1. KAHBPS 2015-04-25, Gyeongju, Korea
Long-term outcome after resection of huge hepatocellular carcinoma ≥10 cm: Single-institution experience with 471 patients: Proposal of a prognostic prediction system
Shin Hwang, Young-Joo Lee, Ki-Hun Kim, Chul-Soo Ahn, Deok-Bog Moon, Tae-Yong Ha, Gi-Won Song, Sung-Gyu Lee
Department of Surgery, Asan Medical Center,
University of Ulsan College of Medicine, Seoul, Korea

2. Huge HCC > 10 cm
China > 20% of all HCC, Japan & Korea >10% of all HCC

3. Proportions of survival
Overall and disease-free survival
perioperative mortality: n=2
n=100
57%
Proportions of survival
Study period:
31%
Overall
Disease-free
Postoperation months
Lee, Hwang et al. World J Surg 2007

4. Background
Zhang et al. World J Surg 2013
There is some noticeable survival difference according to tumor size,
but it was not possible to identify any definite cutoff in tumor size.
n=615
OS DFS
OS DFS
Cutoff
in tumor size
2 cm
5 cm
3 cm
8 cm
4 cm
10 cm

5. Current issues
If resectable, there is no limit in size for resection of HCC.
Single HCC is regarded as T1 or T2 unless macroscopic vascular invasion is involved.
The overall surgical outcome of huge HCCs is acceptable, but still worse than that of smaller HCCs.

6. Purpose To assess the long-term outcomes of resection for HCC ≥10 cm
To establish a prognostic model for early recurrence, which will be useful for postoperative surveillance
To validate the reliability of the prognostic model
using an external cohort

7. Incidence of HCC > 10 cm
4148 HCC patients underwent resection
during Jan and Apr. 2012
- Exclusion of mixed pathology
- 471 cases of HCC > 10 cm (11.4%)
- Follow-up to Mar (≥24 mos)

8. Flow of patients Surgical resection 471 patients Preoperative
treatment
(n=52)
n=419
Surgical resection
1-month TACI
(n=167)
Perioperative
mortality
(n=8)
Follow-up
Tumor recurrence
(n=346)
No recurrence
(n=117)

9. Preoperative treatment
TACE
RACE
TACE +
RTx/RFA
RTx/RFA
CTx
n = 37
n = 8
n = 3
n = 4

10. Clinical features
Age (yrs) ±10.8 (range: 20 – 79)
Sex (n)
Male
Female
Primary liver disease (n)
HBV
ALD
HCV
Others
Serum AFP (n=471)
≥100 ng/mL (64.5%)
Median ng/mL ( )
Serum PIVKA-II (n=231)
≥200 mAU/mL (82.3%)
Median mAU/mL ( )
ICG R15 (%) ±8.2
Tumor diameter(median, cm) 13.0 (range, 10 – 26)
Single tumor (n) (93%)
HBV, hepatitis B virus; HCV, hepatitis C virus; ALD, alcoholic liver disease; AFP, alpha-fetoprotein; PIVKA-II, Proteins Induced by Vitamin K Antagonist or Absence; ICG R15, indocyanine green retention test at 15 minutes.

11. Expression of AFP and PIVKA-II
Linear scale
Logarithmic scale
PIVKA-II (mAU/mL)
PIVKA-II (mAU/mL)
AFP (ng/mL)
AFP (ng/mL)

12. Ellipsoid tumor volume
10 cm-sized sphere = mL
13 cm = 1000 mL
10 cm x 9 cm x 8 cm = 360 mL
Mean diameter 13.6±3.1 cm
200 – 499 mL
500 – 999 mL
≥ 1000 mL
n = 182
(38.6%)
n = 175
(37.2%)
n = 114
(24.2%)

13. Extents of resection
Type of liver resection
Systematic resection (n=429) (91.1%)
Right hepatectomy ± S1 resection 251
Left hepatectomy ± S1 resection
Right anterior sectionectomy
Right posterior sectionectomy
Left lateral sectionectomy
Left medial sectionectomy
Central bisectionectomy
Right trisectionectomy
Left trisectionectomy
Non-systematic resection (n=42) (8.9%)
Partial hepatectomy
Combined bile duct resection (1.7%)
Combined resection of adjacent organs (n) 28 (6.0%)
Tumor thrombectomy
Portal vein (10.0%)
Hepatic vein (0.9%)
Curative resection
R0 resection (89.4%)
R1 resection (10.6%)

14. Extents of tumor
Number of tumors (n)
One (93.0%)
Two (4.0%)
≥ (3.0%)
Simple nodular growth (n) 191 (40.6%)
Microvascular invasion (n) (56.3%)
Macrovascular invasion (n) (10.4%)
Satellite nodules (n) (17.0%)
Bile duct invasion (n) (1.9%)
Capsule invasion (n) (18.3%)
Tumor necrosis (n) (80.7%)
Tumor differentiation (n)
Most common Well: 168, Moderate: 194, Poor: 96
Worst Well: 88, Moderate: 261, Poor: 109
Regional lymph node metastasis (n) 12 (2.6%)

15. Long-term survival analysis
Early recurrence prediction model
External validation

16. Proportions of recurrence
Cumulative HCC recurrence
76.0%
77.8%
72.5%
Proportions of recurrence
62.2%
n=471
Postoperation months

17. Proportions of survival
Overall patient survival
Perioperative
mortality:
n=8 (1.7%)
96.4% at 3 mos
Proportions of survival
69.2%
46.9%
35.5%
18.8%
Postoperation months

18. First recurrence timing and treatment
First rec. site Treatment No. of patients
Liver (n=253)
TACE 213
TACI
RFA
Resection
EBRT
PEIT
None
Lung (n=49)
Chemotherapy 29
Resection
EBRT
None
Bone (n=7)
EBRT
Adrenal (n=4)
Adrenalectomy
EBRT
Thyroid (n=1)
Thyroid lobectomy 1
Multiple recurrence
(n=32) Specific treatment 22
None
TACE, transarterial chemoembolization; TACI, transarterial chemoinfusion; RFA, radiofrequency ablation; EBRT, external beam radiotherapy; PEIT, percutaneous ethanol injection therapy.
Disease-free survival
4 mos
6 mos
p=0.003
Surgical resection (n=20)

19. Overall survival respect to the first recurrence sites
Disease-free survival
Overall patient survival
20 mos
10 mos
21 mos
p=0.009
p=0.003 +
Post-recurrence survival
6 mos
12 mos
16 mos
p=0.000

20. Univariate analyses for tumor recurrence and patient survival
Variables HCC recurrence Patient survival
Median disease-free p-value Median overall p-value
survival period (mos) survival period (mos)
Serum AFP
< 100 ng/mL
≥ 100 ng/mL
Serum PIVKA-II
< 200 mAU/mL
≥ 200 mAU/mL
FDG-PET
Not hypermetabolic > 5 years
Hypermetabolic
Satellite nodule
Absent
Present
Microvascular invasion
Absent
Present
Macrovascular invasion
Absent
Present
Tumor volume
< 500 mL
50–999 mL
≥ 1000 mL
Type of resection R R
AFP, alpha-fetoprotein; PIVKA-II, proteins induced by vitamin K antagonist or absence-II; FDG-PET, 2-18F-fluoro-2-deoxy-d-glucose positron emission tomography.

21. Multivariate analyses for tumor recurrence and patient survival
Variables HCC recurrence Patient survival
Hazard 95% p-value Hazard 95% p-value
ratio CI ratio CI
Serum AFP
≥ 100 ng/mL – –
vs. < 100 ng/mL
FDG-PET
Hypermetabolic – –
vs. not hypermetabolic
Satellite nodule
Present – –
vs. absent
Microvascular invasion
Present – –
95% CI, 95% confidence interval; AFP, alpha-fetoprotein; HCC, hepatocellular carcinoma; PIVKA-II, proteins induced by vitamin K antagonist or absence-II; FDG-PET, 2-18F-fluoro-2-deoxy-d-glucose positron emission tomography.

22. Long-term survival analysis
Early recurrence prediction model
External validation

23. Training cohort 4148 HCC patients underwent resection
during Jan and Apr. 2012
- 257 cases of HCC > 10 cm
- Follow-up to Mar (≥24 mos)
- Meeting 4 factors: AFP, PET, pathology
(satellite nodule, MVI)

24. Multiple regression for 3-month recurrence
Variables Beta SE of Beta B SE of B p-value
AFP
(< vs. ≥ 100 ng/mL)
FDG-PET
(Not hypermetabolic vs. hypermetabolic)
Satellite nodule
(Absent vs. present)
Microvascular invasion
Beta, standardized coefficient; B, unstandardized coefficient; SE, standard error; AFP, alpha-fetoprotein; FDG-PET, 2-18F-fluoro-2-deoxy-d-glucose positron emission tomography.
Training cohort of 257 patients

25. 4-risk factor prediction model
- Training cohort of 257 patients
- No. of risk factors
: AFP, PET, satellite nodule, microvascular invasion
Recurrence rate at 3 mos
63.2%
45.0%
Percentage of recurrence
30.0%
12.1% 0%
No. of risk factors

26. Internal validation of 4-risk factor model
for 12-month recurrence
Tumor recurrence
Patient survival
18.7%
30.3%
58.7%
79.0%
92.1%
p=0.000
- Training cohort of 257 patients
- No. of risk factors: AFP, PET, satellite nodule, microvascular invasion

27. Long-term survival analysis
Early recurrence prediction model
External validation

28. External validation cohort
Study period: May 2012 – Feb. 2014
- 92 cases of HCC > 10 cm
- Follow-up to Jan (≥12 mos)
- Patient profiles
Age: 48.2 ± 11.3 (range, 23–73)
Sex: male 71 (77.2%)
HBV: 75 (81.5%)
Single tumor: 84 (91.3%)
Median tumor size: 12.8 cm
R0 resection

29. External validation of 4-risk factor model for 12-month recurrence
Tumor recurrence
Patient survival
33.4%
31.6%
58.3%
78.3%
92.9%
p=0.000
- Validation cohort of 92 patients
- No. of risk factors: AFP, PET, satellite nodule, microvascular invasion
The same discriminating power was obtained.

30. This study is under R2 minor revision in World Journal of Surgery.
Conclusions
Hepatic resection combined with active treatment of recurrence enhanced long-term survival in patients with HCC ≥10 cm.
Our 4-factor risk prediction model appears to contribute to quantitative postoperative risk estimation for early HCC recurrence.
Further validation is necessary with large patient populations in multicenter studies.
This study is under R2 minor revision in
World Journal of Surgery.