Features of extrahepatic metastasis after radiofrequency ablation for hepatocellular carcinoma

Table 1 Baseline characteristics of enrolled patients

	Total (n = 661)	Patients without extrahepatic metastasis (n = 617)	Patients with extrahepatic metastasis (n = 44)	P value
Age (yr)	66.9 ± 10.20	66.8 ± 10.2	68.4 ± 9.98	0.301
Male, n (%)	497 (75.2)	469 (76.0)	28 (63.6)	0.066
Etiology of liver cirrhosis, n (%)				0.084
Alcohol	137 (20.7)	131 (21.2)	6 (13.6)
HBV	351 (53.1)	322 (52.2)	29 (65.9)
HCV	111 (16.8)	108 (17.5)	3 (6.8)
Combined	40 (6.1)	38 (6.2)	2 (4.5)
Others	22 (3.3)	18 (2.9)	4 (9.1)
Platelet (× 103/μL)	127.8 ± 55.1	127 ± 54.7	141.2 ± 63.1	0.304
AST (IU/mL)	49.0 ± 45.6	48.6 ± 43.2	54.7 ± 72.1	0.40
ALT (IU/mL)	37.2 ± 46.8	36.7 ± 44.9	43.0 ± 69.2	0.392
ALP (U/L)	97.4 ± 38.6	96.7 ± 38.7	107.4 ± 35.2	0.076
Albumin (mg/dL)	4.3 ± 2.9	4.3 ± 3.0	3.9 ± 0.6	0.015
Total bilirubin (mg/dL)	0.93 ± 0.83	0.92 ± 0.84	1.04 ± 0.67	0.378
Serum AFP (IU/mL)	209.7 ± 1558.3	185.5 ± 1503.8	548.3 ± 2179.0	0.283
PIVKA-II (mAU/mL)	331.9 ± 2901.4	336.3 ± 2973.6	246.1 ± 542.6	0.907
BCLC stage, n (%)				0.034
0	257 (39.0)	248 (40.2)	9 (20.5)
A	378 (57.1)	345 (55.8)	33 (75.0)
B	26 (3.9)	24 (3.9)	2 (4.5)
mUICC stage, n (%)				0.096
I	298 (45.0)	28 (46.0)	13 (29.5)
II	316 (47.7)	288 (46.6)	28 (63.6)
III	48 (7.3)	45 (7.3)	3 (6.8)
Tumor size (cm)	2.42 ± 1.02	2.41 ± 1.02	2.62 ± 1.05	0.18
Ablation size/tumor size ratio	2.04 ± 0.97	2.07 ± 0.97	1.57 ± 0.74	0.001
Tumor number	1.19 ± 0.45	1.19 ± 0.46	1.16 ± 0.37	0.356
Encapsulated tumor, n (%)	157 (23.7)	146 (24.2)	11 (25.6)	0.840
Subcapsular tumor, n (%)	263 (39.7)	240 (39.4)	23 (53.5)	0.069
Follow-up duration, d (median, range)	1204 (183-5016)	1175 (183-5016)	1379 (187-4541)	0.270

Values are presented as mean ± SD. SD: Standard deviation; HBV: Hepatitis B virus; HCV: Hepatitis C virus; AST: Aspartate transaminase; ALT: Alanine transaminase; ALP: Alkaline phosphatase; AFP: Alpha-fetoprotein; PIVKA-II: Protein induced by vitamin K absence or antagonist-II; BCLC: Barcelona Clinic Liver Cancer; mUICC: Modified Union for International Cancer Control.

Table 2 Characteristics of patients with first recurrence following radiofrequency ablation (n = 333)

	Patients without extrahepatic metastasis(n = 289)	Patients with extrahepatic metastasis(n = 44)	P value
AFP level
Initial (median, range)	8.13 (0.70-30000.0)	21.750 (0.836-13148.0)	0.291
1st recurrence (median, range)	7.08 (0.93-50000.0)	28.15 (0.73-70000.0)	0.274
CTP score, n (%)			0.044
A	277 (95.8)	39 (88.6)
B	12 (4.2)	5 (11.4)
Recurrence free survival, d (median, range)	821 (49-3944)	389 (79-2041)	< 0.001
First recurred site, n (%)			< 0.001
RFA site	53 (18.3)	7 (15.3)
Same hepatic lobe	145 (50.2)	20 (45.5)
Different hepatic lobe	60 (20.8)	8 (18.2)
Both hepatic lobe	31 (10.7)	1 (3.1)
Extrahepatic area	0 (0.0)	8 (18.2)
Peritoneum		5
Lymph nodes		3
mUICC stage at 1st recurrence, n (%)			< 0.001
I	140 (48.4)	17 (38.6)
II	101 (34.9)	13 (29.5)
III	38 (13.1)	4 (9.1)
IVa	5 (1.7)	2 (4.5)
IVb	0 (0.0)	8 (18.2)
Rescue Treatment modalities, n (%)			0.003
TACE	138 (47.7)	15 (34.1)
RFA	110 (38.2)	13 (29.5)
Sorafenib	1 (0.3)	-
Surgery	8 (2.8)	3 (6.8)
Radiotherapy	1 (0.3)	3 (6.8)
Liver transplantation	1 (0.3)	-
TACE	11 (3.8)	3 (6.8)
RFA PEIT	1 (0.3)	-
None	9 (3.1)	5 (11.4)
Follow-up loss	9 (3.1)	2 (4.5)

RFA: Radiofrequency ablation; AFP: Alpha-fetoprotein; CTP: Current procedural terminology; mUICC: Modified Union for International Cancer Control; TACE: Transarterial chemoembolization; PEIT: Percutaneous ethanol injection therapy.

Table 3 Clinical features of patients with extrahepatic metastasis (n = 44), n (%)

Clinical features	Value
Location of metastasis1
Lymph nodes	16 (36.3)
Bone	12 (27.3)
Lung	13 (29.5)
Solitary/multiple	4 (30.7)/9 (69.2)
Unilateral/Bilateral	4 (30.7)/9 (69.2)
Lower lobe/non-lower lobe/all lobes	2 (15.4)/9 (69.2)/2 (15.4)
Peritoneum	12 (27.3)
Diagnostic modality
Abdomen enhanced CT	30 (68.2)
Abdomen enhanced MRI	3 (6.8)
Spine MRI	3 (6.8)
PET-CT	5 (11.4)
Chest X-ray	3 (6.8)
Chest enhanced CT	3 (6.8%)
Tumor marker increment (AFP, PIVKA)
Both	14 (36.8)
Either	17 (44.7)
AFP/PIVKA	15 (39.5)/2 (5.3)
None	7 (18.4)
N/A	6
Patients diagnosed of EHM with either of abdomen enhanced CT or serum AFP elevation (> 15 IU/mL)	38 (86.4)
Time to extrahepatic metastasis (years, median, range)	2.68 (0.38-10.6)
Intra-hepatic HCC status at diagnosis of EHM (mUICC T stage)
T0/T1/T2	19 (43.2)/5 (11.4)/7 (15.9)
T3/T4a	2 (4.5)/11 (25.0)

¹Nine patients had multiple EHM occurrences (3 patients: lymph node and bone, 3 patients: Lymph node and lung, 1 patient: bone and lung, and 1 patient: Bone and peritoneum). CT: Computed tomography; MRI: Magnetic resonance imaging; PET: Positron emission tomography; AFP: Alpha-fetoprotein; PIVKA-II: Protein induced by vitamin K absence or antagonist-II; N/A: Not applicable; EHM: Extrahepatic metastasis; HCC: Hepatocellular carcinoma; mUICC: Modified Union for International Cancer Control.

Table 4 Univariate and multivariate analysis of factors associated with extrahepatic metastasis

	Univariate analysis		Multivariate analysis
	OR (95%CI)	P value	OR (95%CI)	P value
BCLC stage (0 vs A, B)	2.93 (1.38–6.20)	0.003
mUICC stage (I vs II, III)	2.04 (1.04–3.96)	0.034
Post-RFA complication (fever, abscess)	2.78 (1.31–5.92)	0.050
Presence of intra-hepatic recurrence	48.8 (6.68–356.63)	0.000
ALP > 97 U/L	2.29 (1.23-4.26)	0.008
1st recurrence free survival < 2 yr	2.88 (1.54-5.38)	0.001	2.44 (1.16-5.14)	0.019
Ratio of ablation zone and tumor size < 2	3.84 (1.76-8.39)	0.001	3.33 (1.34-8.27)	0.010
Presence of tumoral thrombosis	2.57 (1.13-5.84)	0.024
AFP > 400 IU/mL at 1st recurrence	4.52 (2.03-10.07)	0.000	3.35 (1.33-8.43)	0.010
mUICC stage > 2 at 1st recurrence	2.49 (1.22-5.06)	0.012

OR: Odds ratio; CI: Confidence interval; BCLC: Barcelona Clinic Liver Cancer; mUICC: Modified Union for International Cancer Control; RFA: Radiofrequency ablation; ALP: Alkaline phosphatase; AFP: Alpha-fetoprotein.