Systematic Reviews
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Dec 7, 2015; 21(45): 12896-12953
Published online Dec 7, 2015. doi: 10.3748/wjg.v21.i45.12896
Possible association between hepatitis C virus and malignancies different from hepatocellular carcinoma: A systematic review
Sirio Fiorino, Letizia Bacchi-Reggiani, Dario de Biase, Adele Fornelli, Michele Masetti, Andrea Tura, Fabio Grizzi, Matteo Zanello, Laura Mastrangelo, Raffaele Lombardi, Giorgia Acquaviva, Luca di Tommaso, Arrigo Bondi, Michela Visani, Sergio Sabbatani, Laura Pontoriero, Carlo Fabbri, Andrea Cuppini, Annalisa Pession, Elio Jovine
Sirio Fiorino, Andrea Cuppini, Unità Operativa di Medicina Interna, Ospedale di Budrio, Budrio, 40054 Bologna, Italy
Letizia Bacchi-Reggiani, Dipartimento di Medicina Sperimentale, Istituto di Cardiologia Policlinico S. Orsola-Malpighi, Università degli Studi di Bologna, 40138 Bologna, Italy
Dario de Biase, Giorgia Acquaviva, Dipartimento di Medicina Sperimentale, Università di Bologna, Unità Operativa Biologia Molecolare, Anatomia Patologica Ospedale Bellaria, 40139 Bologna, Italy
Adele Fornelli, Arrigo Bondi, Servizio di Anatomia Patologica, Ospedale Maggiore, 40133 Bologna, Italy
Michele Masetti, Matteo Zanello, Laura Mastrangelo, Raffaele Lombardi, Elio Jovine, Unità Operativa di Chirurgia A, Ospedale Maggiore, 40133 Bologna, Italy
Andrea Tura, Institute of Neuroscience, National Research Council, 35127 Padova, Italy
Fabio Grizzi, Luca di Tommaso, Humanitas Clinical and Research Center, Rozzano, 20089 Milano, Italy
Michela Visani, Annalisa Pession, Dipartimento di Farmacia e Biotecnologie, Università di Bologna, 40139 Bologna, Italy
Sergio Sabbatani, Istituto di Malattie Infettive, Policlinico S. Orsola-Malpighi, Università degli Studi di Bologna, 40138 Bologna, Italy
Laura Pontoriero, Unità di Cura Materno-Infantile, Distretto Lametino, ASP, 88100 Catanzaro, Italy
Carlo Fabbri, U.O. Endoscopia, Ospedale Maggiore, 40133 Bologna, Italy
Author contributions: Fiorino S conceived the study and coordinated the search activity of colleagues; Visani M and Acquaviva G contributed to the design of the review and coordinated the preparation of the first draft of manuscript; Masetti M and Lombardi R independently and in a parallel manner, performed the literature search, identified and screened the articles; Bacchi-Reggiani L and Fornelli A supervised the literature search analysis; Grizzi F and di Tommaso L contributed to write the first draft of manuscript; Tura A and Pontoriero L checked the accuracy of data collection; Zanello M and Mastrangelo L independently extracted and tabulated all relevant data from included studies by means of a standardized flow path and contributed to writing the manuscript; Fabbri C and Cuppini A commented on drafts of the manuscript; Bondi A and Pession A supervised and critically reviewed the manuscript; Sabbatani S and Jovine E were responsible for the final approval of manuscript; de Biase D contributed to the design of the study and commented on drafts of the manuscript; all authors approved the final version of the manuscript.
Conflict-of-interest statement: All authors declare that they have no competing interest.
Data sharing statement: The dataset is available from the corresponding author at
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: Sirio Fiorino, MD, Unità Operativa di Medicina Interna, Ospedale di Budrio, Via Benni 44, Budrio, 40054 Bologna, Italy.
Telephone: +39-51-809259 Fax: +39-51-809296
Received: April 17, 2015
Peer-review started: April 19, 2015
First decision: July 14, 2015
Revised: August 5, 2015
Accepted: October 13, 2015
Article in press: October 13, 2015
Published online: December 7, 2015

AIM: To summarize the current knowledge about the potential relationship between hepatitis C virus (HCV) infection and the risk of several extra-liver cancers.

METHODS: We performed a systematic review of the literature, according to the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) Statement. We extracted the pertinent articles, published in MEDLINE and the Cochrane Library, using the following search terms: neoplasm/cancer/malignancy/tumor/carcinoma/adeno-carcinoma and non-Hodgkin lymphomas, kidney/renal-, cholangio-, pancreatic-, thyroid-, breast-,oral-, skin-, prostate-, lung-, colon-, stomach-, haematologic. Case series, case-series with control-group, case-control, cohort-studies as well as meta-analyses, written in English were collected. Some of the main characteristics of retrieved trials, which were designed to investigate the prevalence of HCV infection in each type of the above-mentioned human malignancies were summarised. A main table was defined and included a short description in the text for each of these tumours, whether at least five studies about a specific neoplasm, meeting inclusion criteria, were available in literature. According to these criteria, we created the following sections and the corresponding tables and we indicated the number of included or excluded articles, as well as of meta-analyses and reviews: (1) HCV and haematopoietic malignancies; (2) HCV and cholangiocarcinoma; (3) HCV and pancreatic cancer; (4) HCV and breast cancer; (5) HCV and kidney cancer; (6) HCV and skin or oral cancer; and (7) HCV and thyroid cancer.

RESULTS: According to available data, a clear correlation between regions of HCV prevalence and risk of extra-liver cancers has emerged only for a very small group of types and histological subtypes of malignancies. In particular, HCV infection has been associated with: (1) a higher incidence of some B-cell Non-Hodgkin-Lymphoma types, in countries, where an elevated prevalence of this pathogen is detectable, accounting to a percentage of about 10%; (2) an increased risk of intra-hepatic cholangiocarcinoma; and (3) a correlation between HCV prevalence and pancreatic cancer (PAC) incidence.

CONCLUSION: To date no definitive conclusions may be obtained from the analysis of relationship between HCV and extra-hepatic cancers. Further studies, recruiting an adequate number of patients are required to confirm or deny this association.

Keywords: Neoplasm, Cancer, Hepatitis C virus, Risk factors, Extra-hepatic malignancies, Hepatocellular carcinoma, Pancreatic cancer, Cholangiocarcinoma

Core tip: Hepatitis C virus (HCV) is an oncogenic virus and a well-known risk factor for hepatocellular carcinoma. Some reports suggested that its infection is associated with development of cholangiocarcinoma and some types of lymphomas, but a comprehensive assessment of the possible role of HCV in extrahepatic carcinogenesis has not been yet performed. Aim of this review is to focus on HCV infection association with extra-liver neoplasms, as lymphomas, pancreatic cancer and breast-, renal-, oral- and thyroid-cancers. Our results strongly support the need of additional studies to ensure a precise estimate of the effect of HCV on these different types of extra-hepatic cancers.