Incidence, risk factors, and prognosis in patients with primary hepatocellular carcinoma and lung metastasis: a population-based study

Figures & data

Figure 1 Flowchart of the enrolled patients in the study according to inclusion and exclusion criterion.

Abbreviations: HCC, hepatocellular carcinoma; SEER, Surveillance, Epidemiology, and End Results.

Table 1 Baseline clinical demographics and multivariable logistic regression for analyzing risk factor for initial lung metastasis of primary hepatocellular carcinoma patients in SEER database (2010–2015)

Variables	Lung metastasis free		Lung metastasis		OR (95% CI)	P-value
	No. of patients	%	No. of patients	%
Gender						0.026
Female	7,111	23.2	440	21.1	1 (Reference)	1
Male	23,498	76.8	1,644	78.9	1.131 (1.014–1.260)	0.026
Age at diagnosis (years)						<0.001
18–39	298	1.0	61	2.9	1 (Reference)	1
40–59	10,484	34.2	758	36.4	0.353 (0.266–0.470)	<0.001
60–79	16,992	55.5	1,051	50.4	0.302 (0.228–0.401)	<0.001
≥80	2,835	9.3	214	10.3	0.369 (0.271–0.502)	<0.001
Race						<0.001
White	21,304	69.6	1,322	63.4	1 (Reference)	1
Black	4,192	13.7	361	17.3	1.388 (1.230–1.566)	<0.001
Others	4,960	16.2	392	18.8	1.274 (1.133–1.432)	<0.001
Unknown	153	0.5	9	0.5	NA	NA
Marital status at diagnosis						<0.001
Married	22,396	73.2	1,429	68.6	1 (Reference)	1
Unmarried	6,602	21.5	553	26.5	1.313 (1.186–1.454)	<0.001
Unknown	1,611	5.3	102	4.9	NA	NA
Insurance status						<0.001
Insured	29,010	94.8	1,893	90.8	1 (Reference)	1
Uninsured	1,110	3.6	144	6.9	1.988 (1.661–2.380)	<0.001
Unknown	489	1.6	47	2.3	NA	NA
Year at diagnosis						0.968
2010	4,374	14.3	295	14.2	1 (Reference)	1
2011	4,655	15.2	324	15.6	1.032 (0.877–1.215)	0.705
2012	5,034	16.5	355	17.0	1.046 (0.891–1.227)	0.584
2013	5,296	17.3	361	17.3	1.011 (0.862–1.185)	0.896
2014	5,576	18.2	371	17.8	0.987 (0.842–1.155)	0.866
2015	5,674	18.5	378	18.1	0.988 (0.844–1.156)	0.878
Alpha-fetoprotein interpretation						<0.001
Positive/elevated	17,845	58.3	1,414	67.9	1 (Reference)	1
Negative/normal	7,062	23.1	211	10.1	0.377 (0.325–0.437)	<0.001
Borderline	65	0.2	6	0.3	1.165 (0.504–2.693)	0.721
Unknown	5,637	18.4	453	21.7	NA	NA
Maximum primary tumor size (mm)						<0.001
0–20	3,364	11.0	69	3.3	1 (Reference)	1
20–50	13,101	42.8	234	11.2	0.871 (0.664–1.142)	0.317
50–100	7,737	25.3	541	26.0	3.409 (2.645–4.394)	<0.001
≥100	3,970	13.0	605	29.0	7.430 (5.768–9.571)	<0.001
Unknown	2,437	7.9	635	30.5	NA	NA
7th AJCC TNM staging						<0.001
I	13,735	44.9	0	0.0	1 (Reference)	1
II	6,615	21.6	0	0.0	NA	NA
III	6,078	19.9	0	0.0	NA	NA
IV	4,181	13.6	2084	100	1.498 (1.472–1.525)	<0.001
Lymph node status						<0.001
Negative	28,144	91.9	1,290	61.9	1 (Reference)	1
Positive	2,073	6.8	411	19.7	4.326 (3.838–4.875)	<0.001
Unknown	392	1.3	383	18.4	NA	NA
Bone metastasis						<0.001
No	29,436	96.2	1,667	80.0	1 (Reference)	1
Yes	1,128	3.7	351	16.8	5.495 (4.827–6.255)	<0.001
Unknown	45	0.1	66	3.2	NA	NA
Brain metastasis						<0.001
No	30,501	99.7	1960	94.1	1 (Reference)	1
Yes	65	0.2	48	2.3	11.492 (7.892–16.734)	<0.001
Unknown	43	0.1	76	3.6	NA	NA
Surgery for primary site						<0.001
No surgery	22,213	72.6	2038	97.8	1 (Reference)	1
Local tumor destructiona	3,613	11.8	19	0.9	0.057 (0.036–0.090)	<0.001
Surgery	4,712	15.4	25	1.2	0.058 (0.039–0.086)	<0.001
Unknown	71	0.2	2	0.1	NA	NA
Grade						<0.001
Well differentiated	3,424	11.2	103	4.9	1 (Reference)	1
Moderately differentiated	5,225	17.1	236	11.3	1.501 (1.187–1.900)	0.001
Poorly differentiated	2,140	7.0	276	13.3	4.287 (3.397–5.410)	<0.001
Undifferentiated	167	0.5	21	1.0	4.180 (2.550–6.853)	<0.001
Unknown	19,653	64.2	1,448	69.5	NA	NA

Note:

a Local tumor destruction includes percutaneous ethanol injection, heat-radiofrequency ablation, cryosurgery, photodynamic therapy, electrocautery, fulguration (includes use of hot forceps for tumor destruction), laser, and others (ultrasound, acetic acid).

Abbreviation: SEER, Surveillance, Epidemiology, and End Results.

Figure 2 Kaplan–Meier analysis of (A) overall survival and (B) cancer-specific survival in hepatocellular carcinoma patients with or without initial lung metastasis.

Abbreviations: LM, lung metastasis; LMF, lung metastasis free.

Figure 3 Kaplan–Meier analysis of overall survival in hepatocellular carcinoma patients with initial lung metastasis stratified by (A) age at diagnosis, (B) gender, (C) race, (D) marital status at diagnosis, (E) insurance status at diagnosis, (F) lymph node status, (G) maximum primary tumor size, (H) primary tumor differential grade, (I) alpha-fetoprotein level, (J) surgery for primary tumor, (K) bone metastasis, and (L) brain metastasis.

Figure 4 Kaplan–Meier analysis of cancer-specific survival in hepatocellular carcinoma patients with initial lung metastasis stratified by (A) age at diagnosis, (B) gender, (C) race, (D) marital status at diagnosis, (E) insurance status at diagnosis, (F) lymph node status, (G) maximum primary tumor size, (H) primary tumor differential grade, (I) alpha-fetoprotein level, (J) surgery for primary tumor, (K) bone metastasis, and (L) brain metastasis.

Table 2 Univariate and multivariate analysis of overall survival in patients with primary hepatocellular carcinoma lung metastasis in SEER database (2010–2015)

Variables	Univariate analysis		Multivariate analysis
	HR (95% CI)	P-value	HR (95% CI)	P-value
Gender
Female	Reference
Male	1.089 (0.974–1.219)	0.134
Age at diagnosis (years)
18–39	Reference		Reference
40–59	1.793 (1.321–2.434)	<0.001	1.860 (1.365–2.533)	<0.001
60–79	1.774 (1.310–2.402)	<0.001	1.883 (1.384–2.563)	<0.001
≥80	1.868 (1.345–2.595)	<0.001	2.068 (1.478–2.896)	<0.001
Race
White	Reference
Black	0.975 (0.864–1.100)	0.680
Others	0.942 (0.836–1.061)	0.322
Unknown	NA	NA
Marital status at diagnosis
Married	Reference		Reference
Unmarried	1.198 (1.003–1.431)	0.046	1.134 (1.019–1.261)	0.021
Unknown	NA	NA	NA	NA
Insurance status
Insured	Reference
Uninsured	1.088 (0.982–1.206)	0.107
Unknown	NA	NA
Alpha-fetoprotein interpretation
Positive/elevated	Reference		Reference
Negative/normal	0.811 (0.695–0.946)	0.008	0.882 (0.754–1.030)	0.113
Borderline	0.140 (0.137–1.324)	0.140	0.473 (0.152–1.470)	0.196
Unknown	NA	NA	NA	NA
Surgery for primary site
No surgery	Reference		Reference
Local tumor destruction	0.268 (0.151–0.473)	<0.001	0.282 (0.159–0.500)	<0.001
Surgery	0.335 (0.201–0.557)	<0.001	0.390 (0.232–0.654)	<0.001
Unknown	NA	NA	NA	NA
Maximum primary tumor size (mm)
0–20	Reference
20–50	0.923 (0.696–1.225)	0.581
50–100	1.059 (0.814–1.379)	0.669
≥100	1.182 (0.909–1.536)	0.212
Unknown	NA	NA
Lymph node status
Negative	Reference		Reference
Positive	1.152 (1.026–1.294)	0.017	1.099 (0.977–1.236)	0.117
Unknown	NA	NA	NA	NA
Bone metastasis
No	Reference
Yes	1.010 (0.896–1.138)	0.876
Unknown	1.201 (0.928–1.555)	0.165
Brain metastasis
No	Reference
Yes	1.073 (0.798–1.443)	0.639
Unknown	NA	NA
Grade
Well differentiated	Reference		Reference
Moderately differentiated	1.159 (0.902–1.489)	0.247	1.206 (0.938–1.551)	0.145
Poorly differentiated	1.705 (1.337–2.176)	<0.001	1.732 (1.355–2.213)	<0.001
Undifferentiated	1.912 (1.163–3.142)	0.011	2.217 (1.342–3.661)	0.002
Unknown	NA	NA	NA	NA

Abbreviation: SEER, Surveillance, Epidemiology, and End Results.

Table 3 Univariate and multivariate analysis of cancer-specific survival in patients with primary hepatocellular carcinoma lung metastasis in SEER database (2010–2015)

Variables	Univariate analysis		Multivariate analysis
	HR (95% CI)	P-value	HR (95% CI)	P-value
Gender
Female	Reference
Male	1.105 (0.982–1.244)	0.098
Age at diagnosis (years)
18–39	Reference		Reference
40–59	1.716 (1.255–2.347)	0.001	1.738 (1.268–2.382)	0.001
60–79	1.685 (1.235–2.299)	0.001	1.747 (1.277–2.391)	<0.001
≥80	1.704 (1.214–2.392)	0.002	1.832 (1.300–2.583)	0.001
Race
White	Reference
Black	0.936 (0.823–1.065)	0.317
Others	0.971 (0.858–1.099)	0.643
Unknown	NA	NA
Marital status at diagnosis
Married	Reference
Unmarried	1.070 (0.961–1.193)	0.218
Unknown	NA	NA
Insurance status
Insured	Reference		Reference
Uninsured	1.214 (1.008–1.462)	0.041	1.163 (0.963–1.405)	0.117
Unknown	NA	NA	NA	NA
Alpha-fetoprotein interpretation
Positive/elevated	Reference		Reference
Negative/normal	0.734 (0.621–0.868)	<0.001	0.792 (0.669–0.937)	0.007
Borderline	0.152 (0.021–1.079)	0.060	0.174 (0.024–1.235)	0.080
Unknown	NA	NA	NA	NA
Surgery for primary site
No surgery	Reference		Reference
Local tumor destruction	0.246 (0.132–0.459)	<0.001	0.276 (0.148–0.516)	<0.001
Surgery	0.370 (0.222–0.617)	<0.001	0.430 (0.256–0.722)	0.001
Unknown	NA	NA	NA	NA
Maximum primary tumor size (mm)
0–20	Reference
20–50	0.906 (0.675–1.218)	0.514
50–100	1.049 (0.797–1.381)	0.733
≥100	1.165 (0.886–1.531)	0.274
Unknown	NA	NA
Lymph node status
Negative	Reference		Reference
Positive	1.177 (1.043–1.328)	0.008	1.112 (0.983–1.257)	0.091
Unknown	NA	NA	NA	NA
Bone metastasis
No	Reference
Yes	1.043 (0.922–1.181)	0.501
Unknown	NA	NA
Brain metastasis
No	Reference
Yes	1.105 (0.813–1.501)	0.524
Unknown	NA	NA
Grade
Well differentiated	Reference		Reference
Moderately differentiated	1.159 (0.902–1.489)	0.274	1.182 (0.907–1.542)	0.216
Poorly differentiated	1.765 (1.366–2.280)	<0.001	1.762 (1.362–2.281)	<0.001
Undifferentiated	1.920 (1.136–3.246)	0.015	2.139 (1.259–3.633)	0.005
Unknown	NA	NA	NA	NA

Abbreviation: SEER, Surveillance, Epidemiology, and End Results.