Limitations of Nerve Fiber Density as a Prognostic Marker in Predicting Oncological Outcomes in Hepatocellular Carcinoma
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Patients
2.2. Staging and Surgical Technique
2.3. Assessment of Nerve Fibers
2.4. Statistical Analysis
3. Results
3.1. Patient Cohort
3.2. Survival Analysis with Respect to the Presence of Nerve Fibers in the Tumor Microenvironment and Nerve Fiber Density
3.3. Cox Regression Analysis of the Overall Cohort
3.4. Comparative Analysis of the Overall Patient Cohort with Respect to Nerve Fibers
3.5. Histological Characteristics
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Variables | Overall Cohort (n = 153) | NF Positive (n = 76) | NF Negative (n = 77) | p Value |
---|---|---|---|---|
Demographics | ||||
Gender, m/f (%) | 105 (68.6)/48 (31.4) | 47 (61.8)/29 (38.2) | 58 (75.3)/19 (24.7) | 0.072 |
Age (years) | 69 (61–75) | 68 (59–75) | 70 (63–76) | 0.071 |
BMI (kg/m2) | 26 (23–29) | 26 (23–29) | 27 (23–30) | 0.512 |
Recurrence resection, n (%) | 13 (8.5) | 9 (11.8) | 4 (5.2) | 0.374 |
Preoperative treatment | ||||
Preoperative PVE, n (%) | 7 (4.6) | 3 (3.9) | 4 (5.2) | 0.712 |
Preoperative TACE, n (%) | 8 (5.2) | 4 (5.3) | 4 (5.2) | 0.985 |
Preoperative TARE, n (%) | 2 (1.3) | 2 (2.6) | 0 | 0.152 |
ASA, n (%) | 0.508 | |||
I | 2 (1.3) | 2 (2.6) | 0 | |
II | 50 (32.7) | 23 (30.3) | 27 (35.1) | |
III | 97 (63.4) | 49 (64.5) | 48 (62.3) | |
IV | 4 (2.6) | 2 (2.6) | 2 (2.6) | |
V | 0 | 0 | 0 | |
Liver disease, n (%) | 0.575 | |||
ALD | 34 (22.2) | 15 (19.7) | 19 (24.7) | |
NAFLD | 60 (39.2) | 28 (36.8) | 32 (41.6) | |
Viral | 39 (25.5) | 23 (30.3) | 16 (20.8) | |
Cryptogenic/others | 20 (13.1) | 10 (13.2) | 10 (13.0) | |
Preoperative liver function | ||||
MELD Score | 6 (6–7) | 6 (6–7) | 6 (6–7) | 0.965 |
AFP (ng/mL) | 8 (3–53) | 11 (3–95) | 6 (3–45) | 0.202 |
Albumin (g/dL) | 4.1 (3.7–4.5) | 4.1 (3.6–4.4) | 4.1 (3.8–4.5) | 0.269 |
AST (U/L) | 40 (27–58) | 40 (28–63) | 38 (26–58) | 0.374 |
ALT (U/L) | 33 (23–54) | 37 (25–58) | 30 (21–51) | 0.123 |
GGT (U/L) | 90 (51–213) | 92 (55–178) | 90 (50–267) | 0.822 |
Total bilirubin (mg/dL) | 0.5 (0.4–0.8) | 0.5 (0.4–0.8) | 0.6 (0.4–0.8) | 0.515 |
Platelet count (/nL) | 221 (163–279) | 225 (161–278) | 206 (168–282) | 0.818 |
Alkaline Phosphatase (U/L) | 100 (77–140) | 95 (75–180) | 103 (79–134) | 0.860 |
Prothrombin time (%) | 93 (85–101) | 92 (83–104) | 93 (85–100) | 0.868 |
INR | 1.05 (0.98–1.11) | 1.05 (0.98–1.10) | 1.04 (0.98–1.11) | 0.898 |
Creatinine (mg/dL) | 0.85 (0.70–1.04) | 0.84 (0.70–1.01) | 0.87 (0.72–1.09) | 0.526 |
Hemoglobin (g/dL) | 13.2 (11.7–14.4) | 12.8 (11.7–14.1) | 13.5 (11.9–14.8) | 0.131 |
Child-Pugh, n (%) | 0.088 | |||
A | 139 (90.8) | 66 (86.8) | 73 (94.8) | |
B | 14 (9.2) | 10 (13.2) | 4 (5.2) | |
Preoperative Imaging features | ||||
Number of nodules | 1 (1–2) | 1 (1–2) | 1 (1–2) | 0.324 |
Largest nodule diameter (mm) | 50 (32–80) | 49 (32–78) | 53 (34–84) | 0.340 |
Tumor burden >50%, n (%) | 7 (4.6) | 4 (5.3) | 3 (3.9) | 0.686 |
Overall macrovascular invasion, n (%) | 39 (25.5) | 21 (27.6) | 18 (23.4) | 0.546 |
Portal vein invasion, n (%) | 24 (15.7) | 14 (18.4) | 10 (13.0) | 0.355 |
Extrahepatic vascular invasion, n (%) | 8 (5.2) | 3 (3.9) | 5 (6.5) | 0.479 |
Portal vein thrombosis, n (%) | 6 (3.9) | 3 (3.9) | 3 (3.9) | 0.987 |
Ascites, n (%) | 6 (3.9) | 3 (3.9) | 3 (3.9) | 0.987 |
BCLC, n (%) | 0.709 | |||
0 | 7 (4.6) | 4 (5.3) | 3 (3.9) | |
A | 89 (58.2) | 41 (53.9) | 48 (62.3) | |
B | 33 (21.6) | 17 (22.4) | 16 (20.8) | |
C | 24 (15.7) | 14 (18.4) | 10 (13.0) | |
D | 0 | 0 | 0 | |
Operative Data | ||||
Laparoscopic resection, n (%) | 58 (37.9) | 28 (36.8) | 30 (39.0) | 0.787 |
Conversation rate, n (%) | 5 (8.6) | 2 (7.1) | 3 (10.0) | 0.698 |
Operative time (minutes) | 204 (146–274) | 206 (140–274) | 199 (150–273) | 0.469 |
Operative procedure, n (%) | 0.575 | |||
Atypical | 59 (38.6) | 27 (35.5) | 32 (41.6) | |
Segmentectomy | 21 (13.7) | 8 (10.5) | 13 (16.9) | |
Bisegmentectomy | 15 (9.8) | 8 (10.5) | 7 (9.1) | |
Hemihepatectomy | 34 (22.2) | 17 (22.4) | 17 (22.1) | |
Extended liver resection | 17 (11.1) | 12 (15.8) | 5 (6.5) | |
ALPPS/TSH/other | 7 (4.6) | 4 (5.2) | 3 (3.9) | |
Additional procedures (RFA, etc.), n (%) | 7 (4.6) | 3 (3.9) | 4 (5.2) | 0.712 |
Pringle maneuver, n (%) | 10 (6.6) | 4 (5.3) | 6 (7.9) | 0.513 |
Duration of pringle maneuver (min) * | 18 (10–24) | 11 (6–33) | 20 (14–24) | 0.352 |
Intraoperative blood transfusion, n (%) | 42 (28.0) | 21 (27.6) | 21 (27.6) | 0.919 |
Intraoperative FFP, n (%) | 58 (38.7) | 25 (33.8) | 33 (43.4) | 0.226 |
Intraoperative platelet transfusion, n (%) | 4 (2.7) | 1 (1.4) | 3 (3.9) | 0.324 |
Pathological examination | ||||
R0 resection, n (%) | 147 (96.1) | 75 (98.7) | 72 (93.5) | 0.099 |
T category, n (%) | 0.532 | |||
T1 | 67 (34.8) | 36 (47.4) | 31 (40.3) | |
T2 | 57 (37.3) | 25 (32.9) | 32 (41.6) | |
T3/T4 | 29 (19.0) | 15 (19.7) | 14 (18.2) | |
Microvascular invasion, n (%) | 62 (44.0) | 32 (45.1) | 30 (42.9) | 0.791 |
Tumor grading, n (%) | 0.253 | |||
G1/G2 | 122 (80.3) | 63 (84.0) | 59 (76.6) | |
G3/G4 | 30 (19.7) | 12 (16.0) | 18 (23.4) | |
NF, n (%) | 76 (49.7) | 76 (100) | 0 | <0.001 |
NFD | 0 (0–5) | 6 (2–10) | 0 (0–0) | <0.001 |
Postoperative Data | ||||
Intensive care stay, days | 1 (1–1) | 1 (1–1) | 1 (1–1) | 0.946 |
Hospitalization, days | 8 (6–8) | 8 (5–15) | 8 (6–13) | 0.772 |
Postoperative complications, n (%) | 0.520 | |||
No complications | 81 (52.9) | 38 (50.0) | 43 (55.8) | |
Clavien-Dindo I | 15 (9.8) | 11 (14.5) | 4 (5.2) | |
Clavien-Dindo II | 24 (15.7) | 12 (15.8) | 12 (15.6) | |
Clavien-Dindo IIIa | 19 (12.4) | 8 (10.5) | 11 (14.3) | |
Clavien-Dindo IIIb | 7 (4.6) | 4 (5.3) | 3 (3.9) | |
Clavien-Dindo IVa | 6 (3.9) | 3 (3.9) | 3 (3.9) | |
Clavien-Dindo IVb | 1 (0.7) | 0 | 1 (1.3) | |
Clavien-Dindo V | 0 | 0 | 0 | |
PHLF 50-50 criteria *, n (%) | 0 | 0 | 0 | n.a. |
PHLF ISGLS *, n (%) | 25 (16.3) | 12 (15.8) | 13 (16.9) | 0.855 |
ISGLS Grade, n (%) | 0.755 | |||
A | 20 (80.0) | 9 (75.0) | 11 (84.6) | |
B | 4 (16.0) | 2 (16.7) | 2 (15.4) | |
C | 1 (4.0) | 1 (8.3) | 0 | |
Postoperative blood transfusion | 19 (12.7) | 8 (10.8) | 11 (14.5) | 0.500 |
Postoperative FFP | 6 (4.0) | 4 (5.4) | 2 (2.6) | 0.386 |
Postoperative platelet transfusion | 1 (0.7) | 1 (1.4) | 1 (1.3) | 0.309 |
Follow-up Data | ||||
Recurrence-free survival (months) | 23 (16–30) | 26 (12–40) | 18 (9–27) | 0.666 |
Overall survival (months) | 54 (34–74) | 66 (30–102) | 42 (21–63) | 0.804 |
Variables | Univariate Analysis | Multivariable Analysis | ||
---|---|---|---|---|
HR (95% CI) | p-Value | HR (95% CI) | p-Value | |
Demographics | ||||
Gender (male = 1) | 1.82 (1.04–3.16) | 0.035 | 0.123 | |
Age (≤65 years = 1) | 1.03 (0.62–1.70) | 0.915 | ||
BMI (≤25 kg/m2 = 1) | 0.95 (0.58–1.57) | 0.851 | ||
Recurrence resection (no = 1) | 0.62 (0.20–1.99) | 0.424 | ||
ASA (I/II = 1) | 2.09 (1.18–3.69) | 0.011 | 0.188 | |
Liver disease | 0.116 | |||
ALD | 1 | |||
NAFLD | 0.52 (0.28–0.96) | |||
Viral | 0.65 (0.33–1.21) | |||
Cryptogenic/others | 0.41 (0.16–1.04) | |||
Preoperative liver function | ||||
MELD Score (≤6 = 1) | 1.91 (1.12–3.24) | 0.017 | 2.08 (1.07–4.05) | 0.032 |
Albumin (≤40 g/L = 1) | 0.57 (0.34–0.94) | 0.027 | 0.726 | |
AFP (≤10 µg/L = 1) | 2.56 (1.40–4.67) | 0.002 | excl. | |
AST (≤40 U/L = 1) | 1.89 (1.12–3.18) | 0.016 | 0.551 | |
ALT (≤40 U/L = 1) | 1.64 (0.94–2.84) | 0.079 | ||
GGT (≤100 U/L = 1) | 2.66 (1.54–4.60) | <0.001 | 0.354 | |
Bilirubin (≤1 mg/dL = 1) | 1.82 (0.96–3.43) | 0.066 | ||
AP (≤100 U/L = 1) | 1.95 (1.16–3.28) | 0.011 | 0.462 | |
Platelet count (≤200/nL = 1) | 1.00 (0.60–1.65) | 0.988 | ||
INR (≤1 = 1) | 1.82 (1.03–3.20) | 0.039 | 0.130 | |
Creatinine (≤1 = 1) | 1.19 (0.70–2.02) | 0.531 | ||
Hemoglobin (≤12 g/dL = 1) | 0.80 (0.48–1.34) | 0.399 | ||
Child Pugh (A = 1) | 2.96 (1.44–6.07) | 0.003 | 0.556 | |
Preoperative Imaging features | ||||
Number of nodules (1 = 1) | 3.20 (1.95–5.24) | <0.001 | 2.01 (1.20–4.05) | 0.010 |
Largest nodule diameter (≤50 mm = 1) | 1.89 (1.14–3.13) | 0.013 | 0.405 | |
Tumor burden (≤50% = 1) | 2.90 (1.25–6.76) | 0.014 | 0.484 | |
Macrovascular invasion (no = 1) | 2.23 (1.33–3.71) | 0.002 | 0.999 | |
Portal vein invasion (no = 1) | 2.88 (1.63–5.09) | <0.001 | 0.084 | |
Extrahepatic vascular invasion (no = 1) | 2.40 (1.03–5.59) | 0.042 | 0.700 | |
Portal vein thrombosis (no = 1) | 3.09 (1.23–7.72) | 0.016 | 0.117 | |
Ascites (no = 1) | 3.24 (1.15–9.09) | 0.025 | 6.24 (1.30–29.98) | 0.022 |
BCLC | <0.001 | 0.190 | ||
0/A | 1 | |||
B | 3.17 (1.80–5.58) | |||
C | 4.30 (2.29–8.07) | |||
Operative Data | ||||
Laparoscopic resection (no = 1) | 1.94 (1.05–3.58) | 0.034 | 0.664 | |
Operative time (≤180 min = 1) | 1.44 (0.86–2.41) | 0.163 | ||
Operative procedure (minor = 1) | 1.15 (0.70–1.87) | 0.588 | ||
Additional procedures (no = 1) | 1.25 (0.39–4.02) | 0.705 | ||
Pringle maneuver (yes = 1) | 0.56 (0.24–1.32) | 0.185 | ||
Intraop blood transfusion (no = 1) | 1.50 (0.89–2.53) | 0.128 | ||
Intraop FFP (no = 1) | 1.36 (0.83–2.23) | 0.219 | ||
Pathological data | ||||
R1 resection (no = 1) | 3.58 (1.54–8.33) | 0.003 | 5.52 (1.86–16.38) | 0.002 |
pT category | <0.001 | 0.192 | ||
T1 | 1 | |||
T2 | 2.86 (1.51–5.43) | |||
T3/T4 | 6.19 (3.15–12.18) | |||
Tumor grading (G1/G2 = 1) | 1.41 (0.79–2.51) | 0.248 | ||
MVI (no = 1) | 4.27 (2.39–7.63) | <0.001 | 4.27 (2.18–8.37) | <0.001 |
NF (no = 1) | 1.06 (0.65–1.73) | 0.806 | ||
Postoperative Data | ||||
Intensive care stay (≤1 day = 1) | 1.19 (0.57–2.51) | 0.641 | ||
Hospitalization (≤7 days = 1) | 2.44 (1.35–4.42) | 0.003 | 0.094 | |
Postop complications (I/II = 1) | 1.22 (0.70–2.13) | 0.482 | ||
PHLF ISGLS (no = 1) | 1.14 (0.62–2.09) | 0.682 | ||
Postop blood transfusion (no = 1) | 1.33 (0.67–2.61) | 0.414 | ||
Postop FFP (no = 1) | 0.51 (0.12–2.09) | 0.348 |
Univariate Analysis | Multivariable Analysis | |||
---|---|---|---|---|
HR (95% CI) | p-Value | HR (95% CI) | p-Value | |
Demographics | ||||
Gender (male = 1) | 1.00 (0.63–1.58) | 0.985 | ||
Age (≤65 years = 1) | 0.77 (0.49–1.20) | 0.249 | ||
BMI (≤25 kg/m2 = 1) | 0.83 (0.54–1.30) | 0.830 | ||
Recurrence resection (no = 1) | 1.07 (0.49–2.33) | 0.863 | ||
ASA (I/II = 1) | 1.05 (0.67–1.66) | 0.836 | ||
Liver disease | 0.316 | |||
ALD | 1 | |||
NAFLD | 0.63 (0.35–1.14) | |||
Viral | 1.00 (0.55–1.79) | |||
Cryptogenic/others | 0.77 (0.35–1.71) | |||
Preoperative liver function | ||||
MELD Score (≤6 = 1) | ||||
Albumin (≤40 g/L = 1) | 1.42 (0.88–2.33) | 0.155 | ||
AFP (≤10 µg/L = 1) | 0.91 (0.58–1.41) | 0.662 | ||
AST (≤40 U/L = 1) | 2.15 (1.29–3.57) | 0.003 | Excl. | |
ALT (≤40 U/L = 1) | 2.45 (1.53–3.93) | <0.001 | 2.35 (1.30–4.25) | 0.005 |
GGT (≤100 U/L = 1) | 2.05 (1.25–3.36) | 0.005 | 0.743 | |
Bilirubin (≤1 mg/dL = 1) | 1.84 (1.15–2.93) | 0.011 | 0.303 | |
AP (≤100 U/L = 1) | 1.77 (0.97–3.23) | 0.062 | ||
Platelet count (≤200/nL = 1) | 1.85 (1.17–2.92) | 0.009 | 0.215 | |
INR (≤1 = 1) | 0.90 (0.57–1.41) | 0.631 | ||
Creatinine (≤1 = 1) | 1.50 (0.92–2.45) | 0.108 | ||
Hemoglobin (≤12 g/dL = 1) | 0.77 (0.46–1.26) | 0.297 | ||
Child Pugh (A = 1) | 0.79 (0.50–1.26) | 0.330 | ||
Preoperative Imaging features | 2.20 (1.00–4.84) | 0.050 | ||
Number of nodules (1 = 1) | ||||
Largest nodule diameter (≤ 50 mm = 1) | ||||
Tumor burden (≤50% = 1) | 3.78 (2.38–6.00) | <0.001 | 0.663 | |
Macrovascular invasion (no = 1) | 1.76 (1.13–2.74) | 0.013 | 0.519 | |
Portal vein invasion (no = 1) | 2.39 (0.96–5.96) | 0.061 | ||
Extrahepatic vascular invasion (no = 1) | 1.93 (1.19–3.13) | 0.007 | 0.669 | |
Portal vein thrombosis (no = 1) | 2.42 (1.37–4.26) | 0.002 | 2.44 (1.09–5.45) | 0.030 |
Ascites (no = 1) | 2.48 (0.99–6.20) | 0.051 | ||
BCLC | 5.90 (2.06–16.91) | 0.001 | 0.689 | |
0/A | 1.34 (0.33–5.51) | 0.685 | ||
B | <0.001 | 0.725 | ||
C | 1 | |||
Operative Data | 3.13 (1.89–5.19) | |||
Laparoscopic resection (no = 1) | 3.42 (1.86–6.26) | |||
Operative time (≤180 min = 1) | ||||
Operative procedure (minor = 1) | ||||
Additional procedures (no = 1) | 1.32 (0.81–2.16) | 0.263 | ||
Pringle maneuver (yes = 1) | 1.25 (0.80–1.97) | 0.327 | ||
Intraop blood transfusion (no = 1) | 1.29 (0.83–2.02) | 0.259 | ||
Intraop FFP (no = 1) | 1.30 (0.47–3.55) | 0.616 | ||
Pathological data | 0.55 (0.24–1.26) | 0.156 | ||
R1 resection (no = 1) | 1.23 (0.75–2.00) | 0.414 | ||
pT category | 1.07 (0.68–1.68) | 0.784 | ||
T1 | ||||
T2 | 4.91 (2.10–11.49) | <0.001 | 0.243 | |
T3/T4 | <0.001 | <0.001 | ||
Tumor grading (G1/G2 = 1) | 1 | 1 | ||
MVI (no = 1) | 3.28 (1.91–5.64) | 6.04 (2.89–12.60) | ||
NF (no = 1) | 5.98 (3.15–11.38) | 6.02 (2.35–15.43) | ||
Postoperative Data | 1.18 (0.68–2.04) | 0.565 | ||
Intensive care stay (≤1 day = 1) | 2.38 (1.55–3.96) | <0.001 | 0.897 | |
Hospitalization (≤7 days = 1) | 0.80 (0.52–1.24) | 0.322 | ||
Postop complications (I/II = 1) | ||||
PHLF ISGLS (no = 1) | 1.22 (0.64–2.31) | 0.547 | ||
Postop blood transfusion (no = 1) | 1.14 (0.72–1.79) | 0.572 | ||
Postop FFP (no = 1) | 0.92 (0.52–1.62) | 0.774 |
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Bednarsch, J.; Tan, X.; Czigany, Z.; Wiltberger, G.; Buelow, R.D.; Boor, P.; Lang, S.A.; Ulmer, T.F.; Neumann, U.P.; Heij, L.R. Limitations of Nerve Fiber Density as a Prognostic Marker in Predicting Oncological Outcomes in Hepatocellular Carcinoma. Cancers 2022, 14, 2237. https://doi.org/10.3390/cancers14092237
Bednarsch J, Tan X, Czigany Z, Wiltberger G, Buelow RD, Boor P, Lang SA, Ulmer TF, Neumann UP, Heij LR. Limitations of Nerve Fiber Density as a Prognostic Marker in Predicting Oncological Outcomes in Hepatocellular Carcinoma. Cancers. 2022; 14(9):2237. https://doi.org/10.3390/cancers14092237
Chicago/Turabian StyleBednarsch, Jan, Xiuxiang Tan, Zoltan Czigany, Georg Wiltberger, Roman David Buelow, Peter Boor, Sven Arke Lang, Tom Florian Ulmer, Ulf Peter Neumann, and Lara Rosaline Heij. 2022. "Limitations of Nerve Fiber Density as a Prognostic Marker in Predicting Oncological Outcomes in Hepatocellular Carcinoma" Cancers 14, no. 9: 2237. https://doi.org/10.3390/cancers14092237