Clinical features and prognosis of patients with extrahepatic metastases from hepatocellular carcinoma

Table 1 Clinical profile of 151 HCC patients with extrahepatic metastases at the initial diagnosis of extrahepatic metastases

Age (yr)	64 (21-82)
Sex (male/female)	117/34
Etiology (HBV/HCV/HBV + HCV/others)	33/89/5/24
PS (0/1/2/3/4)	90/43/9/6/3
Intrahepatic tumor stage (T0/1/2/3/4)	11/4/13/43/80
Intrahepatic main tumor size (mm)	48 (0-160)
Intrahepatic tumor volume (< 50%/≥ 50%)	103/48
Intrahepatic tumor morphology (nodular type/non nodular type/no intrahepatic HCC)	83/57/11
Grade of portal vein invasion (Vp 0/1/2/3/4)	74/0/26/28/23
Child-Pugh grade (A/B/C)	88/48/15
AFP (ng/mL)	741.8 (< 5-861 600)
DCP (mAU/mL)	1300 (< 10-391 400)
Site of extrahepatic metastases, n (%)
Lung	63 (42)
Lymph nodes	60 (40)
Bone	51 (34)
Adrenal	16 (11)
Peritoneum	1 (0.7)
Pancreas	1 (0.7)
Nasal passages	1 (0.7)

Data are expressed as medians and ranges unless indicated otherwise. HBV: hepatitis B virus; HCV: hepatitis C virus; PS: Eastern Cooperative Oncology Group performance status; T0: no intrahepatic HCC; Portal invasion assessed Vp1: tumor thrombus in a third or more of the peripheral branches; Vp2: in the second branch; Vp3: in the first branch; Vp4: in the trunk; AFP: alpha-fetoprotein; DCP: Des-γ-carboxy prothrombin.

Table 2 Sites of extrahepatic HCC detected throughout the entire follow-up period

Site	Patients (n = 151), n (%)
Lung	71 (47)
Lymph nodes	68 (45)
Bone	56 (37)
Adrenal	18 (12)
Brain	2 (1)
Peritoneum	1 (0.7)
Pancreas	1 (0.7)
Nasal	1 (0.7)
Muscle	1 (0.7)
Skin	1 (0.7)
Diaphragm	1 (0.7)
Colon	1 (0.7)

Table 3 Univariate analysis of predictors of survival after initial diagnosis of extrahepatic metastases in 151 patients

Variable	Hazard Ratio	95% CI	P
PS (0 vs 1-4)	2.181	1.50-3.17	< 0.001
Age ( ≤ 65 vs > 65 yr)	0.988	0.97-1.0	0.18
Sex (M vs F)	0.889	0.57-1.38	0.601
Child Pugh stage (A vs B, C)	2.323	1.73-3.12	< 0.001
Intrahepatic main tumor size ( ≤ 50 vs > 50 mm)	2.321	1.52-3.54	< 0.001
Intrahepatic tumor volume ( ≤ 50 vs > 50%)	2.523	1.71-3.72	< 0.001
Intrahepatic tumor morphology (nodular vs non nodular)	1.506	1.04-2.18	0.03
Vp (0-2 vs 3, 4)	2.247	1.53-3.29	< 0.001
AFP ( ≤ 400 vs > 400 ng/mL)	1.158	0.80-1.68	0.439
DCP ( ≤ 1000 vs > 1000 mAU/mL)	1.584	1.08-2.33	0.02
Treatment (performed vs not performed)1	2.385	1.51-3.77	< 0.001
Site (lung vs others)2	1.065	0.74-1.52	0.731
Site (bone vs others)	1.61	1.11-2.33	0.012
Site (only lymph node vs others)	1.133	0.74-1.74	0.567

¹Treatments: various treatments for extrahepatic metastases (surgical resection, TACE, systemic chemotherapy and/or radiotherapy);

²Site: site of extrahepatic metastases.

Table 4 Multivariate analysis of predictors of survival after initial diagnosis of extrahepatic metastases among 151 patients

Variable	Hazard ratio	95% CI	P
PS (0 vs 1-4)	5.576	2.431-12.152	< 0.001
Vp (0-2 vs 3, 4)	4.792	2.137-10.712	< 0.001
Treatment (performed vs not performed)	4.134	1.539-11.011	0.003
Child pugh stage (A vs B, C)	2.372	1.247-4.914	0.008

Table 5 Clinical profile of 14 patients who died of extrahepatic metastases during the follow-up period

Case	Presentation	Site	IntrahepaticHCC stage	Sex	Age(yr)	Child-Pugh stage	Etiology
1	R	Lung	T3	M	65	A	HCV
2	R	Lung	T4	M	35	CH	HBV
3	R	Lung	T3	M	56	A	HBV
4	R	Lung, vertebra	T0	M	40	CH	HBV
5	R	Lung, vertebra	T1	M	69	A	HBV
6	R	Lung, LN	T0	M	63	B	HBV
7	R	Lung, vertebra, nasal	T0	M	50	A	HBV
8	R	Lung	T3	M	73	A	NBNC
9	I	Skull	T1	M	57	A	HCV
10	I	Skull	T2	F	72	C	HCV
11	I	Skull	T3	M	56	B	HCV
12	A	Vertebra	T3	M	69	A	HCV
13	O	Lung, rib, LN	T1	M	74	A	HCV
14	O	Vertebra, LN	T1	M	70	B	HCV

All patients with intrahepatic tumor stage T0-T2 were treated previously for intrahepatic HCC. R: respiratory failure; CH: chronic hepatitis; LN: lymph node; NBNC: no hepatitis B virus or hepatitis C virus; I: intracranial hypertension symptom; A: aspiration-related pneumonia; O: obstructive jaundice.

Table 6 Causes of death of 126 HCC patients with extrahepatic metastases

Intrahepatic tumor stage	Intrahepatic HCC orliver failure	Extrahepatic HCC
T0-2 (n = 17)	53% (9/17)	47% (8/17)
T3-4 (n = 109)	94% (103/109)	6% (6/109)