | > 9 cm | | P-value | |
(n = 422) | (n = 1072) | (n = 266) | ≤ 3 vs. 3 ~ 9 | 3 ~ 9 vs. >9 | ≤ 3 vs. >9 |
Age, year | | | | | | |
≤ 50 | 212 (50.2%) | 534 (49.8%) | 139 (52.3%) | 0.928 | 0.519 | 0.662 |
> 50 | 210 (49.8%) | 538 (50.2%) | 127 (47.7%) | | | |
Sex | | | | | | |
Male | 346 (82.0%) | 928 (86.6%) | 223 (83.8%) | 0.0303 | 0.293 | 0.604 |
Female | 76 (18.0%) | 144 (13.4%) | 43 (16.2%) | | | |
AFP, ng/mL | | | | | | |
≤ 20 | 183 (43.4%) | 471 (43.9%) | 72 (27.1%) | < 0.001 | < 0.001 | < 0.001 |
20–400 | 140 (33.2%) | 249 (23.2%) | 62 (23.3%) | | | |
≥ 400 | 99 (23.5%) | 352 (32.8%) | 132 (49.6%) | | | |
HBV DNA, IU/ml | | | | | |
≤ 1000 | 213 (50.5%) | 488 (45.5%) | 100 (37.6%) | 0.0951 | 0.0236 | 0.00126 |
> 1000 | 209 (49.5%) | 584 (54.5%) | 166 (62.4%) | | | |
White blood cells, 109/L | | | | | |
< 4 | 131 (31.0%) | 236 (22.0%) | 41 (15.4%) | < 0.001 | 0.0218 | < 0.001 |
≥ 4 | 291 (69.0%) | 836 (78.0%) | 225 (84.6%) | | | |
Platelet count, 109/L | | | | | |
< 100 | 115 (27.3%) | 193 (18.0%) | 15 (5.6%) | < 0.001 | < 0.001 | < 0.001 |
≥ 100 | 307 (72.7%) | 879 (82.0%) | 251 (94.4%) | | | |
Albumin, g/L | | | | | |
< 35 | 10 (2.4%) | 29 (2.7%) | 14 (5.3%) | 0.852 | 0.0545 | 0.0717 |
≥ 35 | 412 (97.6%) | 1043 (97.3%) | 252 (94.7%) | | | |
Total bilirubin, µmol/L | | | | | |
≤ 17.1 | 314 (74.4%) | 822 (76.7%) | 205 (77.1%) | 0.391 | 0.958 | 0.485 |
> 17.1 | 108 (25.6%) | 250 (23.3%) | 61 (22.9%) | | | |
γ-glutamyl transferase, IU/L | | | | | |
≤ 64 | 300 (71.1%) | 663 (61.8%) | 62 (23.3%) | < 0.001 | < 0.001 | < 0.001 |
> 64 | 122 (28.9%) | 409 (38.2%) | 204 (76.7%) | | | |
Alkaline phosphatase, IU/L | | | | | |
≤ 129 | 410 (97.2%) | 998 (93.1%) | 181 (68.0%) | 0.00362 | < 0.001 | < 0.001 |
> 129 | 12 (2.8%) | 74 (6.9%) | 85 (32.0%) | | | |
ALBI Grade | | | | | | |
≤-2.63 | 321 (76.1%) | 795 (74.2%) | 154 (57.9%) | 0.486 | < 0.001 | < 0.001 |
> 2.63 | 101 (23.9%) | 277 (25.8%) | 112 (42.1%) | | | |
Blood loss, mL | | | | | |
< 800 | 417 (98.8%) | 1024 (95.5%) | 209 (78.6%) | 0.00326 | < 0.001 | < 0.001 |
≥ 800 | 5 (1.2%) | 48 (4.5%) | 57 (21.4%) | | | |
Differentiation degree | | | | | |
I/II | 105 (24.9%) | 174 (16.2%) | 16 (6.0%) | < 0.001 | < 0.001 | < 0.001 |
III/IV | 317 (75.1%) | 898 (83.8%) | 250 (94.0%) | | | |
Microvascular invasion | | | | | |
Negative | 349 (82.7%) | 830 (77.4%) | 175 (65.8%) | 0.0292 | < 0.001 | < 0.001 |
Positive | 73 (17.3%) | 242 (22.6%) | 91 (34.2%) | | | |
Tumor capsule | | | | | |
Incomplete/absent | 292 (69.2%) | 735 (68.6%) | 205 (77.1%) | 0.861 | 0.00827 | 0.0309 |
Complete | 130 (30.8%) | 337 (31.4%) | 61 (22.9%) | | | |
Cirrhosis | | | | | | |
Absent | 157 (37.2%) | 588 (54.9%) | 182 (68.4%) | < 0.001 | < 0.001 | < 0.001 |
Present | 265 (62.8%) | 484 (45.1%) | 84 (31.6%) | | | |
In addition, we divided patients into four new categories: ≤ 2 cm (n = 121), > 2 and ≤ 5 cm (n = 907), > 5 and ≤ 10 cm (n = 518), and > 10 cm (n = 214). And the comparison of clinicopathologic characteristics among these four classifications (Table 6) showed that the increase of tumor size was associated with only AFP and PLT.
Table 6
Comparison of clinicopathologic characteristics among four new classifications
| ≤ 2 cm | 2 ~ 5 cm | 5 ~ 10 cm | > 10 cm | P-value |
(n = 121) | (n = 907) | (n = 518) | (n = 214) | ≤ 2 vs. 2 ~ 5 | ≤ 2 vs. 5 ~ 10 | ≤ 2 vs. >10 | 2 ~ 5 vs. 5 ~ 10 | 2 ~ 5 vs. >10 | 5 ~ 10 vs. >10 |
Age, year | | | | | | | | | | |
≤ 50 | 65 (53.7%) | 444 (49.0%) | 258 (49.8%) | 118 (55.1%) | 0.374 | 0.5 | 0.891 | 0.799 | 0.121 | 0.218 |
> 50 | 56 (46.3%) | 463 (51.0%) | 260 (50.2%) | 96 (44.9%) | | | | | | |
Sex | | | | | | | | | | |
Male | 98 (81.0%) | 770 (84.9%) | 448 (86.5%) | 181 (84.6%) | 0.328 | 0.162 | 0.488 | 0.458 | 0.992 | 0.577 |
Female | 23 (19.0%) | 137 (15.1%) | 70 (13.5%) | 33 (15.4%) | | | | | | |
AFP, ng/mL | | | | | | | | | | |
≤ 20 | 51 (42.1%) | 431 (47.5%) | 189 (36.5%) | 55 (25.7%) | < 0.001 | < 0.001 | < 0.001 | < 0.001 | < 0.001 | 0.00871 |
20–400 | 52 (43.0%) | 224 (24.7%) | 124 (23.9%) | 51 (23.8%) | | | | | | |
≥ 400 | 18 (14.9%) | 252 (27.8%) | 205 (39.6%) | 108 (50.5%) | | | | | | |
HBV DNA, IU/ml | | | | | | | | | |
≤ 1000 | 67 (55.4%) | 431 (47.5%) | 220 (42.5%) | 83 (38.8%) | 0.127 | 0.0136 | 0.00483 | 0.0743 | 0.0257 | 0.402 |
> 1000 | 54 (44.6%) | 476 (52.5%) | 298 (57.5%) | 131 (61.2%) | | | | | | |
White blood cells, 109/L | | | | | | | | | |
< 4 | 39 (32.2%) | 245 (27.0%) | 93 (18.0%) | 31 (14.5%) | 0.272 | < 0.001 | < 0.001 | < 0.001 | < 0.001 | 0.303 |
≥ 4 | 82 (67.8%) | 662 (73.0%) | 425 (82.0%) | 183 (85.5%) | | | | | | |
Platelet count, 109/L | | | | | | | | | |
< 100 | 36 (29.8%) | 211 (23.3%) | 67 (12.9%) | 9 (4.2%) | 0.145 | < 0.001 | < 0.001 | < 0.001 | < 0.001 | < 0.001 |
≥ 100 | 85 (70.2%) | 696 (76.7%) | 451 (87.1%) | 205 (95.8%) | | | | | | |
Albumin, g/L | | | | | | | | | |
< 35 | 3 (2.5%) | 24 (2.6%) | 16 (3.1%) | 10 (4.7%) | 1 | 0.954 | 0.481 | 0.749 | 0.182 | 0.404 |
≥ 35 | 118 (97.5%) | 883 (97.4%) | 502 (96.9%) | 204 (95.3%) | | | | | | |
Total bilirubin, µmol/L | | | | | | | | | |
≤ 17.1 | 94 (77.7%) | 669 (73.8%) | 411 (79.3%) | 167 (78.0%) | 0.414 | 0.78 | 1 | 0.0213 | 0.228 | 0.768 |
> 17.1 | 27 (22.3%) | 238 (26.2%) | 107 (20.7%) | 47 (22.0%) | | | | | | |
γ-glutamyl transferase, IU/L | | | | | | | | | |
≤ 64 | 88 (72.7%) | 637 (70.2%) | 255 (49.2%) | 45 (21.0%) | 0.646 | < 0.001 | < 0.001 | < 0.001 | < 0.001 | < 0.001 |
> 64 | 33 (27.3%) | 270 (29.8%) | 263 (50.8%) | 169 (79.0%) | | | | | | |
Alkaline phosphatase, IU/L | | | | | | | | | |
≤ 129 | 120 (99.2%) | 864 (95.3%) | 467 (90.2%) | 138 (64.5%) | 0.0786 | 0.00205 | < 0.001 | < 0.001 | < 0.001 | < 0.001 |
> 129 | 1 (0.8%) | 43 (4.7%) | 51 (9.8%) | 76 (35.5%) | | | | | | |
ALBI Grade | | | | | | | | | | |
≤-2.63 | 101 (83.5%) | 688 (75.9%) | 355 (68.5%) | 126 (58.9%) | 0.0804 | 0.00157 | < 0.001 | 0.00329 | < 0.001 | 0.0156 |
> 2.63 | 20 (16.5%) | 219 (24.1%) | 163 (31.5%) | 88 (41.1%) | | | | | | |
Blood loss, mL | | | | | | | | | |
< 800 | 120 (99.2%) | 890 (98.1%) | 476 (91.9%) | 164 (76.6%) | 0.648 | 0.00743 | < 0.001 | < 0.001 | < 0.001 | < 0.001 |
≥ 800 | 1 (0.8%) | 17 (1.9%) | 42 (8.1%) | 50 (23.4%) | | | | | | |
Differentiation degree | | | | | | | | | |
I/II | 39 (32.2%) | 190 (20.9%) | 54 (10.4%) | 12 (5.6%) | 0.00724 | < 0.001 | < 0.001 | < 0.001 | < 0.001 | 0.0539 |
III/IV | 82 (67.8%) | 717 (79.1%) | 464 (89.6%) | 202 (94.4%) | | | | | | |
Microvascular invasion | | | | | | | | | |
Negative | 104 (86.0%) | 715 (78.8%) | 395 (76.3%) | 140 (65.4%) | 0.0877 | 0.0278 | < 0.001 | 0.289 | < 0.001 | 0.00356 |
Positive | 17 (14.0%) | 192 (21.2%) | 123 (23.7%) | 74 (34.6%) | | | | | | |
Tumor capsule | | | | | | | | | |
Incomplete/absent | 76 (62.8%) | 631 (69.6%) | 362 (69.9%) | 163 (76.2%) | 0.161 | 0.161 | 0.0135 | 0.949 | 0.0678 | 0.104 |
Complete | 45 (37.2%) | 276 (30.4%) | 156 (30.1%) | 51 (23.8%) | | | | | | |
Cirrhosis | | | | | | | | | | |
Absent | 44 (36.4%) | 415 (45.8%) | 317 (61.2%) | 151 (70.6%) | 0.0637 | < 0.001 | < 0.001 | < 0.001 | < 0.001 | 0.0206 |
Present | 77 (63.6%) | 492 (54.2%) | 201 (38.8%) | 63 (29.4%) | | | | | | |
3.5 Overall survival of the new three groups
Based on these biological characteristics and prognostic findings, we suggested 3/9 cm could be appropriate cutoff for tumor size of solitary HBV related HCC. The overall 1-, 3-, and 5-year survival rates were 94.5%, 84.5%, and 69.0% in patients with HCC ≤ 3 cm, 92.0%, 76.3%, and 58.3% in patients with HCC > 3 and ≤ 9 cm, and 79.3%, 60.5%, and 37.4% in patients with HCC > 9 cm, respectively. The comparison of the overall survival rates between any two subgroups showed statistical differences (all p = 0.000) (Fig. 2).