A total of 346 HCCs were enrolled from January 2013 to June 2022, with a median follow-up of 27 months (Fig. 1). Among the 346 HCCs, 64 HCCs exhibited LTP, and 282 HCCs did not exhibit LTP. The tumor size was 23.58 ± 9.55 mm. Biopsy of the peritumoral parenchyma showed that the degree of inflammation was distributed as follows: G1 (44, 12.7%), G2 (154, 44.5%), G3 (110, 31.8%) and G4 (38, 11.0%); the degree of fibrosis was distributed as follows: S0 (3, 0.9%), S1 (22, 6.4%), S2 (71, 20.5%), S3 (150, 43.4%) and S4 (100, 28.9%) (Table 1).
Table 1
| | Overall |
| | N = 346 |
Sex (%) | Female | 59 (17.1%) |
| Male | 287 (82.9%) |
Age (year) | | 54.99 ± 9.87 |
BMI | | 23.32 ± 3.11 |
Child (%) | A | 333 (96.2%) |
| B | 13 (3.8%) |
ALT (U/L) | | 35.27 ± 15.80 |
AST (U/L) | | 35.83 ± 18.82 |
ALB (g/L) | | 39.78 ± 4.63 |
TB (µmol/L) | | 15.17 ± 10.54 |
DB (µmol/L) | | 6.32 ± 6.21 |
PLT (10^9/L) | | 125.61 ± 61.18 |
INR | | 1.10 ± 0.12 |
AFP (%) | ≤ 20U/L | 187 (54.0%) |
| >20U/L | 159 (46.0%) |
Tumor Size (mm) | | 23.58 ± 9.55 |
G (%) | 1 | 44 (12.7%) |
| 2 | 154 (44.5%) |
| 3 | 110 (31.8%) |
| 4 | 38 (11.0%) |
S (%) | 0 | 3 (0.9%) |
| 1 | 22 (6.4%) |
| 2 | 71 (20.5%) |
| 3 | 150 (43.4%) |
| 4 | 100 (28.9%) |
Note: Values are mean ± standard deviation or number (%). ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; ALB = Serum albumin; TB = Total bilirubin; DB = Direct Bilirubin; PTL = Platelets; INR = International normalized ratio; AFP = Alpha fetoprotein; G = Grade of necorinflammatory activity; S = Stage of fibrosis. |
Risk factor analysis:
Univariate and multivariate analyses were used to assess the influence of inflammation, fibrosis, and other variables on LTP. Univariate analysis showed that PLT (p = 0.016), tumor size (p < 0.001) and S-stage (p = 0.0015) were influencing factors in LTP, but multivariate analyses showed that only tumor size (p < 0.001) and S-stage (p = 0.004) were independent influencing factors in LTP. Tumor size was a risk factor in LTP with an HR of 1.05 (95% CI: 1.03–1.07), and S-stage was a protective factor in LTP with an HR of 0.70 (95% CI: 0.55–0.89) (Table 2).
Table 2
Univariate/Multivariate analysis of LTP
| Risk factor analysis of LTP |
Variable | Univariate analysis | Multivariate analysis |
| HR (95% CI for HR) | p | HR (95% CI for HR) | p |
Sex | 0.94 (0.5–1.8) | 0.85 | | |
Age | 0.99 (0.96-1) | 0.4 | | |
BMI | 0.97 (0.9–1.1) | 0.51 | | |
Child | 1.1 (0.28–4.7) | 0.85 | | |
ALT | 1 (0.99-1) | 0.74 | | |
AST | 1 (0.99-1) | 0.94 | | |
ALB | 1 (0.96–1.1) | 0.73 | | |
TB | 0.98 (0.95-1) | 0.19 | | |
DB | 0.98 (0.93-1) | 0.41 | | |
PLT | 1 (1–1) | 0.016 | | |
INR | 0.29 (0.03–2.7) | 0.28 | | |
AFP | 1.4 (0.87–2.3) | 0.16 | | |
Tumor size | 1.1 (1-1.1) | < 0.001 | 1.05 (1.03–1.07) | < 0.001 |
G stage | 1 (0.76–1.3) | 0.96 | | |
S stage | 0.67 (0.53–0.86) | 0.0015 | 0.70 (0.55–0.89) | 0.004 |
Note: LTP = Local Tumor Progression; ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; ALB = Serum albumin; TB = Total bilirubin; DB = Direct Bilirubin; PTL = Platelets; INR = International normalized ratio; AFP = Alpha fetoprotein; G = Grade of necorinflammatory activity; S = Stage of fibrosis. |
Classify tumors by S-stage:
We explored three grouping methods, S01 vs. S234, S012 vs. S34, and S0123 vs. S4. There was no significant difference in LTP incidence between S01 and S234 (p = 0.15), but there was a significant difference between S012 and S34 (p < 0.001) and between S0123 and S4 (p = 0.03). S012 vs. S34 exhibited the highest Wald test, lowest p value, and most stable HR, so we combined S0, S1 and S2 into the low fibrosis group and combined S3 and S4 into the high fibrosis group (Fig. 2).
Subgroup analysis:
Subgroup analyses of gender, age, and tumor size were performed to evaluate the relationship between tumor group and LTP in different subgroups. For HCCs overall, high fibrosis was a protective factor in LTP, with an HR of 0.44 (95% CI: 0.27–0.72). Subgroup analysis showed that in the male group (HR = 0.50 (95% CI: 0.29–0.87)), female group (HR = 0.26 (95% CI: 0.08–0.80)), more than 60 years group (HR = 0.26 (95% CI: 0.11–0.60)), less than 60 years group (HR = 0.53 (95% CI: 0.29–0.98)), tumor larger than 30 mm group (HR = 0.41 (95% CI: 0.17–0.92)) and tumor smaller than 30 mm group (HR = 0.42 (95% CI: 0.23–0.78)), high fibrosis was always a protective factor in LTP (Fig. 3, Supplementary Fig. 1).
Reason for the influence of fibrosis on LTP:
First, we compared the detection rates of satellite foci between the low fibrosis group and the high fibrosis group. In the low fibrosis group, satellite foci were detected in the peritumoral parenchyma of 15 HCCs, and in 81 HCCs, satellite foci were not detected in the peritumoral parenchyma. The detection rate of satellite foci in the low fibrosis group was 15.6%. In the high fibrosis group, satellite foci were detected had in the peritumoral parenchyma of 21 HCCs, and in 229 HCCs, satellite foci were not detected in the peritumoral parenchyma. The detection rate of satellite foci in the high fibrosis group was 8.4%. Therefore, the detection rate of peritumoral satellite foci in the low-fibrosis group was significantly higher than that in the high-fibrosis group (15.6% vs. 8.4%, p = 0.048, Table 3).
Table 3
With peritumoral satellite focus in different fibrosis groups
| With peritumoral satellite focus | Without peritumoral satellite focus | Total | p |
Low fibrosis group (S0, S1, S2) | 15 | 81 | 96 | 0.048 |
Occurrence rate | 0.156 | | |
High fibrosis group (S3, S4) | 21 | 229 | 250 |
Occurrence rate | 0.084 | | |
Note: S = Stage of fibrosis. |
Then, we compared the total ablation energy and the ablation volume after treatment between the low fibrosis group and the high fibrosis group. In the original cohort, there was a significant difference in ALT, ALB, and DB between the two groups, so we balanced the baseline of the two groups by PSM. After PSM, all baselines were comparable, and each group included 93 HCCs (Table 4). The tumor size (23.58 ± 9.82 mm vs. 23.16 ± 9.57 mm, p = 0.768) and ablation volume after treatment (32.21 ± 27.05 mL vs. 31.10 ± 26.98 mL, p = 0.779) were comparable between the two groups, but the ablation energy in the low fibrosis group was significantly lower than that in the high fibrosis group (22637 ± 9424 J vs. 33352 ± 13779 J, p < 0.001). The results for the original cohort were similar (Supplementary Table 1).
Table 4
Difference of ablation parameter between Low and High fibrosis groups after treatment (PSM)
| | Low fibrosis group | High fibrosis group | p |
| | N = 93 | N = 93 | |
Clinical baseline |
Sex (%) | Female | 14 (15.1%) | 13 (14.0%) | 1 |
| Male | 79 (84.9%) | 80 (86.0%) | |
Age (year) | | 55.54 ± 9.85 | 55.56 ± 9.60 | 0.988 |
BMI | | 23.34 ± 2.82 | 23.57 ± 3.34 | 0.616 |
Child (%) | A | 92 (98.9%) | 92 (98.9%) | 1 |
| B | 1 (1.1%) | 1 (1.1%) | |
ALT (U/L) | | 31.65 ± 12.16 | 31.91 ± 11.87 | 0.883 |
AST (U/L) | | 34.41 ± 19.56 | 34.38 ± 17.16 | 0.99 |
ALB (g/L) | | 40.54 ± 4.39 | 39.72 ± 4.37 | 0.205 |
TB (µmol/L) | | 13.13 ± 7.45 | 14.73 ± 10.15 | 0.223 |
DB (µmol/L) | | 4.97 ± 3.14 | 5.66 ± 3.70 | 0.169 |
PLT (10^9/L) | | 135.11 ± 62.18 | 122.76 ± 57.22 | 0.161 |
INR | | 1.09 ± 0.13 | 1.10 ± 0.10 | 0.708 |
AFP (%) | ≤ 20U/L | 54 (58.1%) | 50 (53.8%) | 0.658 |
| >20U/L | 39 (41.9%) | 43 (46.2%) | |
Tumor Size (mm) | | 23.58 ± 9.82 | 23.16 ± 9.57 | 0.768 |
Ablation parameter |
Ablation volume after treatment (mL) | | 32.21 ± 27.05 | 31.10 ± 26.98 | 0.779 |
Ablation energy (J) | | 22637.42 ± 9424.47 | 33352.26 ± 13779.79 | < 0.001 |
Note: Values are mean ± standard deviation or number (%). PSM = Propensity Score Matching; ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; ALB = Serum albumin; TB = Total bilirubin; DB = Direct Bilirubin; PTL = Platelets; INR = International normalized ratio; AFP = Alpha fetoprotein. |
Table 5
Difference of ablation parameter between Low and High fibrosis groups after one-month (PSM)
| | Low-S group | High-S group | p |
| | N = 43 | N = 43 | |
Clinical baseline |
Sex (%) | Female | 5 (11.6%) | 6 (14.0%) | 1 |
| Male | 38 (88.4%) | 37 (86.0%) | |
Age (year) | | 55.84 ± 8.91 | 56.49 ± 8.84 | 0.735 |
BMI | | 23.24 ± 2.79 | 23.59 ± 2.98 | 0.582 |
Child (%) | A | 43 (100.0%) | 43 (100.0%) | NA |
ALT (U/L) | | 30.89 ± 11.49 | 30.74 ± 12.22 | 0.954 |
AST (U/L) | | 34.21 ± 16.05 | 32.37 ± 18.23 | 0.622 |
ALB (g/L) | | 40.53 ± 5.00 | 40.25 ± 4.31 | 0.782 |
TB (µmol/L) | | 12.65 ± 7.51 | 13.03 ± 8.57 | 0.829 |
DB (µmol/L) | | 4.86 ± 2.42 | 5.06 ± 3.13 | 0.738 |
PLT (10^9/L) | | 144.16 ± 68.05 | 138.81 ± 69.83 | 0.72 |
INR | | 1.09 ± 0.11 | 1.11 ± 0.11 | 0.462 |
AFP (%) | ≤ 20U/L | 25 (58.1%) | 27 (62.8%) | 0.825 |
| >20U/L | 18 (41.9%) | 16 (37.2%) | |
Tumor Size (mm) | | 22.84 ± 9.50 | 24.35 ± 9.13 | 0.454 |
Ablation parameter |
Ablation energy (J) | | 21923.72 ± 9121.64 | 35062.33 ± 13152.41 | < 0.001 |
Ablation volume after treatment (mL) | | 30.05 ± 23.90 | 33.13 ± 25.08 | 0.561 |
Ablation volume after one-month (mL) | | 19.85 ± 16.43 | 21.77 ± 18.21 | 0.609 |
Volume reduction rate | | 0.33 ± 0.06 | 0.25 ± 0.07 | < 0.001 |
Note: Values are mean ± standard deviation or number (%). PSM = Propensity Score Matching; ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; ALB = Serum albumin; TB = Total bilirubin; DB = Direct Bilirubin; PTL = Platelets; INR = International normalized ratio; AFP = Alpha fetoprotein. |
Then, we compared the ablation volume after treatment, ablation volume after one month and volume reduction rate between the low fibrosis group and the high fibrosis group. The ablation volume by follow-up MRI after one month was calculated for a total of 178 HCCs, including 47 in the low fibrosis group and 131 in the high fibrosis group. In the original cohort, there was a significant difference in ALT and PLT between the two groups, so we balanced the baseline of the two groups by PSM. After PSM, all baselines were comparable, and each group included 43 HCCs (Table 4). The tumor size (22.84 ± 9.50 mm vs. 24.35 ± 9.13 mm, p = 0.377) and ablation volume after treatment (30.05 ± 23.90 mL vs. 33.13 ± 25.08 mL, p = 0.362) were comparable between the two groups, but the volume reduction rate in the low fibrosis group was significantly higher than that in the high fibrosis group (0.33 ± 0.06 vs. 0.25 ± 0.06, p < 0.001). The results for the original cohort were similar (Supplementary Table 2).