Update on the association of hepatitis B with intrahepatic cholangiocarcinoma: Is there new evidence?

Table 1 Summary of epidemiological studies evaluating hepatitis B virus infection and risk of intrahepatic cholangiocarcinoma

Ref.	Study design	Region	Dates	Source	Age (yr)	Gender (% male)	Cases		Controls		OR (95%CI) for HBV infection
							Total	With exposure (%)	Total	With exposure (%)
Petrick et al[4], 2017	Case-control	United States	2000-2011	Population	78.0	46.6	2092	25 (1.2)	323615	1200 (0.4%)	2.97 (1.97-4.46)
Choi et al[5], 2016	Case-control	United States	2000-2014	Hospital	60.6	42.9	1169	10 (0.95)	4769	8 (0.2%)	12.9 (2.69-61.61)
Huang et al[6], 2017	Case-control	Taiwan area of China	2003-2009	Population	67.7	52.1	4695	138 (2.9)	46942	513 (1.1%)	2.23 (1.80-2.76)
Lee et al[7], 2015	Case-control	South Korea	2007-2013	Hospital	67.8	50.4	83	19 (22.9)	166	9 (5.4%)	4.58 (2.00-10.50)
Chaiteerakij et al[8], 2013	Case-control	United States	2000-2010	Hospital	61.2	50.3	612	3 (0.5)	594	3 (0.5%)	0.97 (0.20-4.80)
Chang et al[9], 2013	Case-control	China	2004-2008	Population	NR	56.1	2978	257 (8.6)	11912	229 (1.9%)	4.9 (4.1-5.9)
Wu et al[10], 2012	Case-control	China	2002-2008	Hospital	57.9	62.1	23	12 (52.2)	52	2 (3.9%)	38.9 (7.52-201.04)
Wu et al[11], 2012	Case-control	China	1998-2010	Hospital	58.7	55.9	102	28 (22.5)	809	27 (3.3%)	10.52 (5.94-18.62)
Peng et al[12], 2011	Case-control	China	2002-2009	Hospital	53.8	60.2	98	31 (31.6)	196	25 (12.8%)	2.75 (1.27-5.95)
Welzel et al[13], 2011	Case-control	United States	1994-2005	Population	76.4	52.5	743	11 (1.5)	195953	442 (0.2%)	3.07 (1.43-6.58)
Tao et al[14], 2010	Case-control	China	1998-2008	Hospital	58.7	60.7	61	17 (27.9)	380	19 (5.0%)	7.3 (3.1-17.2)
Zhou et al[15], 2010	Case-control	China	2003-2006	Hospital	53.1	70.3	317	154 (48.6)	634	42 (6.6%)	9.67 (6.33-14.77)
Lee et al[16], 2009	Case-control	Taiwan area of China	1991-2005	Hospital	61.5	63.1	160	60 (37.5)	160	22 (13.8%)	4.99 (2.78-8.95)
Lee et al[17], 2008	Case-control	South Korea	2000-2004	Hospital	60.7	69.1	622	84 (13.5)	2488	125 (5.0%)	2.3 (1.6-3.3)
Zhou et al[18], 2008	Case-control	China	2004-2006	Hospital	53.2	66.0	312	151 (48.4)	438	42 (9.6%)	8.88 (5.97-13.19)
Shaib et al[19], 2007	Case-control	United States	1992-2002	Hospital	59.8	55.4	83	1 (1.2)	236	1 (0.4%)	2.9 (0.1-236.8)
Choi et al[20], 2006	Case-control	South Korea	2003-2004	Hospital	64.0	62.2	51	4 (7.8)	51	5 (9.8%)	0.8 (0.19-3.02)
Shaib et al[21], 2005	Case-control	United States	1993-1999	Population	78.7	51.7	625	1 (0.2)	90834	182 (0.2%)	0.8 (0.1-5.9)
Yamamoto et al[22], 2004	Case-control	Japan	1991-2002	Hospital	64.6	58.0	50	2 (4.0)	205	5 (2.5%)	1.84 (0.34-10.11)
Donato et al[23], 2001	Case-control	Italy	1995-2000	Hospital	65.0	80.8	23	3 (13.0)	824	45 (5.5%)	2.7 (0.4-18.5)
Tanaka et al[24], 2010	Cohort	Japan	1991-1993	Population	40-60	54.4	9.08/100000 p-yrs		0.66/100000 p-yrs		8.56 (1.33-55.20)
Fwu et al[25], 2011	Cohort	Taiwan area of China	1983-2000	Population	28.29	0	0.43/100000 p-yrs		0.09/100000 p-yrs		4.80 (1.88-12.20)

Hepatitis B virus infection status was identified by positive serum Hepatitis B surface antigen (HBsAg), unless reported otherwise. Cohort studies reported incidence rates of intrahepatic cholangiocarcinoma per 100000 HBsAg seropositive person-years (p-yrs). CI: Confidence interval; HBsAg: Hepatitis B surface antigen; HBV: Hepatitis B virus; iCCA: Intrahepatic cholangiocarcinoma; NR: Not reported; OR: Odds ratio.

Table 2 Summary of meta-analyses evaluating hepatitis B virus infection as a risk factor for intrahepatic cholangiocarcinoma

Ref.	Number of included studies	Data collection period	Regions	Cases	Controls	Pooled OR (95%CI) for HBV infection	Heterogeneity	Publication bias
Clements et al[3], 2020	Case-control = 18	1991-2014	Eastern = 12. Western = 6	14825	681181	4.57 (3.43-6.09)	I2 = 83% Q = 100.88 (P < 0.001)	Funnel plot: Symmetrical. No bias
Tan et al[38], 2020	Case-control = 6	1998-2013	Eastern = 6	3623	13597	5.98 (4.08-8.76)	I2 = 69% Q = 16.01 (P = 0.07)	Funnel plot: Relatively symmetrical. Moderate bias
Zhang et al[39], 2016	Case-control = 11	1991-2013	Eastern = 11	4966	17752	3.18 (2.35-4.30)	I2 = 84% Q: P < 0.001	Begg's test: P = 0.75, Egger's test: P = 0.42. No bias
Li et al[40], 2012	Case-control = 11. Cohort = 2	1991-2008	Eastern = 10. Western = 3	2402. NA	96266. NA	3.42 (2.46-4.74)	I2 = 75% Q = 48.37 (P < 0.001)	Funnel plot: Symmetrical Begg's test: P = 0.70, Egger's test: P = 0.26. No bias
Palmer et al[41], 2012	Case-control = 8	1991-2008	Eastern = 5. Western = 3	2753	291756	5.54 (3.19-9.63)	I2 = 86.3% Q = 51.2 (P < 0.001)	Funnel plot: Symmetrical. No bias
Zhou et al[42], 2012	Case-control = 12. Cohort: = 2	1987-2009	Eastern = 11. Western = 3	2362. NA	96452. NA	3.17 (1.88-5.34)	I2 = 81% Q: P < 0.001	Funnel plot: Asymmetry. Moderate bias

Statistical heterogeneity was assessed by the Cochran’s Q statistic and I² statistic. Significant heterogeneity is considered if Q: P < 0.10 or I² > 60%. Publication bias was evaluated using the Begg’s funnel plot and Egger’s test with P < 0.10 as an indication of publication bias. CI: Confidence interval; HBV: Hepatitis B virus; ICC: Intrahepatic cholangiocarcinoma; NA: Not applicable; OR: Odds ratio.

Table 3 American Joint Committee on Cancer staging classification for intrahepatic cholangiocarcinoma (8^th edition, 2017)

Staging classification
T1a	Solitary tumor ≤ 5 cm without vascular invasion
T1b	Solitary tumor > 5 cm without vascular invasion
T2	Solitary tumor with vascular invasion, or multiple tumors with or without vascular invasion
T3	Tumor perforating the visceral peritoneum
T4	Tumor involving the local extrahepatic structures by direct invasion
N0	No regional lymph node metastasis
N1	Regional lymph node metastasis present
M0	No distant metastasis
M1	Distant metastasis present

Table 4 American Joint Committee on Cancer staging classification for intrahepatic cholangiocarcinoma (8^th edition, 2017)

Stage	T	N	M
Ia	T1a	N0	M0
Ib	T1b	N0	M0
II	T2	N0	M0
IIIa	T3	N0	M0
IIIb	T4	N0	M0
	Any T	N1	M0
IV	Any T	Any N	M1