Possible association between hepatitis C virus and malignancies different from hepatocellular carcinoma: A systematic review

Table 2 Characteristics of available studies, reported in English, assessing the association between hepatitis C virus infection and cholangiocarcinomas (A) or bile duct dysplasia (B)

Author/Journal/Publication year	Study design study period	CCA diagnosis	HCV positive colangiocarcinoma (n)/total colangiocarcinoma cases (n)	Total patients enrolled and control source	HCV positive controls (n)/controls (n)	Percentage of HCV-positive cases with 95%CI	Main conclusion
(A)
Abdel Wahab M 2007	Case series Period: Januiary 1995-October 2004	Histologic confirmation/CT/MRI/ERCP/PTD	440 patients with hilar cholangiocarcinoma 238 anti-HCV positive patients 238/440 (54%)	NR	NR	54.1 (49.4-58.7)	Liver cirrhosis and HCV may be risk factors For hilar cholangiocarcinoma in Egypt
Barusrux S Asian Pacific J Cancer Prev 2012	Case series with control group Period: NR	Histologic confirmation	8/295 (2.7%)	Total patients: 6120 Controls randomly selected from people in 4 provinces in Thailand, representing 4 geographically distinct areas and thus, populations in the North, North-east, South and Center of the country, respectively	125/5825 (2.15%) HCV-Ab prevalence in Thailand ranging from 1.5% to 2.15%. Sunanchaikarn S, Theamboonlers A, Chongsrisawat V et al (2007). Seroepidemiology and genotypes of hepatitis C virus in Thailand. Asian Pac J Allergy, 25, 175-182	2.7 (0.8-4.5)	No significant association between CAA and HCV in northeast Thailand, with prevalence of HCV infection comparable among CCA and general population
Chantajitr S J Hepatobiliary Pancreat Surg 2006	Case series with control group Period: 2000-2004	Histologic confirmation	HCC-CCA = 25 15 patients with test for anti- HCV 2/15 (13.3%)	Total patients: 75. 50 individuals, diagnosed with HCC at Ramathibodi Hospital	HCC = 50 32 patients with test for anti- HCV 1/32 (3.1%)	13.3 (1.6-40.5)	No significant differences in presence of hepatitis C virus (HCV) antibody (13% vs 3%) as etiologic risk factor between HCC-CC and HCC patients
Donato F Cancer Causes and control 2001	Hospital-based case-control study Period: January 1, 1995-July 31, 2000	Histologic confirmation	6/24 (25%)	Total individuals: 848. Subjects unaffected by liver diseases or malignant neoplasms, admitted to the Department of Ophtalmology, Dermatology, Urology, Surgery, Cardiology, Internal Medicine in the two main Hospitals in Brescia, enrolled as controls	50/824 (6%)	25 (7.7-42.3)	HCV as possible risk factor for ICC in Western countries
El-Serag H Hepatology 2009	Cohort study Period: October 1, 1988, and September 30, 2004	Identification of PAC cases by means of ICD-9-CM diagnosis codes (157.0, 157.1, 157.2, 157.3, 157.8, 157.9) Identification of HCV infected subjects by means of ICD-9-CM diagnosis codes (070.41, 070.44, 070.51, 070.54 and V02.62)	HCV-infected cohort: 146394 patients ICC = 14 ECC = 15	718687 patients (146394 HCV-infected cohort, 572293 HCV-uninfected cohort) , ICC: 37 and ECC: 75 (14 ICC and 15 ECC in HCV infected patients, 23 ICC and 60 ECC in HCV uninfected subjects)	HCV-uninfected cohort: 572293 patients ICC = 23 ECC = 60	ICC: 0.01 (0-0.15) ECC: 0.01 (0-0.15)	A more than twofold elevated risk of ICC in patients with HCV infection, absence of an association with ECC
Hai S Dig Surg 2005	Case series with control group Period: January 1997 - December 2002	Histologic confirmation	19/50 (38%)	Total patients: 50 Subjects admitted to the Osaka City University Hospital or the Osaka City General Hospital	31/50 (62%)	38 (24.5-51.4)	Possibility to detect a small ICC or a hepatocellular carcinoma by means of a follow-up for patients with chronic HCV by imaging series at regular intervals
Hsing AW Int J Cancer 2008	Population- based case-control study Period: June 1997 - May 2001,	Histologic confirmation or by means of ERCP	3/234 (2%) with gallbladder cancers 2/134 (1.5%) with extrahepatic bile duct cancers 1/49 (2%) with Ampulla of Vater carcinomas	Total patients: 1696 Controls represented by biliary stone case patients and by healthy subjects without a history of cancer, randomly selected from all permanent residents listed in the Shanghai Resident Registry	2/301 (0.7%) patients with gallbladder stones, 5/216 (2.3%) with bile duct stones and 15/762 (2%) healthy individuals	1.5 (0-3.5)	Low prevalence of HCV infection in this population (2%), therefore limited ability to detect an association with biliary diseases
Kobayashi M Cancer 2000	Case series with control group Period: 1980-1997	Cirrhosis confirmation by means of liver biopsy, peritoneoscopy, or both	14/600 (2.3%) developed CCA 11/14 patients with CCA 3/14 patients with CCA-HCC	600 HCV positive patients in follow-up between 1980 to 1997	206/600 (34.3%) patients developed HCC in the same period	2.3 (1.1-3.5)	HCV-related cirrhosis as a major risk factor for primary CCA in Japanese patients
Kuper H Soz Praventivmed 2001	Case-control study Period: January 1995-December 1998	Histologic confirmation	0/6 with CCA	Total subjects: 699 Controls represented by patients with injuries or eye, ear, nose and throat conditions admitted to three teaching Hospitals in Athens	52/333 (16%) with HCC 1/360 (0.3%) controls	0 (0-45.9)	No HCV positivity in CCA patients
Lee CH Br J Cancer 2009	Case-control study Period: 1991-2005	Histologic confirmation	21/160 (13.1%)	Individuals generally surveyed for any disease Chang Gung Memorial Hospital at the Lin-Ko Medical Center	10/160 (6.3%)	13.1 (7.9-18.3)	HCV-associated ICC and HCC shared common disease process for carcinogenesis and, possibly, both arose from the hepatic progenitor cells
Lee TY Am J Gastroenterol 2008	Hospital-based case-control study Period: 2000- 2004	Histologic confirmation	12/622 (1.9%)	Total subjects:3110 2488 healthy controls selected from 192655 individuals undergoing routine health examinations at the health promotion center at Asan Medical Center, Seoul	47/2488 (1.9%)	1.9 (0.8-3)	No significant association between ICC and HCV
Lee WS Surg Today 2006	Case series with control group Period: November 1994- December 2003	Histologic confirmation	ICC = 3/79 (3.8%) HCC-CCA = 4/33 (12.1%)	Total patients: 952, subjects, undergoing surgical resection at Samsung Medical Center, because of: HCC-CCA = 33 ICC = 79 HCC = 832	HCC = 61/832 (6.5%)	3.8 (0-8)	Significantly poorer survival rates of patients with transitional type HCC-CCA in comparison with HCC after hepatic resection
Matsumoto K Intern Med 2014	Case series with control group Period: NR	Histologic confirmation	145 patients undergoing surgical resection because of ICC: 50 ECC: 95 (1) ECC: 7/95 (7.4%) (2) ICC: 10/50 (20%)	General Japanese population (individuals ≥ 20 yr of age)	HCV-Ab prevalence equal to 1.2% in the Japanese individuals ≥ 20 yr of age	(1) 7.4 (2.1-12.6) (2) 20 (8.9-31)	HCV infection as a possible risk factor for the development of CCA. Surveillance of ICC and ECC required in HCV carriers
Mohammad-Alizadeh AH Asian Pac J Cancer Prev 2012	Case series with control group Period: 2004-2011	Histologic confirmation ERCP MRCP	CCA: 43/283 (15.2%) No distinction between HCV and number of ICC and ECC cases	Total subjects: 566 Patients with the primary or final diagnosis of CAA, admitted to gastroenterology ward of a tertiary academic center in Tehran-Iran	Gallstones 72/283 (25.4%), diabetes 70/283 (24.6%), HBV infection 52/283 (18.3%), primary sclerosing cholangitis 16/283 (5.6%) smoking 120/283 (42.3%)	15.2 (11-19.3)	In current study smoking, opiate and alcohol use as the most common risk factors in CCA patients, chronic hepatitis C infection and cirrhosis represent further risk factors
Nuzzo G Updates Surg 2010	Case series with control group Period: 1997- 2008	Histologic confirmation	8/55 (14.5%) (2 patients with HBV coinfection), undergoing surgical resection at Policlinico Gemelli, Rome	Total subjects: 55	47/55 (76.5%)	14.5 (5.2-23.8)	ICC associated with chronic HCV infection in 14.5% of patients
Perumal V Human Pathology 2006	Case series with control group Period: NR	Histologic confirmation	2/11 (18.2%)	10 liver specimens from anti-HCV negative individuals and 13 liver specimens from individuals who were negative for HBV surface antigen by serologic testing, used as negative controls HCV RNA-positive liver tissues from HCV positive cases used as positive controls for HCV RNA detection, at Johns Hopkins Hospital, Baltimore	Total subjects: 21	18.2 (2.2-51.8)	Possible etiologic role of HCV in some cases of ICC
Portolani N Annals of Surgical Oncology 2008	Case series with control group Period: 1990-2006	Histologic confirmation or typical findings on ultrasound, CT-, MRI- examination	ICC = 33 patients undergoing resection and 16 not resected 6/33 (18.1%)	Total subjects: 51 Patients diagnosed with ICC-HCC at the Surgical Clinic of Brescia University, Italy	ICC-HCC = 18 patients undergoing resection 11/18 (61.1%)	18.1 (5-31.3)	HCV infection and cirrhosis as a risk condition for ICC and combined HCC-ICC
Qu Z Asia-Pacific Journal of Clinical Oncology 2012	Case series with control group Period: January 1990 - June 2001	Histologic confirmation of ECC	ECC: 305, 139 with test for anti- HCV ECC: 6/139 (4.3%)	Total subjects: 353 Patients with BBD with cholelithiasis or acute cholangitis, undergoing surgical intervention selected as controls at Tianjin Nankai Hospital, Tianjin Third Central Hospital, Tianjin Medical University General Hospital and The Second Hospital of Tianjin Medical University hospitals in the corresponding time period	BBD:480, 214 with test for anti-HCV BBD:12/214 (5.6%)	4.3 (0.9-7.6)	No association between chronic HCV infection and ECC
Shaib YH Gastroenterology 2005	Hospital-Based Case-Control Study Period: 1993-1999	Histologic confirmation HCV defined by using ICD-9 codes for HCV (ICD-9 codes 070.41, 070.44, 070.51, 070.54, and V02.62) or for unspecified hepatitis (ICD-9 codes 070.9, 571.4, 571.8, and 571.9)	Data obtained from the National Cancer Institute (NCI)’s Surveillance, Epidemiology and End Results program SEER-Medicare database, linking SEER registry information with Medicare claims data, it is a program of the NCI to collect population-based cancer incidence and survival data, including population-based cancer registries in 5 states and 6 metropolitan areas ( about 14% of the United States population). ICC cases: 625 (3) HCV-specific codes: 5/625 (0.8%) (1) HCV (including unspecified hepatitis):35/625 (5.6%)	Controls included in the study derived from the 5% random sample of Medicare-enrolled beneficiaries with no cancer of any type residing in the geographic regions of SEER registries	90834 controls (1) HCV (including unspecified hepatitis): 940 (1%) (3) HCV-specific codes: 161 (0.2%)	0.8 (0.1-1.4)	Chronic HCV infection as possible risk factors for ICC
Shaib YH Am J Gastroenterol 2007	Hospital-Based Case-control Study Period: 1992-2002	Histologic confirmation	246 patients undergoing surgical resection because of ICC: 5/83 (6%) ECC: 6/163 (3.7%)	Total patients: 482 Controls randomly selected from an existing database of healthy individuals at M.D. Anderson	2/236 (0.8%)	ICC: 6 (0.9-11.1) ECC: 3.7 (0.8-6.5)	Chronic HCV infection as possible risk factors for ICC but not ECC
Shin RH Int J Epidemiol 1996	Case-control study Period: August 1990-August 1993	Histologic confirmation or typical findings on ultrasound, CT-, MRI- examination	41 patients with CCAs 203 patients with HCC (1) 29/41 patients with tests for antiHCV/HBV status. 4/29 (13.8%) HCV positive (2) 128/203 patients with test for antiHCV/HBV status 17/128 (13.3%) HCV positive	(1) Inpatients without liver disease, systemic disease, and malignant disorders from the Departments of Ophthalmology or Otorhinolaryngology (2) healthy people who had visited the Non-Communicable Disease Control Center All subjects were visited at the Tnje University Pusan Paik Hospital	(3) 203 (4) 203 394/406 subjects with tests for anti-HCV status. 23/394 (6.6%) HCV positive	(1) 13.8 (1.2-26.3) (2) 13.3 (7.4-19.1)	No association between chronic HCV infection and CCA
Songsivilai S Trans R Soc Trop Med Hyg 1996	Case series with control group Period: July 1993 - June 1995	Histologic confirmation	0/30	Total subjects: 110 Patients with HCC, undergoing surgical resection at Siriraj Hospital, Mahidol University, Bangkok	9/80 (11.2%)	0 (0-11.6)	No association between chronic HCV infection and CCA
Srivatanakul P Asian Pacific J Cancer Prev 2010	Case-control study Period: September 1999 -2001	Histology, or typical findings on ultrasound examination with an elevated titre (≥ 40 units/mL) of CA 19-9 and normal level of alpha-fetoprotein (AFP < 20 ng/mL)	7/103 (6.8%)	Total subjects: 206 Community hospitals in Nakhon Phanom Province and Nakhon Phanom Provincial Hospital	0/103	6.8 (1.9-11.6)	Possible role of HCV infection in the development of CCA in northeast Thailand
Taguchi J J Gatroenterol Hepatol 1996	Case series with control group Period: January 1988-July 1995	Histologic confirmation	14/20 (70%)	Total subjects: 367 HCC-CCA: 23/367, 20 patients with anti-HCV markers	6/20 (30%)	70 (49.9-90)	HCC-CCA associated with chronic HCV infection in 70% of patients
Tanaka M J Viral Hepat 2010	Cohort study Period: 1991-1993	ICC cases identified by the ICD-10 code (C22.1). diagnosis of ICC was based on histological examination and/or combined clinical, radiological (echography, CT and endoscopic retrograde cholangio-pancreatography) and laboratory findings	ICC: 11 cases 1/11 (9.1%)	154814 study subjects voluntary blood donors	1927/154814 (1.2%)	9.1 (0.2-41.3)	No association between HCV infection and ICC development
Tomimatsu M Cancer 1993	Case series with control group Period: January 1985 - December 1990	Histologic confirmation	(1) CCA: Anti-HCV +: 4/13 (30.8%) HBsAg+: 3/13 (23.1%) Anti-HCV-/HBsAg-: 6/13 (46.1%) (2) CCA-HCC: Anti-HCV +: 5/7 (71.4%) HBsAg+: 1/7 (14.3%) Anti-HCV- /HBsAg-: 1/7 (14.3%)	Total subjects: 141 Patients with HCC, undergoing surgical resection at the Institute of Gastroenterology of Tokyo Women’s Medical College	Anti-HCV +: 85/121 (70.3%), Anti-HCV+ /HBsAg+: 5/121 (4.1%) HBsAg+: 16/121 (13.2%) HBsAg-/anti-HCV -: 15/121 (12.4%)	(1) 30.8 (9-61.4) (2) 71.4 (29-96.3)	The anti-HCV-positive rate was high in combined HCC-CC as well as in HCC
Uenishi T Journal of Surgical Oncology 2014	Case series with control group Period: January 2000 - December 2011	Histological confirmation	33/90 (36.7%)	Total subjects: 90 Patients enrolled at Hirakata and Osaka University Hospital	57/90 (63.4%)	36.7 (26.7-46.6)	HCC-related death often occurred in patients undergoing curative resection for HCV-related ICC. HCV as adverse prognostic factor after curative resection for mass-forming ICC
Yamamoto M Cancer 1998	Case-series Period: February 1990 - March 1996	Histologic confirmation	50 patients with ICC Anti-HCV positive: 16/50 (32%) HBsAg+/Anti-HCV positive: 1 (2%)	NR	NR	32 (19-44.9)	Minute nodular ICC appears to be related to hepatitis viral infection and could be detected at an early stage, similar to hepatocellular carcinoma, by following up cases of chronic hepatitis or cirrhosis
Yamamoto S Cancer Sci 2004	Hospital case-control based study Period: January 1991 - December 2002	Histologic confirmation	18/50 (36%)	Total subjects: 255 Control patients enrolled at the two major medical centers of Osaka City	7/205 (3%)	36 (22.7-49.3)	HCV infection as a possible etiology of ICC in Japan
Yano Y Jpn J Clin Oncol 2003	Case-control study Period: January 1978 - December 1998	Histologic confirmation	HCV alone: (1) HCC-CCA = 10/26 (38.5%) (2) CCA = 5/53 (9.4%) HCV + HBV: 1/53 (2%)	Total subjects: 1172 Patients with HCC, undergoing surgical resection at the Department of Surgery, National Cancer Center Hospital, Tokyo	HCV alone: HCC = 526/1093 (48%) HCV + HBV: 16/1093 (1%)	(1) 38.5 (19.8-57.1) (2) 9.4 (1.5-17.3)	HCC-CCA represents a variant of ordinary HCC with cholangiocellular features, rather than an intermediate disease entity between HCC and CCA
Wahab A M Hepatogastro-enterology 2007	Case series Period: January 1995 - October 2004	Histologic confirmation or typical findings on CT, ERCP, MRI and PTD	Total patients: 440238/440 (54.1%)	NR	NR	54.1 (49.4-58.7)	HCV chronic infection as possible risk factor for hilar CCA in Egypt
Welzel TM Clin Gastroenterol Hepatol 2007	Population-based case-control study Period: 1993-1999	Identification of CAA cases from the Surveillance, Epidemiology and End Results-Medicare databases by means of ICD-9-CM diagnosis codes: (C22.0, C22.1, C24.0, 8010, 8020, 8041, 8070, 8140, 8144, 8160, 8161, 8260, 8310, 8480, 8490, 8560). Identification of HCV infection by means of ICD-9-CM diagnosis codes 070.41, 070.44, 070.51, 070.54 and 070.7	(1) ICC = 5/535 (0.9%) (2) ECC = 5/549 (0.9%)	102782 cancer-free controls identified using the Surveillance, Epidemiology and End Results-Medicare databases	142/102782	ICC: 0.9 (0.1-1.7) ECC: 0.9 (0.1-1.7)	Association between HCV infection and ICC
Zhou HQ Hepatobiliary Pancreat Dis Int 2007	Case-series Period: January 1996 - November 2005	Histologic confirmation	(1) HCC: 132 patients Anti-HCV positive: 26/132 (19.7%) (2) CCA: 44 patients Anti-HCV positive: 4/44 (9.1%) (3) HCC-CCA: 15 anti-HCV positive: 3/15 (20%)	NR	NR	(1) 19.7 (12.9-26.4) (2) 9.1 (0.6-17.5) (3) 20 (4.3-48)	Percentage of cHCC-CC patients with serum anti-HCV antibodies were similar to those of HCC patients but different from CC patients
Zhou YM World J Gastroenterol 2008	Hospital-based-case control Study Period: February 2004 - May 2006	Histologic confirmation	9/312 (2.9%)	Total patients: 750 Controls were selected from patients who were unaffected by liver diseases in the Changhai Hospital of the Second Military Medical University	6/438 (1.4%)	2.9 (0.9-4.7)	No significant difference between cases and controls in the prevalence of anti-HCV seropositivity
(B)
Torbenson M Am J Surg Pathol 2007	Review of liver explants with control group from 3 transplant centers Period: 1995 -2005	Histologic confirmation in explanted livers	(1) HCV alone = 10/511 (2%) (2) HCV + alcohol = 4/85 (5%)	1058 total liver explants Control groups included: (1) alcohol cirrhosis, (2) chronic hepatitis B infection, (3) nonviral causes of cirrhosis such as cryptogenic cirrhosis, (4) noncirrhotic livers that were transplanted for fulminant liver failure	(1) Alcohol cirrhosis = 5/ 112 (4%) (2) HBVchronic hepatitis = 0/67 (0%) (3) Cirrhosis from nonviral and non alcohol causes = 0/149 (0%) (4) Noncirrhotic =/134 (0%)	(1) 2 (0.7-3.1) (2) 4.7 (0.2-9.2)	Dysplasia detectable within the intrahepatic bile ducts in chronic HCV cirrhosis; chronic HCV, alone or in association with alcohol, as major risk factor for ICC
Wu TT Cancer 2009	Review of liver explants with control group at Mayo Clinic Rochester, Minnesota Period: 1995 - 2007	Histologic confirmation in explanted livers	(1) Alcohol-related and HCV-related cirrhosis: 24/26 (92%) (2) HCV-related cirrhosis: 27/44 (61%)	244 total liver explants Causes: 94 alcohol-related cirrhosis, 44 HCV-related cirrhosis, 26 alcohol- and HCV-related cirrhosis, 28 massive hepatic necrosis, 24 correction of metabolic conditions, 16 primary or metastatic tumors, 8 nodular regenerative hyperplasia, 2 subacute Budd- Chiari syndrome, 2 liver failure during the first week after transplantation	Noncirrhotic 27/80 (34%) alcohol-related cirrhosis 86/94 (91%)	(1) 92.3 (74.9-99) (2) 61.4 (46.9-75.7)	Epidemiologic role of HCV and alcohol in the development of CCA

BIN: Biliary intraepithelial neoplasia; BBD: Benign biliary disease; CT: Computed tomography; ERCP: Endoscopic retrograde cholangiopancreatography; HBsAg: Hepatitis surface antigen; cHCC-CC patients: Combined HCC and CCA; ICC: Intrahepatic colangiocarcinoma; ECC: Extrahepatic colangiocarcinoma colangiocarcinoma; CCA: Colangiocarcinoma; HCC: Hepatocellular carcinoma; MRI: Magnetic resonance imaging; PTD: Percutaneous transhepatic cholangiography; NR: Not reported; NA: Not available.