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Tsutsumi Y, Ito S, Shiratori S, Teshima T. Hepatitis C Virus (HCV)-Ribonucleic Acid (RNA) As a Biomarker for Lymphoid Malignancy with HCV Infection. Cancers (Basel) 2023; 15:2852. [PMID: 37345190 DOI: 10.3390/cancers15102852] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 05/15/2023] [Accepted: 05/15/2023] [Indexed: 06/23/2023] Open
Abstract
The hepatitis C virus (HCV) is potentially associated with liver cancer, and advances in various drugs have led to progress in the treatment of hepatitis C and attempts to prevent its transition to liver cancer. Furthermore, reactivation of HCV has been observed in the treatment of lymphoma, during which the immortalization and proliferation of lymphocytes occur, which leads to the possibility of further stimulating cytokines and the like and possibly to the development of lymphoid malignancy. There are also cases in which the disappearance of lymphoid malignancy has been observed by treating HCV and suppressing HCV-Ribonucleic acid (RNA), as well as cases of recurrence with an increase in HCV-RNA. While HCV-associated lymphoma has a poor prognosis, improving the prognosis with Direct Acting Antivirals (DAA) has recently been reported. The reduction and eradication of HCV-RNA by means of DAA is thus important for the treatment of lymphoid malignancy associated with HCV infection, and HCV-RNA can presumably play a role as a biomarker. This review provides an overview of what is currently known about HCV-associated lymphoma, its epidemiology, the mechanisms underlying the progression to lymphoma, its treatment, the potential and limits of HCV-RNA as a therapeutic biomarker, and biomarkers that are expected now that DAA therapy has been developed.
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Affiliation(s)
- Yutaka Tsutsumi
- Department of Hematology, Hakodate Municipal Hospital, Hakodate, 1-10-1, Minato-cho, Hakodate 041-8680, Japan
| | - Shinichi Ito
- Department of Hematology, Hakodate Municipal Hospital, Hakodate, 1-10-1, Minato-cho, Hakodate 041-8680, Japan
| | - Souichi Shiratori
- Department of Hematology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan
| | - Takanori Teshima
- Department of Hematology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan
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Salari N, Kazeminia M, Hemati N, Ammari-Allahyari M, Mohammadi M, Shohaimi S. Global prevalence of hepatitis C in general population: A systematic review and meta-analysis. Travel Med Infect Dis 2022; 46:102255. [PMID: 35007756 DOI: 10.1016/j.tmaid.2022.102255] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Revised: 12/14/2021] [Accepted: 01/05/2022] [Indexed: 10/19/2022]
Abstract
BACKGROUND According to published reports from the World Health Organization, it is estimated that more than 3% of the world's population is infected with HCV. Given the impact of various factors on the prevalence of HCV in the world's population and the lack of general statistics around the world, this study aims to review the studies conducted in this field and statistical analysis of the results of general statistical studies on the prevalence of HCV in the world population. METHODS In this study, systematic review and meta-analysis of information of the studies related to the prevalence of HCV in the world using keywords including: Prevalence, HCV, Hepatitis C, Healthy Population, Healthy subjects, and General Population in SID, MagIran, IranMedex, IranDoc, ScienceDirect, Embase, Scopus, PubMed, Web of Science (WoS) databases and Google Scholar search engine were extracted without time limit until April 2020. In order to perform the analysis of qualified studies, the model of random effects was used, and the inconsistency of studies with I2 index was investigated. Data analysis was performed with Comprehensive Meta-Analysis (Version 2). RESULTS In a study of 98 studies with a total sample size of 236,964 people in the world, the overall prevalence of HCV was 1.8% (95% CI: 1.4%-2.3%). Also, according to the subgroup analysis in different continents; the highest prevalence of HCV in the African continent was 7.1% (95% CI: 4.4-11.5%). CONCLUSION The results of this study show that the prevalence of hepatitis C in the world's population, especially in Africa, is almost high. Therefore, the officials of the World Health Organization should design measures to prevent the spread of this infection.
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Affiliation(s)
- Nader Salari
- Department of Biostatistics, School of Health, Kermanshah University of Medical Sciences, Kermanshah, Iran.
| | - Mohsen Kazeminia
- Student Research Committee, Kermanshah University of Medical Sciences, Kermanshah, Iran.
| | - Niloufar Hemati
- Department of Internal Medicine, Faculty of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran.
| | | | - Masoud Mohammadi
- Cellular and Molecular Research Center, Gerash University of Medical Sciences, Gerash, Iran.
| | - Shamarina Shohaimi
- Department of Biology, Faculty of Science, University Putra Malaysia, Serdang, Selangor, Malaysia.
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3
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Mullen CJR, Volesky KD, Greenwald ZR, El-Zein M, Franco EL. Is Hodgkin Lymphoma Associated with Hepatitis B and C Viruses? A Systematic Review and Meta-analysis. Cancer Epidemiol Biomarkers Prev 2021; 30:2167-2175. [PMID: 34548328 DOI: 10.1158/1055-9965.epi-21-0548] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 07/19/2021] [Accepted: 09/09/2021] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Apart from the Epstein-Barr virus (EBV), the etiology of the hematologic malignancy Hodgkin lymphoma (HL) is not well defined. Hepatitis B virus (HBV) and hepatitis C virus (HCV) are associated with some lymphoproliferative diseases with similarities to HL. METHODS We performed a systematic review and meta-analysis, by searching Embase, MEDLINE, and Web of Science databases on March 9, 2021, for studies reporting a measure of association for HBV and HL or HCV and HL. We calculated pooled relative risks (RR) and their 95% confidence intervals (CI). RESULTS Pooling nine HBV studies with 1,762 HL cases yielded an RR of 1.39 (95% CI, 1.00-1.94) and pooling 15 HCV studies with 4,837 HL cases resulted in an RR of 1.09 (95% CI, 0.88-1.35). Meta-analyzing by study design, hepatitis detection method, and region revealed two subgroups with statistically significant associations-HCV studies that used hospital-based controls and/or were conducted in the West Pacific. No included study assessed age or EBV tumor status in relation to HL. CONCLUSIONS Although we did not find an association between HBV or HCV and HL, research assessing the impact of age and EBV tumor status was lacking. IMPACT The effect of HBV or HCV infection in the development of HL remains unclear.
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Affiliation(s)
- Callum J R Mullen
- Division of Cancer Epidemiology, McGill University, Montreal, Quebec, Canada.
| | - Karena D Volesky
- Division of Cancer Epidemiology, McGill University, Montreal, Quebec, Canada
| | - Zoë R Greenwald
- Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
| | - Mariam El-Zein
- Division of Cancer Epidemiology, McGill University, Montreal, Quebec, Canada
| | - Eduardo L Franco
- Division of Cancer Epidemiology, McGill University, Montreal, Quebec, Canada
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Alkrekshi A, Kassem A, Park C, Tse W. Risk of Non-Hodgkin's Lymphoma in HCV Patients in the United States Between 2013 and 2020: A Population-Based Study. CLINICAL LYMPHOMA MYELOMA & LEUKEMIA 2021; 21:e832-e838. [PMID: 34330674 DOI: 10.1016/j.clml.2021.06.014] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 06/09/2021] [Accepted: 06/19/2021] [Indexed: 12/11/2022]
Abstract
Hepatitis C virus (HCV) is a significant healthcare problem affecting ~1% of the United States population. Meta-analyses of epidemiological studies reported a strong association between non-Hodgkin's lymphoma (NHL) and HCV. Direct oncogenic properties of HCV proteins and chronic antigenic stimulation are possible etiologies. We explored if NHL's prevalence has changed since older HCV therapy based on interferon that shared antiviral and anti-lymphoma properties was replaced with interferon-free direct-acting antivirals (DAA). We reviewed data from a nationwide database (Explorys, IBM) that aggregates records from 26 health-care-systems. We identified patients with chronic hepatitis C infection between June 2013 and June 2020. The control group was gender, race, and age-matched HCV-negative population. Statistical analysis used the odds ratio (OR) with P value <.001 for significance. There were 940 cases of NHL of 129,970 patients in the HCV group versus 107,480 cases of NHL of 37,961,970 in the control cohort [OR 2.6, 95% confidence interval (CI) 2.4-2.7]. A positive association was present for chronic lymphocytic leukemia, follicular lymphoma, marginal zone lymphoma, lymphoplasmacytic lymphoma, diffuse large B-cell lymphoma, Burkitt's lymphoma, non-Hodgkin T-cell lymphoma, and primary cutaneous T-cell lymphoma. There were no differences in Mantle cell lymphoma. The increased risk of HCV-associated lymphoma was persistent across genders, Caucasians and African-Americans, and age groups. While the risk of NHL in the HCV-negative population was higher in Caucasians than African-Americans (OR 1.8, 95% CI 1.7-1.8), the risk of HCV-associated NHL was not different. Further prospective studies examining the risk of HCV-associated lymphoma following DAA are warranted.
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Affiliation(s)
- Akram Alkrekshi
- Department of Hematology and Oncology, The MetroHealth System campus of Case Western Reserve University, Cleveland, OH.
| | - Ahmad Kassem
- Department of Hematology and Oncology, The MetroHealth System campus of Case Western Reserve University, Cleveland, OH
| | - Changsu Park
- Department of Hematology and Oncology, The MetroHealth System campus of Case Western Reserve University, Cleveland, OH
| | - William Tse
- Department of Hematology and Oncology, The MetroHealth System campus of Case Western Reserve University, Cleveland, OH
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Kim H, Chung YK, Kim I. Recognition criteria for occupational cancers in relation to hepatitis B virus and hepatitis C virus in Korea. Ann Occup Environ Med 2018; 30:6. [PMID: 29423229 PMCID: PMC5791172 DOI: 10.1186/s40557-018-0217-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2017] [Accepted: 01/17/2018] [Indexed: 01/05/2023] Open
Abstract
The goal of this study was to review the scientific basis for the recognition of occupational cancer, in relation to hepatitis viral infections in Korea. Most Hepatitis B virus (HBV) infections in Korea occur as vertical infections, but these are decreasing rapidly due to vaccination. Hepatitis C virus (HCV) is known to be transmitted through parenteral routes, but the transmission route is often unclear. Most occupational infections of hepatitis virus involve accidental injuries of medical institution workers while using virus-contaminated medical devices. Many cohort studies and case-control studies have consistently reported that HBV and HCV infection increases the risk of hepatocellular carcinoma (HCC) and the strength of this association is high. Non-Hodgkin’s lymphoma appears to be associated with HCV. Cholangiocarcinoma, pancreatic cancer, leukemia, and thyroid cancer are considered to be less related or unrelated to epidemiological causation. There are no uniform international specific criteria for occupational cancer caused through occupational exposure to a hepatitis virus. In establishing appropriate standards applicable to Korea, there should be sufficient consideration of latency, virus exposure levels and frequency, and other cancers, apart from HCC. In conclusion, we recommend keeping the current specific criteria. However, if a worker is injured at work when using a sharp medical device, and HBV and HCV viral infections are confirmed through serologic tests; if the worker is diagnosed as having a chronic HBV or HCV infection, a subsequent HCC (or Non-Hodgkin’s lymphoma following chronic HCV infection) can then be considered highly related to the worker’s occupation.
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Affiliation(s)
- Hogil Kim
- 1Department of Occupational and Environmental Medicine, Hanyang University College of Medicine, 222-1, Wansimniro, Seongdonggu, Seoul, 04763 South Korea
| | | | - Inah Kim
- 1Department of Occupational and Environmental Medicine, Hanyang University College of Medicine, 222-1, Wansimniro, Seongdonggu, Seoul, 04763 South Korea
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Hepatitis C virus - Associated marginal zone lymphoma. Best Pract Res Clin Haematol 2017; 30:41-49. [PMID: 28288715 DOI: 10.1016/j.beha.2017.02.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2017] [Accepted: 02/06/2017] [Indexed: 12/18/2022]
Abstract
The link between hepatitis C virus (HCV) infection and the development of B-cell non-Hodgkin lymphoma is now well established and based on a number of epidemiological studies. It is further supported by the observation of lymphoma regression after HCV eradication by antiviral treatment. The far most frequent entities are marginal zone lymphoma (MZL) and diffuse large B-cell lymphoma (DLBCL). MZL usually emerge on a background of mixed cryoglobulinemia, a low-grade lymphoproliferation, and often transform into DLBCL, thereby following a multistep oncogenesis process. The role of HCV in lymphomagenesis is not yet fully understood but several mechanisms have been proposed including (i) chronic external stimulation through the B-cell receptor and other surface receptors, and (ii) direct transformation by intracellular viral proteins, the former being probably predominant in MZL. Regression of HCV-associated MZL can be achieved with antiviral therapy and the novel generation of direct-acting antiviral agents appears highly effective and safe for the treatment of these lymphoma.
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Fiorino S, Bacchi-Reggiani L, de Biase D, Fornelli A, Masetti M, Tura A, Grizzi F, Zanello M, Mastrangelo L, Lombardi R, Acquaviva G, di Tommaso L, Bondi A, Visani M, Sabbatani S, Pontoriero L, Fabbri C, Cuppini A, Pession A, Jovine E. Possible association between hepatitis C virus and malignancies different from hepatocellular carcinoma: A systematic review. World J Gastroenterol 2015; 21:12896-12953. [PMID: 26668515 PMCID: PMC4671046 DOI: 10.3748/wjg.v21.i45.12896] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2015] [Revised: 08/05/2015] [Accepted: 10/13/2015] [Indexed: 02/06/2023] Open
Abstract
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.
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8
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Khoury T, Chen S, Adar T, Jacob EO, Mizrahi M. Hepatitis C infection and lymphoproliferative disease: accidental comorbidities? World J Gastroenterol 2014; 20:16197-16202. [PMID: 25473174 PMCID: PMC4239508 DOI: 10.3748/wjg.v20.i43.16197] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2013] [Revised: 06/04/2014] [Accepted: 06/26/2014] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis C virus (HCV) infection has been associated with liver cancer and cirrhosis, autoimmune disorders such as thyroiditis and mixed cryoglobulinema, and alterations in immune function and chronic inflammation, both implicated in B cell lymphoproliferative diseases that may progress to non-Hodgkin lymphoma (NHL). HCV bound to B cell surface receptors can induce lymphoproliferation, leading to DNA mutations and/or lower antigen response thresholds. These findings and epidemiological reports suggest an association between HCV infection and NHL. We performed a systematic review of the literature to clarify this potential relationship. We searched the English-language literature utilizing Medline, Embase, Paper First, Web of Science, Google Scholar, and the Cochrane Database of Systematic Reviews, with search terms broadly defined to capture discussions of HCV and its relationship with NHL and/or lymphoproliferative diseases. References were screened to further identify relevant studies and literature in the basic sciences. A total of 62 reports discussing the relationship between HCV, NHL, and lymphoproliferative diseases were identified. Epidemiological studies suggest that at least a portion of NHL may be etiologically attributable to HCV, particularly in areas with high HCV prevalence. Studies that showed a lack of association between HCV infection and lymphoma may have been influenced by small sample size, short follow-up periods, and database limitations. The association appears strongest with the B-cell lymphomas relative to other lymphoproliferative diseases. Mechanisms by which chronic HCV infection promotes lymphoproliferative disease remains unclear. Lymphomagenesis is a multifactorial process involving genetic, environmental, and infectious factors. HCV most probably have a role in the lymphomagenesis but further study to clarify the association and underlying mechanisms is warranted.
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9
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Waldenström macroglobulinemia in hepatitis C: case report and review of the current literature. Case Rep Oncol Med 2014; 2014:165670. [PMID: 25247100 PMCID: PMC4163423 DOI: 10.1155/2014/165670] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2014] [Accepted: 08/12/2014] [Indexed: 12/16/2022] Open
Abstract
Background. Recent literature has associated hepatitis C virus with the development of non-Hodgkin lymphoma. Hepatitis C virus infection appears to promote lymphoproliferation, providing a plausible mechanism for a causative association; however, despite prior reports of patients with comorbid hepatitis C infection and Waldenström macroglobulinemia, the literature is in disagreement regarding whether there exists an association between these two conditions. Case Presentation. This case report describes a 57-year-old African-American male with chronic hepatitis C infection and cryoglobulinemia who presented with several episodes of transient confusion and paralysis and was found to have symptomatic hyperviscosity. The recognition of his condition was facilitated by characteristic findings on ophthalmologic examination. He was subsequently diagnosed with Waldenström macroglobulinemia on bone marrow biopsy. Conclusions. An up to date, comprehensive review of the literature suggests an association between hepatitis C and Waldenström macroglobulinemia. Data on optimal treatment of patients with comorbid hepatitis C infection and Waldenström macroglobulinemia is limited. We have provided a comprehensive review of previously explored treatment options to guide management of other similar patients. Our patient has since been treated with repeated plasmapheresis with a plan to pursue antiviral therapy.
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Younossi ZM, Kanwal F, Saab S, Brown KA, El-Serag HB, Kim WR, Ahmed A, Kugelmas M, Gordon SC. The impact of hepatitis C burden: an evidence-based approach. Aliment Pharmacol Ther 2014; 39:518-31. [PMID: 24461160 DOI: 10.1111/apt.12625] [Citation(s) in RCA: 81] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2013] [Revised: 10/11/2013] [Accepted: 12/30/2013] [Indexed: 12/08/2022]
Abstract
BACKGROUND Infection with the hepatitis C virus (HCV) has been considered a major cause of mortality, morbidity and resource utilisation in the US. In addition, HCV is the main cause of hepatocellular cancer (HCC) in the US. Recent developments in the diagnosis and treatment of HCV, including new recommendations pertaining to screening for HCV by the Centers for Disease Control and Prevention and newer treatment regimens with high efficacy, short duration and the potential for interferon-free therapies, have energised the health care practitioners regarding HCV management. AIM To assess the full impact of HCV burden on clinical, economic and patient-reported outcomes. METHODS An expert panel was convened to assess the full impact of HCV burden on a number of important outcomes using an evidence-based approach predicated on Grading of Recommendations Assessment, Development and Evaluation methodology. The literature was summarised, graded using an evidence-based approach and presented during the workshop. Workshop presentations were intended to review recent, relevant evidence-based literature and provide graded summary statements pertaining to HCV burden on topics including the relationships between HCV and the development of important outcomes. RESULTS The associations of HCV with cirrhosis, HCC, liver-related mortality, type 2 diabetes mellitus, rheumatological diseases and quality of life impairments are supported by strong evidence. Also, there is strong evidence that sustained viral eradication of HCV can improve important outcomes such as mortality and quality of life. CONCLUSIONS The current evidence suggests that HCV has been associated with tremendous clinical, economic and quality of life burden.
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Affiliation(s)
- Z M Younossi
- Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, VA, USA; Department of Medicine, Center for Liver Disease, Inova Fairfax Hospital, Falls Church, VA, USA
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Coskun A, Yukselen O, Yukselen V, Karaoglu AO. Lacrimal gland marginal zone lymphoma: regression after treatment of chronic hepatitis C virus infection: case report and review of the literature. Intern Med 2013; 52:2615-8. [PMID: 24292750 DOI: 10.2169/internalmedicine.52.0450] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
A 43-year-old woman was first admitted to the ophthalmology clinic with the complaint of a mass compressing the right eye. Based on clinical and laboratory examinations she was diagnosed as having marginal zone lymphoma (MZL) of the right lacrimal gland in addition to hepatitis C virus (HCV) infection. After the treatment for HCV infection with pegylated interferon plus ribavirin, a radiographic response of the MZL was obtained; she remains in remission through thirty months of clinical follow-up. In this case, the treatment of HCV infection led to regression of MZL suggesting the necessity of testing for HCV infection and treatment of the HCV infection should be highly considered in all HCV-positive patients with MZL's.
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Affiliation(s)
- Adil Coskun
- Department of Gastroenterology, Adnan Menderes University, School of Medicine, Turkey
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12
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Current understanding of lifestyle and environmental factors and risk of non-hodgkin lymphoma: an epidemiological update. J Cancer Epidemiol 2012; 2012:978930. [PMID: 23008714 PMCID: PMC3447374 DOI: 10.1155/2012/978930] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2012] [Revised: 07/20/2012] [Accepted: 08/04/2012] [Indexed: 01/07/2023] Open
Abstract
The incidence rates of non-Hodgkin lymphoma (NHL) have steadily increased over the last several decades in the United States, and the temporal trends in incidence can only be partially explained by the HIV epidemic. In 1992, an international workshop sponsored by the United States National Cancer Institute concluded that there was an “emerging epidemic” of NHL and emphasized the need to investigate the factors responsible for the increasing incidence of this disease. Over the past two decades, numerous epidemiological studies have examined the risk factors for NHL, particularly for putative environmental and lifestyle risk factors, and international consortia have been established in order to investigate rare exposures and NHL subtype-specific associations. While few consistent risk factors for NHL aside from immunosuppression and certain infectious agents have emerged, suggestive associations with several lifestyle and environmental factors have been reported in epidemiologic studies. Further, increasing evidence has suggested that the effects of these and other exposures may be limited to or stronger for particular NHL subtypes. This paper examines the progress that has been made over the last twenty years in elucidating the etiology of NHL, with a primary emphasis on lifestyle factors and environmental exposures.
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Teng CJ, Liu HT, Liu CY, Hsih CH, Pai JT, Gau JP, Liu JH, Chiou TJ, Hsu HC, Chen PM, Tzeng CH, Yu YB. Chronic hepatitis virus infection in patients with multiple myeloma: clinical characteristics and outcomes. Clinics (Sao Paulo) 2011; 66:2055-61. [PMID: 22189730 PMCID: PMC3226600 DOI: 10.1590/s1807-59322011001200010] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2011] [Accepted: 08/29/2011] [Indexed: 02/06/2023] Open
Abstract
OBJECTIVES Cytotoxic agents and steroids are used to treat lymphoid malignancies, but these compounds may exacerbate chronic viral hepatitis. For patients with multiple myeloma, the impact of preexisting hepatitis virus infection is unclear. The aim of this study is to explore the characteristics and outcomes of myeloma patients with chronic hepatitis virus infection. METHODS From 2003 to 2008, 155 myeloma patients were examined to determine their chronic hepatitis virus infection statuses using serologic tests for the hepatitis B (HBV) and C viruses (HCV). Clinical parameters and outcome variables were retrieved via a medical chart review. RESULTS The estimated prevalences of chronic HBV and HCV infections were 11.0% (n = 17) and 9.0% (n = 14), respectively. The characteristics of patients who were hepatitis virus carriers and those who were not were similar. However, carrier patients had a higher prevalence of conventional cytogenetic abnormalities (64.3% vs. 25.0%). The cumulative incidences of grade 3-4 elevation of the level of alanine transaminase, 30.0% vs. 12.0%, and hyperbilirubinemia, 20.0% vs. 1.6%, were higher in carriers as well. In a Kaplan-Meier analysis, carrier patients had worse overall survival (median: 16.0 vs. 42.4 months). The prognostic value of carrier status was not statistically significant in the multivariate analysis, but an age of more than 65 years old, the presence of cytogenetic abnormalities, a beta-2-microglobulin level of more than 3.5 mg/L, and a serum creatinine level of more than 2 mg/ dL were independent factors associated with poor prognosis. CONCLUSION Myeloma patients with chronic hepatitis virus infections might be a distinct subgroup, and close monitoring of hepatic adverse events should be mandatory.
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Affiliation(s)
- Chung-Jen Teng
- National Yang-Ming University Hospital, Department of Medicine, Division of Hematology and Oncology, Yilan, Taiwan, Republic of China
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Franceschi S, Lise M, Trépo C, Berthillon P, Chuang SC, Nieters A, Travis RC, Vermeulen R, Overvad K, Tjønneland A, Olsen A, Bergmann MM, Boeing H, Kaaks R, Becker N, Trichopoulou A, Lagiou P, Bamia C, Palli D, Sieri S, Panico S, Tumino R, Sacerdote C, Bueno-de-Mesquita B, Peeters PHM, Rodríguez L, Barroso LL, Dorronsoro M, Sánchez MJ, Navarro C, Barricarte A, Regnér S, Borgquist S, Melin B, Hallmans G, Khaw KT, Wareham N, Rinaldi S, Hainaut P, Riboli E, Vineis P. Infection with hepatitis B and C viruses and risk of lymphoid malignancies in the European Prospective Investigation into Cancer and Nutrition (EPIC). Cancer Epidemiol Biomarkers Prev 2011; 20:208-14. [PMID: 21098651 DOI: 10.1158/1055-9965.epi-10-0889] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Case-control studies suggested a moderate, but consistent, association of hepatitis C virus (HCV) infection with lymphoid tissue malignancies, especially non-Hodgkin lymphoma (NHL). More limited data suggested that hepatitis B virus (HBV) infection might also be associated with NHL. However, prospective studies on the topic are few. METHODS A nested case-control study was conducted in eight countries participating in the EPIC prospective study. Seven hundred thirty-nine incident cases of NHL, 238 multiple myeloma (MM), and 46 Hodgkin lymphoma (HL) were matched with 2,028 controls. Seropositivity to anti-HCV, anti-HBc, and HBsAg was evaluated and conditional logistic regression was used to estimate odds ratios (OR) and corresponding 95% confidence intervals (CI) for NHL, MM, or HL, and their combination. RESULTS Anti-HCV seropositivity among controls in different countries ranged from 0% to 5.3%; HBsAg from 0% to 2.7%; and anti-HBc from 1.9% to 45.9%. Similar nonsignificant associations were found with seropositivity to HBsAg for NHL (OR = 1.78; 95% CI: 0.78-4.04), MM (OR = 4.00; 95% CI: 1.00-16.0), and HL (OR = 2.00; 95% CI: 0.13-32.0). The association between HBsAg and the combination of NHL, MM, and HL (OR = 2.21; 95% CI: 1.12-4.33) was similar for cancer diagnosed less than 3 and 3 or more years after blood collection. No significant association was found between anti-HCV and NHL, MM, or HL risk, but the corresponding CIs were very broad. CONCLUSIONS Chronic HBV infection may increase the risk of lymphoid malignancies among healthy European volunteers. IMPACT Treatment directed at control of HBV infection should be evaluated in HBsAg-seropositive patients with lymphoid tissue malignancies.
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Affiliation(s)
- Silvia Franceschi
- International Agency for Research on Cancer, 150 cours Albert Thomas, 69372 Lyon, cedex 08, France.
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King E, Trabue C, Yin D, Yao ZQ, Moorman JP. Hepatitis C: the complications of immune dysfunction. Expert Rev Clin Immunol 2010; 3:145-57. [PMID: 20477104 DOI: 10.1586/1744666x.3.2.145] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Hepatitis C virus (HCV) infection has been linked to numerous diseases of immune dysfunction, including, but not limited to, essential mixed cryoglobulinemia and non-Hodgkin's lymphoma. Clinical studies support these associations and treatment of the underlying HCV infection has been variably successful. Recent studies, focusing on the role of HCV gene products, have discovered evidence of dysregulated responses in multiple aspects of host immunity that may be contributing to the genesis of these diseases. Novel treatments that target these areas of dysregulation offer hope for improved therapy for the diseases associated with immunodysregulation by HCV.
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Affiliation(s)
- Ellis King
- East Tennessee State University, Department of Internal Medicine, James H. Quillen College of Medicine, Box 70622, Johnson City, TN 37614, USA.
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Park SC, Jeong SH, Kim J, Han CJ, Kim YC, Choi KS, Cho JH, Lee M, Jung HH, Ki SS, Chang YH, Lee SS, Park YH, Lee KH. High prevalence of hepatitis B virus infection in patients with B-cell non-Hodgkin's lymphoma in Korea. J Med Virol 2008; 80:960-6. [PMID: 18428141 DOI: 10.1002/jmv.21168] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
This study assessed the association of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection with non-Hodgkin's lymphoma in a highly HBV-endemic area. The prevalence of either HBV or HCV infection in 235 patients with non-Hodgkin's lymphoma was compared with that of an age- and sex-matched hospital control group of 235 patients. The prevalence of HBV infection was higher in B-cell non-Hodgkin's lymphoma (15.5%) than control (8.1%), but the prevalence of HCV infection in the non-Hodgkin's lymphoma patients (2.1%) and control group (3%) was similar. HBV prevalence increased significantly with age in the B-cell non-Hodgkin's lymphoma patients. The presence of HBV proteins and DNA in lymphoma tissues and peripheral blood mononuclear cells (PBMCs) from HBV-infected non-Hodgkin's lymphoma patients was also investigated using immunohistochemistry and PCR. HBV DNA was frequently detected in PBMCs from HBV-infected non-Hodgkin's lymphoma patients, but HBV antigens were not. Therefore, HBV infection, but not HCV infection, was associated with B-cell non-Hodgkin's lymphoma in Korea, suggesting a possible role for HBV in the development of non-Hodgkin's lymphoma.
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Affiliation(s)
- Su Cheol Park
- Department of Internal Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Science, Seoul, South Korea
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Alexander DD, Mink PJ, Adami HO, Chang ET, Cole P, Mandel JS, Trichopoulos D. The non-Hodgkin lymphomas: a review of the epidemiologic literature. Int J Cancer 2007; 120 Suppl 12:1-39. [PMID: 17405121 DOI: 10.1002/ijc.22719] [Citation(s) in RCA: 259] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The non-Hodgkin lymphomas (NHL) are a heterogeneous group of B-cell and T-cell neoplasms that arise primarily in the lymph nodes. NHL incidence rates in the US doubled between about 1970 and 1990, and stabilized during the 1990s. NHL accounts for approximately 3.4% of cancer deaths in the US. Although some of the observed patterns in NHL have been related to HIV/AIDS, these conditions cannot fully explain the magnitude of the changes; neither do changes in classification systems nor improved diagnostic capabilities. Studies of occupational and environmental exposures (e.g., pesticides, solvents) have produced no consistent pattern of significant positive associations. Inverse associations with ultraviolet radiation exposure and alcohol and fish intake, and positive associations with meat and saturated fat intake have been reported in several studies; additional studies are needed to confirm or refute these associations. Family history of NHL or other hematolympho-proliferative cancers and personal history of several autoimmune disorders are associated with increased risk of NHL, but are not likely to account for a large proportion of cases. HIV and other infectious agents, such as human herpesvirus 8 and Epstein-Barr, appear to be associated with differing types of NHL, such as some B-cell lymphomas. Future epidemiologic studies should evaluate associations by NHL type, enhance exposure information collected, and elucidate factors that may identify susceptible (or resistant) subpopulations because of genetic, immunologic or other characteristics. The extent to which the etiology of NHL types may differ is important to resolve in ongoing and future studies.
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18
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Dal Maso L, Franceschi S. Hepatitis C virus and risk of lymphoma and other lymphoid neoplasms: a meta-analysis of epidemiologic studies. Cancer Epidemiol Biomarkers Prev 2007; 15:2078-85. [PMID: 17119031 DOI: 10.1158/1055-9965.epi-06-0308] [Citation(s) in RCA: 216] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
The present meta-analysis was conducted to evaluate the strength and the consistency of the association between hepatitis C virus (HCV) infection and non-Hodgkin lymphoma (NHL) and other lymphoid neoplasms. Only studies with >or=100 cases which were also adjusted for sex and age were included. Fifteen case-control studies and three prospective studies contributed to present analysis, nine of which had not been included in previous meta-analyses. We calculated the pooled relative risks (RR) with corresponding 95% confidence intervals (95% CI), as a weighted average of the estimated RRs by random-effect models. The pooled RR of all NHL among HCV-positive individuals was 2.5 (95% CI, 2.1-3.0), but substantial heterogeneity was found between studies and by study design. Pooled RRs were 2.5 (95% CI, 2.1-3.1) in case-control studies and 2.0 (95% CI, 1.8-2.2) in cohort ones. The strongest source of heterogeneity seemed to be the prevalence of HCV among NHL-free study subjects (RR for NHL among HCV-positive individuals 3.0 and 1.9, respectively, for >or=5% and <5% HCV prevalence). RRs were consistently increased for all major B-NHL subtypes, T-NHL, and primary sites of NHL presentation. Thus, previous suggestions that the RRs for HCV differed by NHL subtype were not confirmed in our meta-analysis. Associations weaker than with NHL were found between HCV infection and Hodgkin's lymphoma (RR, 1.5; 95% CI, 1.0-2.1) and multiple myeloma (RR, 1.6; 95% CI, 0.7-3.6), but they were based on much fewer studies than NHL. The etiologic fraction of NHL attributable to HCV varies greatly by country, and may be upward of 10% in areas where HCV prevalence is high.
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Affiliation(s)
- Luigino Dal Maso
- Epidemiology and Biostatistics Unit, Centro di Riferimento Oncologico, IRCCS, Via Pedemontana occidentale 12, 33081 Aviano PN, Italy.
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19
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Ramos-Casals M, la Civita L, de Vita S, Solans R, Luppi M, Medina F, Caramaschi P, Fadda P, de Marchi G, Lopez-Guillermo A, Font J. Characterization of B cell lymphoma in patients with Sjögren's syndrome and hepatitis C virus infection. ARTHRITIS AND RHEUMATISM 2007; 57:161-170. [PMID: 17266090 DOI: 10.1002/art.22476] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
OBJECTIVE To characterize the clinical and immunologic patterns of expression, response to therapy, and outcome of patients with Sjögren's syndrome (SS) and associated hepatitis C virus (HCV) infection who developed B cell lymphoma. METHODS Various international reference centers constituted a multicenter study group with the purpose of creating a registry of patients with SS-HCV who developed B cell lymphoma. A protocol form was used to record the main characteristics of SS, chronic HCV infection, and B cell lymphoma. RESULTS Twenty-five patients with SS-HCV with B cell lymphoma were included in the registry. There were 22 (88%) women and 3 (12%) men (mean age 55, 58, and 61 years at SS, HCV infection, and lymphoma diagnosis, respectively). The main extraglandular SS manifestations were cutaneous vasculitis in 15 (60%) patients and peripheral neuropathy in 12 (48%); the main immunologic features were positive rheumatoid factor (RF) in 24 (96%) and type II cryoglobulins in 20 (80%). The main histologic subtypes were mucosa-associated lymphoid tissue (MALT) lymphoma in 11 (44%) patients, diffuse large B cell lymphoma in 6 (24%), and follicular center cell lymphoma in 6 (24%). Fifteen (60%) patients had an extranodal primary location, most frequently in the parotid gland (5 patients), liver (4 patients), and stomach (4 patients). Twelve (52%) of 23 patients died after a median followup from the time of lymphoma diagnosis of 4 years, with lymphoma progression being the most frequent cause of death. Survival differed significantly between the main types of B cell lymphoma. CONCLUSION Patients with SS-HCV and B cell lymphoma are clinically characterized by a high frequency of parotid enlargement and vasculitis, an immunologic pattern overwhelmingly dominated by the presence of RF and mixed type II cryoglobulins, a predominance of MALT lymphomas, and an elevated frequency of primary extranodal involvement in organs in which HCV replicates (exocrine glands, liver, and stomach).
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Affiliation(s)
- Manuel Ramos-Casals
- Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, School of Medicine, University of Barcelona, Barcelona, Spain.
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20
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Zignego AL, Ferri C, Pileri SA, Caini P, Bianchi FB. Extrahepatic manifestations of Hepatitis C Virus infection: a general overview and guidelines for a clinical approach. Dig Liver Dis 2007; 39:2-17. [PMID: 16884964 DOI: 10.1016/j.dld.2006.06.008] [Citation(s) in RCA: 181] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2005] [Revised: 06/03/2006] [Accepted: 06/06/2006] [Indexed: 02/08/2023]
Abstract
Hepatitis C Virus is associated with a wide series of extrahepatic manifestations. Based on available data the link between the virus and some of these extrahepatic diseases is only suggested and needs further confirmation. Hepatitis C Virus-related lymphoproliferative disorders, whose prototype is mixed cryoglobulinaemia, represent the most closely related extrahepatic manifestations of Hepatitis C Virus. Other Hepatitis C Virus-associated disorders include nephropathies, thyreopathies, sicca syndrome, idiopathic pulmonary fibrosis, porphyria cutanea tarda, lichen planus, diabetes, chronic polyarthritis, cardiopathy and atherosclerosis. A pathogenetic link between Hepatitis C Virus and some extrahepatic manifestations was confirmed by their responsiveness to antiviral therapy, which is now deemed the first therapeutic option to consider. By contrast, there are diseases where treatment with interferon was ineffective or dangerous. The aim of the present paper is to outline the most recent evidence concerning extrahepatic disorders that are possibly associated with Hepatitis C Virus infection. Special emphasis will be given to discussion of the most appropriate clinical approaches to be adopted in order to diagnose, treat (possibly prevent) and follow-up extrahepathic diseases in patients with Hepatitis C Virus infection.
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Affiliation(s)
- A L Zignego
- Department of Internal Medicine, Medical School, Center for Research, Transfer and High Education DENOthe, Center for the Study of Systemic Manifestations of Hepatitis Viruses MaSVE, University of Florence, Florence, Italy.
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21
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Nieters A, Kallinowski B, Brennan P, Ott M, Maynadié M, Benavente Y, Foretova L, Cocco PL, Staines A, Vornanen M, Whitby D, Boffetta P, Becker N, De Sanjosé S. Hepatitis C and risk of lymphoma: results of the European multicenter case-control study EPILYMPH. Gastroenterology 2006; 131:1879-86. [PMID: 17087949 DOI: 10.1053/j.gastro.2006.09.019] [Citation(s) in RCA: 115] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2006] [Accepted: 09/07/2006] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS Increasing evidence points toward a role of hepatitis C virus (HCV) infection in the etiology of malignant lymphomas. However, previous epidemiologic studies were limited in size to establish an association between HCV infection and specific lymphoma subtypes. We performed a large, multicenter, case-control study to address this question. METHODS The study comprised 5 European countries and included newly diagnosed cases of any lymphoid malignancy recruited between 1998 and 2004. Controls were matched to cases by 5-year age group, sex, and study center. In-person interviews were conducted to collect data on demographic, medical, and family history as well as environmental exposures. Serum samples of 1807 cases and 1788 controls (excluding human immunodeficiency virus-positive and organ-transplantation subjects) were screened for HCV infection using an enzyme immunoassay. Positive as well as randomly selected negative samples were subjected to HCV RNA detection and HCV genotyping. RESULTS HCV infection was detected in 53 (2.9%) lymphoma cases and in 41 (2.3%) control subjects (odds ratio [OR], 1.42; 95% confidence interval [CI]: 0.93-2.15). Restricted to individuals who tested positive for HCV-RNA (indicating persistent infection and active viral replication), the OR was 1.82 (95% CI: 1.13-2.91). In subtype-specific analyses, HCV prevalence was associated with diffuse large B-cell lymphoma (OR, 2.19; 95% CI: 1.23-3.91) but not with chronic lymphocytic leukemia or follicular, Hodgkin's, or T-cell lymphoma. The sample size was not sufficient to derive any conclusions for rare lymphoma entities such as splenic marginal zone lymphoma. CONCLUSIONS These results support a model that chronic HCV replication contributes to lymphomagenesis and establish a specific role of HCV infection in the pathogenesis of diffuse large B-cell lymphoma.
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22
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Visco C, Arcaini L, Brusamolino E, Burcheri S, Ambrosetti A, Merli M, Bonoldi E, Chilosi M, Viglio A, Lazzarino M, Pizzolo G, Rodeghiero F. Distinctive natural history in hepatitis C virus positive diffuse large B-cell lymphoma: analysis of 156 patients from northern Italy. Ann Oncol 2006; 17:1434-40. [PMID: 16766591 DOI: 10.1093/annonc/mdl131] [Citation(s) in RCA: 76] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Diffuse large B-cell lymphoma (DLBCL) has been correlated to hepatitis C virus (HCV) infection in few series, but characteristics and outcome of these patients remain undefined. PATIENTS AND METHODS We analyzed 156 previously untreated consecutive HCV-positive patients with DLBCL observed between 1994 and 2004 in three major institutions from northern Italy. RESULTS Median age at presentation was 63 years and 8% of patients had DLBCL transformed from low-grade lymphomas. Spleen was the most frequently involved extranodal site, followed by liver and stomach. Treatment was delivered with cure-intent in 132 patients, while the remaining 24 patients received monochemotherapy or radiotherapy alone due to old age or seriously impaired hepatic function. Only five patients (4%) had to discontinue chemotherapy due to severe liver function impairment. The addition of rituximab did not seem to affect patients' tolerance to treatment. Five-year overall survival of the entire cohort was 72%, while 5-year progression-free survival (PFS) of the 132 patients treated with cure-intent was 51%. Hepatitis B virus co-infection, advanced Ann Arbor stage and nodal origin of the tumor resulted the strongest adverse prognostic factors. CONCLUSIONS Patients with HCV-positive DLBCL share distinctive clinical features. Future studies should prospectively evaluate the association between HCV and aggressive lymphomas.
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Affiliation(s)
- C Visco
- Department of Hematology, Ospedale S. Bortolo, Vicenza, Italy.
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Caillard S, Agodoa LY, Bohen EM, Abbott KC. Myeloma, Hodgkin disease, and lymphoid leukemia after renal transplantation: characteristics, risk factors and prognosis. Transplantation 2006; 81:888-95. [PMID: 16570013 DOI: 10.1097/01.tp.0000203554.54242.56] [Citation(s) in RCA: 74] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Hodgkin disease and myeloma were recently included in the classification of posttransplant lymphoproliferative disorder (PTLD). However, because their incidence is low, not much is known about their particular features. METHODS The incidence, characteristics, risk, and prognostic factors of myeloma, Hodgkin disease, and lymphoid leukemia using the United States Renal Data System from 1991 to 2000 among 66,159 Medicare patients were analyzed. RESULTS In all, 1,169 recipients developed a lymphoid disease: 823 (1.2%) non-Hodgkin's lymphomas (NHL), 160 (0.24%) myelomas, 60 (0.1%) Hodgkin lymphomas, and 126 (0.2%) lymphoid leukemias. Older age was associated with an increased risk of myeloma and leukemia. The incidence of hepatitis C virus infection was higher in recipients with myeloma (6.9 vs. 3.9%, P=0.05). Induction therapy was associated with a greater risk of myeloma and leukemia, but not Hodgkin disease. Azathioprine was associated with a lower risk of myeloma, and tacrolimus with a lower risk of Hodgkin disease. According to the type of malignancy, ten-year survival rates were significantly different: 42, 26, 55 and 39% respectively for NHL, myeloma, Hodgkin disease, and leukemia. CONCLUSION These results support specific features and risk factors related to the occurrence of each type of lymphoid-proliferation and suggest for the first time a possible association between hepatitis C virus and myeloma in kidney transplant recipients.
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Affiliation(s)
- Sophie Caillard
- Nephrology Service, Walter Reed Army Medical Center, Washington, DC 20307, USA
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24
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Lakatos PL, Fekete S, Horanyi M, Fischer S, Abonyi ME. Development of multiple myeloma in a patient with chronic hepatitis C: A case report and review of the literature. World J Gastroenterol 2006; 12:2297-2300. [PMID: 16610042 PMCID: PMC4087667 DOI: 10.3748/wjg.v12.i14.2297] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2005] [Revised: 10/19/2005] [Accepted: 11/10/2005] [Indexed: 02/06/2023] Open
Abstract
An association between chronic hepatitis C virus (HCV) infection and essential mixed cryoglobulinaemia and non-Hodgkin lymphoma (NHL) has been suggested. However, a causative role of HCV in these conditions has not been established. The authors report a case of a 50 year-old woman with chronic hepatitis C (CHC) who has been followed up since 1998 due to a high viral load, genotype 1b and moderately elevated liver function tests (LFTs). Laboratory data and liver biopsy revealed moderate activity (grade: 5/18, stage: 1/6). In April 1999, one-year interferon therapy was started. HCV-RNA became negative with normalization of LFTs. However, the patient relapsed during treatment. In September 2002, the patient was admitted for chronic back pain. A CT examination demonstrated degenerative changes. In March 2003, multiple myeloma was diagnosed (IgG-kappa, bone ma-rrow biopsy: 50% plasma cell infiltration). MRI revealed a compression fracture of the 5th lumbar vertebral body and an abdominal mass in the right lower quadrant, infiltrating the canalis spinalis. Treatment with vincristine, adriamycin and dexamethasone (VAD) was started and bisphosphonate was administered regularly. In January 2004, after six cycles of VAD therapy, the multiple myeloma regressed. Thalidomide, as a second line treatment of refractory multiple myeloma (MM) was initiated, and followed by peginterferon-alpha2b and ribavirin against the HCV infection in June. In June 2005, LFTs returned to normal, while HCV-RNA was negative, demonstrating an end of treatment response. Although a pathogenic role of HCV infection in malignant lymphoproliferative disorders has not been established, NHL and possibly MM may develop in CHC patients, supporting a role of a complex follow-up in these patients.
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Affiliation(s)
- Peter Laszlo Lakatos
- 1st Department of Medicine, Semmelweis University, Koranyi str. 2/A, H-1083, Hungary.
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Abstract
Non-Hodgkin lymphoma (NHL) includes a group of more than 20 different malignant lymphoproliferative diseases that originate from lymphocytes. Rates of NHL have increased dramatically over the past few decades, although the rate of increase has recently slowed. It is now the sixth most common cancer in Australia. Globally, it is somewhat more common in men than in women, and rates are highest in North America and Australia. The causes of the increase in NHL rates are largely unknown. The best described risk factor for NHL is immune deficiency; rates of NHL are greatly increased, with relative risks of 10-100 or more, in people with immune deficiency associated with immune suppressive therapy after transplantation, HIV/AIDS, and congenital conditions. In addition, some NHL subtypes are associated with specific infections. These include immune-deficiency-associated central nervous system NHL (Epstein-Barr virus); gastric mucosa-associated lymphoid tissue NHL (Helicobacter pylori); adult T-cell leukemia/lymphoma (human T-lymphotrophic virus type 1) and body cavity-based lymphoma (human herpesvirus 8). However, these specific infections account for a very small proportion of total NHL incidence. In addition to immune deficiency and infection, other immune-related conditions are increasingly being recognised as related to NHL risk. Specific autoimmune conditions, including rheumatoid arthritis, systemic lupus erythema, Sjogren's syndrome, psoriasis and coeliac disease are associated with moderately increased risk of NHL. On the other hand, allergic and atopic conditions and their correlates such as early birth order, appear to be associated with a decreased risk of NHL.A variety of other exposures are less strongly related to NHL risk. These include occupational exposures, including some pesticides, herbicides, and solvents. Recently, two studies have reported that sun exposure is associated with a decreased risk of NHL. Smoking appears to be weakly positively associated with risk of follicular NHL, and alcohol intake is associated with a decreased risk of NHL. The pooled analysis of several case-control studies of NHL risk that are currently in the field promises to help clarify which of these risk factors are real, and will contribute to the elucidation of the mechanisms of how disorders of the immune system, and other factors, are related to NHL risk.
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Affiliation(s)
- Andrew E Grulich
- HIV Epidemiology and Prevention Program, National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Darlinghurst, NSW, Australia.
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Abstract
The aetiology of lymphomas is poorly understood and the striking increase in its incidence rate in developed societies remains unexplained. The concept of lymphoma as a virally-induced malignancy is not surprising since viruses are implicated in approximately 15% of all cancers. However, lymphoma represents a complex multistep process and, although viral associations have been identified, integration of the available epidemiological and scientific data poses substantial questions. The study of oncogenic viruses has and will continue to yield major insights into the pathogenesis of lymphoma. Further research is likely to uncover new lymphoma associations between both known and as yet unidentified viruses, may provide cellular and pharmacological targeted antiviral therapy strategies for the treatment of malignant lymphoma, and ultimately may generate the most promising avenue for lymphoma prevention.
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Affiliation(s)
- Maher K Gandhi
- Tumour Immunology Laboratory, Queensland Institute of Medical Research, Brisbane, Australia.
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Abstract
Chronic hepatitis C virus (HCV) infection is frequently associated with a number of extrahepatic complications. In the majority of cases the underlying pathogenetic mechanisms are immune mediated, as evidenced by the presence of circulating autoantibodies (mixed cryoglobulinemia), whereas for others a localized host cellular immune response is implicated (e.g. sialadenitis, lichen planus). In this review, the latest data on the pathogenesis and clinical manifestations of the most common autoimmune extrahepatic manifestations of chronic HCV infection are presented.
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Affiliation(s)
- Dimitrios Vassilopoulos
- Academic Department of Medicine, Athens University School of Medicine, Hippokration General Hospital, Athens, Greece
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28
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Affiliation(s)
- Michael Nalesnik
- Division of Transplant Pathology, University of Pittsburgh, Pittsburgh, PA
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Vallisa D, Bernuzzi P, Arcaini L, Sacchi S, Callea V, Marasca R, Lazzaro A, Trabacchi E, Anselmi E, Arcari AL, Moroni C, Bertè R, Lazzarino M, Cavanna L. Role of anti-hepatitis C virus (HCV) treatment in HCV-related, low-grade, B-cell, non-Hodgkin's lymphoma: a multicenter Italian experience. J Clin Oncol 2005; 23:468-73. [PMID: 15659492 DOI: 10.1200/jco.2005.06.008] [Citation(s) in RCA: 192] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
PURPOSE Hepatitis C virus (HCV) is endemic in some areas of Northwestern Europe and the United States. HCV has been shown to play a role in the development of both hepatocellular carcinoma and B-cell non-Hodgkin's lymphoma (B-NHL). The biologic mechanisms underlying the lymphomagenic activity of the virus so far are under investigation. In this study, the role of antiviral (anti-HCV) treatment in B-NHL associated with HCV infection is evaluated. PATIENTS AND METHODS Thirteen patients with histologically proven low-grade B-NHL characterized by an indolent course (ie, doubling time no less than 1 year, no bulky disease) and carrying HCV infection were enrolled on the study. All patients underwent antiviral treatment alone with pegilated interferon and ribavirin. Response assessment took place at 6 and 12 months. RESULTS Of the twelve assessable patients, seven (58%) achieved complete response and two (16%) partial hematologic response at 14.1 +/- 9.7 months (range, 2 to 24 months, median follow-up, 14 months), while two had stable disease with only one patient experiencing progression of disease. Hematologic responses (complete and partial, 75%) were highly significantly associated to clearance or decrease in serum HCV viral load following treatment (P = .005). Virologic response was more likely to be seen in HCV genotype 2 (P = .035), while hematologic response did not correlate with the viral genotype. Treatment-related toxicity did not cause discontinuation of therapy in all but two patients, one of whom, however, achieved complete response. CONCLUSION This experience strongly provides a role for antiviral treatment in patients affected by HCV-related, low-grade, B-cell NHL.
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Affiliation(s)
- Daniele Vallisa
- Department of Oncology and Hematology, G. da Saliceto Hospital, Piacenza, Via Taverna 49, 29100 Piacenza, Italy.
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30
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Vallat L, Benhamou Y, Gutierrez M, Ghillani P, Hercher C, Thibault V, Charlotte F, Piette JC, Poynard T, Merle-Béral H, Davi F, Cacoub P. Clonal B cell populations in the blood and liver of patients with chronic hepatitis C virus infection. ACTA ACUST UNITED AC 2004; 50:3668-78. [PMID: 15529359 DOI: 10.1002/art.20594] [Citation(s) in RCA: 78] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
OBJECTIVE The association of hepatitis C virus (HCV) infection with type II mixed cryoglobulinemia is well established, but the role of HCV in B cell lymphoma remains controversial. The objective of this study was to determine the frequency of circulating and liver-infiltrating monoclonal B cells in patients with HCV infection. METHODS One hundred sixty patients were studied prospectively, including 115 HCV-positive patients and 45 HCV-negative patients with other nonimmune chronic liver disease(s). B cell clonality was determined by DNA amplification of the IgH rearrangements, followed by polyacrylamide gel electrophoresis. RESULTS A clonal B cell population was detected in the blood of 21 (26%) of 81 HCV-positive patients whose cryoglobulin status was known, including 12 of 25 patients with type II cryoglobulinemia, 2 of 12 patients with type III cryoglobulinemia, and 7 of 44 patients without cryoglobulins. A clonal IgH rearrangement was detected in 26 (32%) of 81 liver biopsy specimens from HCV- infected patients, including 16 patients with a circulating clonal population. A clonal B cell population was not observed in the blood of 40 patients with non-HCV liver diseases and was present in only 1 (3%) of 30 liver biopsy specimens. Logistic regression analysis showed that HCV-infected patients with clonal B cell proliferation in both the blood and liver were older (P = 0.004) and had longer duration of HCV infection (P = 0.009), higher serum cryoglobulin levels (P = 0.001) that were more frequently symptomatic (P < 0.03), and liver disease that was more severe than that in patients without a clonal B cell population in the blood or liver (P = 0.05). In 4 of 16 patients with a clonal B cell population in both the blood and liver, a definite B cell malignancy was finally diagnosed. CONCLUSION Clonal B lymphocytes are frequently detected in the blood and liver of patients with chronic HCV infection, in the absence of overt B cell malignancy. These clones are usually, but not always, associated with the presence of type II cryoglobulins. A high percentage of patients with B cell clonality in both the blood and liver were finally diagnosed as having a definite B cell malignancy.
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Affiliation(s)
- Laurent Vallat
- Department of Hematology, Assistance Publique Hopitaux, Hôpital La Pitié-Salpêtrière, 83 Boulevard de l'Hôpital, 75651 Paris Cedex 13, France
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31
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Abstract
The hepatitis C virus (HCV) infection is a worldwide disease that is characterized by a preferential chronic evolution with mild to severe liver disease, including cirrhosis and, in lesser proportion, hepatocarcinoma. Out of these complications, HCV is frequently reported to complicate extrahepatic manifestations. Among those associated to HCV infection with a high degree of certainty, mixed cryoglobulinemia and its complications (skin, neurological, renal, rheumatological involvement) are the most prevalent (50%) in HCV-infected patients. The other diseases include noncryoglobulinemic systemic vasculitis, splenic lymphoma with villous lymphocytes, fatigue, porphyria cutanea tarda, sicca syndrome, and autoantibodies production. The extrahepatic manifestations that share mild-degree certainty of association with HCV infection include B-cell non-Hodgkin lymphoma, autoimmune thrombocytopenia, pruritus, and type II diabetes mellitus. The other diseases such as autoimmune thyroiditis, lichen planus are more questionable for their eventual association with HCV and others (pulmonary fibrosis with or without polymyositis, progressive encephalomyelitis, Mooren's corneal ulcers, erythema nodosum, chronic polyradiculonevritis) are mostly case reports. Howerver, even in cases of tight association, the mechanisms through which HCV may promote or induce extrahepatic manifestations remain unclear and merit further investigations.
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Affiliation(s)
- Damien Sène
- Department of Internal Medicine, Boulevard de l'hôpital, Paris, France
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32
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Sève P, Renaudier P, Sasco AJ, Dumontet C, Salles G, Coiffier B, Zoulim F, Broussolle C, Trépo C. Hepatitis C virus infection and B-cell non-Hodgkin's lymphoma: a cross-sectional study in Lyon, France. Eur J Gastroenterol Hepatol 2004; 16:1361-5. [PMID: 15618846 DOI: 10.1097/00042737-200412000-00021] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVES The role of hepatitis C virus (HCV) infection in the pathogenesis of non-Hodgkin's lymphoma (NHL) is controversial. A high prevalence of HCV infection in patients with NHL has been reported in Italy and Japan. By contrast, several studies in Northern Europe and Canada have not found any increased prevalence of HCV in B-cell NHL, suggesting a possible geographic variation. We sought to determine whether such an association could be found in patients treated in the Rhone-Alpes region in south-east France. Our main interest was to identify histological subtypes preferentially linked to HCV. METHODS We determined the prevalence of anti-HCV antibodies in 212 consecutive patients with B-cell NHL diagnosed in our institution between January 1997 and December 1998. The comparison group comprised 974 patients tested for HCV before transfusion at the same hospital during the same period. RESULTS Anti-HCV antibodies were found in six (2.8%) NHL patients. The distribution by histopathological category was as follows: three gastric mucosa-associated lymphoid tissue (MALT) lymphomas, one marginal lymphoma and two diffuse large-cell lymphomas. Anti-HCV antibodies were found in 20 (2%) of 974 comparison patients. Overall, there was a positive but non-significant trend towards an association between NHL and HCV infection (odds ratio 1.31; 95% confidence interval 0.51-3.36). However, the prevalence of HCV antibodies was significantly higher in MALT lymphoma patients than in the comparison group (odds ratio 9.87; 95% confidence interval 2.59-37.69). CONCLUSIONS To our knowledge, this is the first French study to show an association between HCV and MALT lymphoma. These results, although derived from a small number of patients, suggest a possible role of HCV in gastric MALT lymphomagenesis.
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MESH Headings
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Antibodies, Viral/analysis
- Biomarkers/analysis
- Cross-Sectional Studies
- Female
- France/epidemiology
- Gastric Mucosa
- Genotype
- Hepatitis C/complications
- Hepatitis C/epidemiology
- Hepatitis C/pathology
- Humans
- Lymphoma, B-Cell/epidemiology
- Lymphoma, B-Cell/etiology
- Lymphoma, B-Cell/pathology
- Lymphoma, B-Cell, Marginal Zone/epidemiology
- Lymphoma, B-Cell, Marginal Zone/etiology
- Lymphoma, B-Cell, Marginal Zone/pathology
- Male
- Middle Aged
- Prevalence
- Sex Distribution
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Affiliation(s)
- Pascal Sève
- Department of Internal Medicine, Lyon Civil Hospices, Lyon, France
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33
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Luppi M, Barozzi P, Potenza L, Riva G, Morselli M, Torelli G. Is it now the time to update treatment protocols for lymphomas with new anti-virus systems? Leukemia 2004; 18:1572-5. [PMID: 15284857 DOI: 10.1038/sj.leu.2403447] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- M Luppi
- Department of Oncology and Haematology, University of Modena and Reggio Emilia, Modena, Italy.
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34
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Kelaidi C, Rollot F, Park S, Tulliez M, Christoforov B, Calmus Y, Podevin P, Bouscary D, Sogni P, Blanche P, Dreyfus F. Response to antiviral treatment in hepatitis C virus-associated marginal zone lymphomas. Leukemia 2004; 18:1711-6. [PMID: 15284859 DOI: 10.1038/sj.leu.2403443] [Citation(s) in RCA: 85] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
A link between chronic hepatitis C virus (HCV) infection and low-grade B-cell lymphomas has been suggested by epidemiological studies. Marginal zone lymphomas (MZLs) including splenic lymphomas with villous lymphocytes are among the most frequently reported subgroups in the setting of chronic HCV infection. In this study, we examined the effect of antiviral treatment in eight patients with HCV-associated MZL. We found that five out of eight patients have responded to interferon alpha and ribavirin. In some cases, hematologic responses were correlated to virologic responses. In addition, we report a case of large granular lymphocyte leukemia occurring in association with MZL and HCV, and responding to interferon and ribavirin. We suggest that there is an etiologic link between HCV and antigen-driven lymphoproliferative disorders.
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Affiliation(s)
- C Kelaidi
- 1Department of Hematology, Hôpital Cochin, Université Paris V, Assistance Publique Hôpitaux de Paris, Paris, France
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35
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Müller AMS, Ihorst G, Mertelsmann R, Engelhardt M. Epidemiology of non-Hodgkin's lymphoma (NHL): trends, geographic distribution, and etiology. Ann Hematol 2004; 84:1-12. [PMID: 15480663 DOI: 10.1007/s00277-004-0939-7] [Citation(s) in RCA: 349] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2004] [Accepted: 08/05/2004] [Indexed: 12/14/2022]
Abstract
While for most cancers incidence and mortality are decreasing, those of non-Hodgkin's lymphoma (NHL) are steadily increasing. Research to define reasons for this increase is extensive, but has not yet resolved them. We have conducted a literature analysis on trends regarding changes in the incidence, geographic distribution, and etiologic factors of NHL. From our own and previous analyses, an increasing NHL incidence at a rate of 3-4% per year was observed for the 1970s and 1980s. This stabilized in the 1990s, nevertheless still with an annual rise of 1-2%, resulting in almost a doubling of the NHL incidence. This rise has been noted worldwide, particularly in elderly persons >55 years. Concerning gender subgroups, a male predominance throughout all age groups is apparent. Although the NHL incidence has historically been higher in whites than blacks, disproportional increases have recently been observed in the latter group. Increases in high-grade NHL and extranodal disease are predominant. Differences in geographic distribution are striking for follicular lymphoma, which is more common in Western countries than elsewhere. Asians have higher rates of aggressive NHL, T-cell lymphomas, and extranodal disease. In the Middle East, high rates of intestinal extranodal disease are observed, whereas in Africa, endemic Burkitt's lymphoma accounts for a substantial proportion. Risks for developing NHL include immunosuppression and a causal link between infectious agents, and lymphomagenesis has also been determined, particularly for human T-cell leukemia/lymphoma virus type 1 (HTLV-1), Epstein-Barr virus (EBV), and Helicobacter pylori infections. Exposure to environmental agents and occupational risks have been studied; however, their significance is as yet uncertain.
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Affiliation(s)
- Antonia M S Müller
- Hematology and Oncology Department, University of Freiburg Medical Hospital, Hugstetterstr. 55, 79106 Freiburg, Germany
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36
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Sasso EH, Martinez M, Yarfitz SL, Ghillani P, Musset L, Piette JC, Cacoub P. Frequent joining of Bcl-2 to a JH6 gene in hepatitis C virus-associated t(14;18). THE JOURNAL OF IMMUNOLOGY 2004; 173:3549-56. [PMID: 15322220 DOI: 10.4049/jimmunol.173.5.3549] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
The t(14;18) chromosomal translocation, which joins the Bcl-2 proto-oncogene to an Ig J(H) gene, has increased prevalence in patients chronically infected with hepatitis C virus (HCV). We now establish a link between the molecular structure and clinical occurrence of HCV-associated t(14;18). A t(14;18) was detected by PCR in leukocytes from 22 of 46 HCV-infected patients (48%) and 11 of 54 healthy controls (20%) (p = 0.0053). Nucleotide sequence analysis of the Bcl-2/J(H) joins found a J(H)6 gene in 18 of 22 (82%) t(14;18) from HCV(+) patients, and 3 of 8 (38%) from controls (p = 0.031). The t(14;18) rarely contained J(H) gene mutations, or an intervening region sequence suggestive of D gene rearrangement or templated nucleotide insertion. Analysis of published t(14;18) nucleotide sequences established that the J(H)6 prevalence in t(14;18) from normal/nonneoplastic controls (48%) was significantly lower than in t(14;18) from our HCV(+) patients (p = 0.004) or from non-Hodgkin's lymphomas (66%, p = 0.003). We conclude that the increased prevalence of t(14;18) in HCV(+) patients occurs with a strong bias for Bcl-2/J(H)6 joins. In this regard, HCV-associated t(14;18) more closely resemble t(14;18) in lymphomas than t(14;18) from normal subjects.
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Affiliation(s)
- Eric H Sasso
- Department of Medicine, University of Washington, Seattle 98105, USA.
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37
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Matsuo K, Kusano A, Sugumar A, Nakamura S, Tajima K, Mueller NE. Effect of hepatitis C virus infection on the risk of non-Hodgkin's lymphoma: a meta-analysis of epidemiological studies. Cancer Sci 2004; 95:745-52. [PMID: 15471561 PMCID: PMC11159764 DOI: 10.1111/j.1349-7006.2004.tb03256.x] [Citation(s) in RCA: 153] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2004] [Revised: 07/14/2004] [Accepted: 07/16/2004] [Indexed: 12/14/2022] Open
Abstract
Although a high prevalence of hepatitis C virus (HCV) infection among non-Hodgkin's lymphoma (NHL) patients had been reported, subsequent epidemiological studies conducted to examine a causal association between HCV and NHL have provided inconsistent results across studies. A strikingly positive association has been reported primarily from Italy and Japan, while no association was found in other regions of the world. To clarify the association between HCV and NHL, we conducted a systematic literature review. Eligible study designs were nested case-control studies, population-based case-control studies, and hospital-based case-control studies using non-cancer subjects as controls. The studies published through January 1991 to August 2003 were searched through Medline. Ultimately, 23 studies with 4049 NHL patients and 1,813,480 controls were identified. Summary statistics were crude odds ratios (ORs) comparing the anti-HCV seropositive and seronegative subjects. As we identified heterogeneity between studies, summary statistics were calculated based on a random-effect model. We did not find any evidence of publication bias. The major sources of variation were the use of blood donor controls and year of publication. The summary OR for NHL was 5.70 (95% confidence interval (CI), 4.09-7.96, P < 0.001). The subgroup analysis by phenotype showed a similar trend for B-cell (5.04, 95% CI: 3.59-7.06) and T-NHL (2.51, 95% CI: 1.39-4.56). In conclusion, we found a strongly positive association between anti-HCV seropositive test subjects and risk of NHL. Further biological studies examining this association are warranted.
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Affiliation(s)
- Keitaro Matsuo
- Division of Epidemiology and Prevention, Aichi Cancer Center, Chikusa-ku, Nagoya 464-8681, Japan.
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38
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Engels EA, Chatterjee N, Cerhan JR, Davis S, Cozen W, Severson RK, Whitby D, Colt JS, Hartge P. Hepatitis C virus infection and non-Hodgkin lymphoma: results of the NCI-SEER multi-center case-control study. Int J Cancer 2004; 111:76-80. [PMID: 15185346 DOI: 10.1002/ijc.20021] [Citation(s) in RCA: 78] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Several studies have noted elevated hepatitis C virus (HCV) prevalence among patients with non-Hodgkin lymphoma (NHL), suggesting that HCV infection increases NHL risk through chronic immune stimulation. Population-based data from the U.S. are lacking. In a population-based case-control study of NHL in the United States, we identified HCV infection using an enzyme immunoassay, confirmed by recombinant immunoblot assay or HCV RNA detection. The association between HCV and NHL was assessed using logistic regression, adjusting for demographic factors, illicit drug use or medical history. Thirty-two of 813 (3.9%) NHL cases and 14 of 684 (2.1%) controls were HCV-infected [odds ratio (OR) 1.96, 95%CI 1.07-4.03]. For separate NHL subtypes, numbers were limited. Nonetheless, positive associations were noted for follicular (OR 2.46, 95%CI 1.01-5.81), marginal zone (3.99, 0-13.6) and mucosa-associated lymphoid tissue (2.04, 0-7.20) NHLs. For all NHLs combined, the HCV-NHL association changed little after adjustment for sex, age, race and study center (OR 1.89, 95%CI 1.00-4.00). HCV was common in controls who had injected drugs (40%) or used other illicit drugs (6.5%), but adjustment for drug use did not affect the HCV-NHL association (OR 1.87, 95%CI 0.95-4.10). Transfusion history was unrelated to HCV status, and adjustment for this exposure did not attenuate the HCV-NHL association (OR 2.15, 95%CI 1.12-4.76). Excluding 4 subjects with a history of hemodialysis or 3 subjects with organ transplants also did not affect the results. Our study demonstrates an association between HCV infection and NHL in the United States. HCV infection may be a cause of NHL.
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Affiliation(s)
- Eric A Engels
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Rockville, MD 20892, USA.
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Negri E, Little D, Boiocchi M, La Vecchia C, Franceschi S. B-cell non-Hodgkin's lymphoma and hepatitis C virus infection: a systematic review. Int J Cancer 2004; 111:1-8. [PMID: 15185336 DOI: 10.1002/ijc.20205] [Citation(s) in RCA: 122] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
A high prevalence of hepatitis C virus (HCV) infection in patients with B-cell non-Hodgkin's lymphoma (B-NHL) has been reported in some, but not all, studies, and the association showed a strong regional variation. We conducted a systematic review of the prevalence of HCV infection in case series of B-NHL and, when an appropriate control group was available, of the odds ratio of B-NHL associated with HCV infection. A high HCV prevalence in B-NHL was found in southern and eastern Europe, Japan and the southern United States, but not in central and northern Europe, Canada, northern United States, or a few Asian countries. Possible sources of heterogeneity and bias are discussed. The odds ratio of B-NHL for HCV infection was relatively weak, ranging from 2 to 4 in most studies. Thus, even if the observed association were causal, the percentage of cases of B-NHL attributable to HCV infection would be relatively low (10%) also in countries with a high prevalence of HCV infection in the general population, and extremely low in other countries. This may explain apparent inconsistencies between studies. Potential mechanisms of action are also discussed.
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Affiliation(s)
- Eva Negri
- Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
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40
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de Sanjose S, Nieters A, Goedert JJ, Domingo-Domenech E, Fernandez de Sevilla A, Bosch R, Herrera P, Domingo A, Petit J, Bosch X, Kallinowski B. Role of hepatitis C virus infection in malignant lymphoma in Spain. Int J Cancer 2004; 111:81-5. [PMID: 15185347 DOI: 10.1002/ijc.11727] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Hepatitis C virus (HCV) has been implicated in the etiology of malignant lymphomas. We estimated the risk of lymphoma associated with detection of HCV infection. Cases (n = 529) were consecutive patients newly diagnosed with a lymphoid malignancy between 1998 and 2002 in 4 centers in Spain. Lymphomas were diagnosed and classified using the WHO Classification. Controls (n = 600) were hospitalized patients matched to the cases by 5-year age group, gender and study center. Several medical conditions associated with severe immunosuppression precluded the eligibility of controls. Patients underwent a personal interview and blood sampling. HCV positive subjects were considered those with antibody response to third generation ELISA or detection of HCV RNA with Amplicor 2.0. Cases were systematically tested for HIV antibodies. We used the chi(2) test and unconditional logistic regression to estimate the odds ratio (OR) and 95% confidence interval (95% CI) for lymphoma associated with HCV. HCV infection was detected in 40 cases (7.5%) and 23 (3.8%) control subjects. Six of 16 patients with HIV-related lymphomas and 4 of 8 organ-recipient-related lymphomas were HCV positive. The analysis, excluding HIV-infected subjects and organ recipients, led to a prevalence of HCV of 5.9% among cases and 3.8% among controls. The age-, gender- and center-adjusted OR for all lymphomas was 1.58 (95% CI = 0.89-2.79). Among all lymphoma categories, HCV was associated with an increased risk of low grade B-cell lymphomas not otherwise specified (NOS) (OR = 35.98, 95% CI = 4.70-275.4). A 2-fold excess risk associated to HCV was observed for marginal B-cell lymphomas, diffuse large B-cell lymphoma and lymphoma B NOS but the associations were not statistically significant. HCV infection is associated with an increased risk of a broad spectrum of lymphoid neoplasms among non severely immunocompromised subjects in Spain.
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Affiliation(s)
- Silvia de Sanjose
- Servei d'Epidemiologia i Registre del Càncer, Institut Català d'Oncologia, Barcelona, Spain.
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41
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Talamini R, Montella M, Crovatto M, Dal Maso L, Crispo A, Negri E, Spina M, Pinto A, Carbone A, Franceschi S. Non-Hodgkin's lymphoma and hepatitis C virus: a case-control study from northern and southern Italy. Int J Cancer 2004; 110:380-5. [PMID: 15095303 DOI: 10.1002/ijc.20137] [Citation(s) in RCA: 84] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
HCV has been associated with NHL, but the evidence from case series and case-control studies is not totally consistent. Between 1999 and 2002, we conducted a hospital case-control study on the association between HCV, HBV and NHL in 2 areas of Italy where HCV infection is relatively frequent. Cases (n = 225, median age 59 years) were consecutive patients with a new diagnosis of NHL admitted to local specialized and general hospitals. Controls (n = 504, median age 63 years) were patients with a wide spectrum of acute conditions admitted to the same hospitals as cases. HCV prevalence was 19.6% among NHL cases and 8.9% among controls (adjusted OR = 2.6, 95% CI 1.6-4.3). The ORs for HCV were similar for low-grade and intermediate-/high-grade B-cell NHL (3.2 and 2.4, respectively) as well as for nodal and extranodal NHL (2.7 and 2.6, respectively). Positivity for HBsAg was found in 3.8% of cases and 0.9% of controls (OR = 4.1, 95% CI 1.2-14.4). An elevated OR was also found for history of hepatitis C (OR = 4.7, 95% CI 2.3-9.5). History of blood transfusion before 1990 was associated with HCV positivity among controls but not with NHL risk. In conclusion, HCV infection was associated with an increase in NHL risk, and the fraction of NHL cases attributable to HCV was 12.4% (range 6.3-18.5%).
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Affiliation(s)
- Renato Talamini
- Servizio di Epidemiologia e Biostatistica, Centro di Riferimento Oncologico, Aviano, Pordenone, Italy
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42
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Morton LM, Engels EA, Holford TR, Leaderer B, Zhang Y, Zahm SH, Boyle P, Zhang B, Flynn S, Tallini G, Owens PH, Zheng T. Hepatitis C Virus and Risk of Non-Hodgkin Lymphoma: A Population-Based Case-Control Study among Connecticut Women. Cancer Epidemiol Biomarkers Prev 2004. [DOI: 10.1158/1055-9965.425.13.3] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Abstract
Objective: Previous epidemiologic studies of hepatitis C virus (HCV) infection and B-cell non-Hodgkin lymphoma (B-NHL) have yielded conflicting results, perhaps due to differences in the classification of B-NHL and the choice of non-population-based control groups that may not reflect the background population prevalence of HCV. To further investigate the link between HCV and NHL, we conducted HCV testing on serum samples of 998 women (464 cases; 534 controls) from a population-based case-control study of women in Connecticut. Methods: Serum samples were screened for HCV antibodies using an enzyme immunoassay; positive samples were confirmed by additional testing for HCV antibodies and for serum HCV RNA. Results: Approximately 2% (8 of 464) of cases and 1% (5 of 534) of controls tested positive for HCV. The risk of NHL associated with HCV infection appeared to be concentrated among B-cell lymphomas [odds ratio (OR) 2.0; 95% confidence interval (CI) 0.6, 8.2], particularly among follicular lymphomas (OR 4.1, 95% CI 0.8, 19.4). Conclusion: The primary strength of this study is our use of a population-based study design, although the low prevalence of HCV among women in Connecticut resulted in wide CIs for the estimated association between HCV and B-NHL subtypes. Our study suggests that HCV may be associated with increased risk of development of B-NHL, and that this risk may vary by B-NHL subtype among women. Due to the relatively low prevalence of HCV in our study population and the scarcity of population-based epidemiological research on this subject, our study highlights the need for additional large, population-based studies of the role of HCV in the etiology of B-NHL.
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Affiliation(s)
| | - Eric A. Engels
- 4Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, MD; and
| | | | | | - Yawei Zhang
- 1Department of Epidemiology and Public Health and
| | - Shelia Hoar Zahm
- 4Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, MD; and
| | - Peter Boyle
- 3Department of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy
| | - Bing Zhang
- 5Department of Epidemiology and Biostatistics, McGill University, Montreal, Canada
| | - Stuart Flynn
- 2Department of Pathology, Yale University School of Medicine, New Haven, CT
| | - Giovanni Tallini
- 2Department of Pathology, Yale University School of Medicine, New Haven, CT
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Gisbert JP, García-Buey L, Arranz R, Blas C, Pinilla I, Khorrami S, Acevedo A, Borque MJ, Pajares JM, Fernández-Rañada JM, Moreno-Otero R. The prevalence of hepatitis C virus infection in patients with non-Hodgkin's lymphoma. Eur J Gastroenterol Hepatol 2004; 16:135-8. [PMID: 15075985 DOI: 10.1097/00042737-200402000-00003] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
AIM Lymphomagenesis is a multifactorial process in which genetic, environmental and infectious factors can be involved. The aim of the present study was to assess the prevalence of hepatitis C virus (HCV) infection among patients with non-Hodgkin's lymphoma (NHL), and to compare it with that of a control group of voluntary blood donors. METHODS All consecutive patients with a histological diagnosis of NHL from January 1996 to December 2001 were included in this prospective study. As control group for HCV infection, voluntary blood donors recruited over the same time period from the same geographical area were considered. The presence of anti-HCV antibodies was investigated by ELISA-II and RIBA-II, and viraemia (HCV RNA) was tested by using a polymerase chain reaction (PCR). HCV genotyping was also performed. RESULTS Ninety-nine patients (mean age 48 years) with NHL were diagnosed during the study period. Histological classification of NHL was high-intermediate grade (63 patients), and low grade (36 patients). Immunophenotype distribution was type B (86 patients) and type T (13 patients). Seven of the 99 NHL patients (7%) were infected with HCV (both using serology and PCR), five of them with immunophenotype B and two with immunophenotype T. The prevalence of HCV infection according to NHL phenotype was 5.8% in B-cell NHL and 15.4% in T-cell NHL. The HCV genotype was 1b in six cases, and 3a in one. In voluntary blood donors (mean age 45 years), HCV infection was detected in 517/55 587 (0.93%). Therefore, HCV infection was more frequent in NHL patients than in controls (odds ratio = 8.1; 95% CI = 3.7-17.6). The odds ratio for the association of HCV and B-cell NHL was 6.2 (95% CI = 2.5-15.3), and for T-cell NHL 16.4 (95% CI = 3.7-72.8). CONCLUSION The prevalence of HCV infection in patients with NHL (both B- and T-type) is higher than that observed in controls, suggesting a role of HCV in lymphoma aetiopathogenesis.
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Affiliation(s)
- Javier P Gisbert
- Gastroenterology and Hepatology Service, Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, Spain.
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Gisbert JP, García-Buey L, Pajares JM, Moreno-Otero R. Prevalence of hepatitis C virus infection in B-cell non-Hodgkin's lymphoma: systematic review and meta-analysis. Gastroenterology 2003; 125:1723-32. [PMID: 14724825 DOI: 10.1053/j.gastro.2003.09.025] [Citation(s) in RCA: 211] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS The aim of our study was to conduct a systematic review of studies evaluating prevalence of hepatitis C virus (HCV) infection in B-cell non-Hodgkin's lymphoma (B-NHL) and to perform a meta-analysis of case-control studies comparing this prevalence with that of a reference group. DATA SOURCES Electronic databases and the Cochrane Controlled Trials Register. STUDY SELECTION Studies evaluating prevalence of HCV infection in patients with B-NHL. Studies comparing HCV prevalence in B-NHL (cases) and in a reference group (controls) were included in the meta-analysis. DATA EXTRACTION Author/country, diagnostic method (serology/PCR), control type, matching/design, and VHC prevalence. DATA SYNTHESIS Prevalence of HCV infection and meta-analysis combining the odds ratios (OR). RESULTS Forty-eight studies (5542 patients) were identified. Mean HCV infection prevalence was 13% (95% CI: 12%-14%), which was higher in Italy (20%) and Japan (14%). Ten studies compared HCV prevalence in B-NHL (17%) and healthy controls (1.5%) (OR: 10.8; 95% CI: 7.4-16), results being homogeneous; OR increased up to 14.1 when only Italian studies were considered. Sixteen studies compared HCV prevalence in B-NHL (13%) and in other hematologic malignancies (2.9%) (OR: 4.2; 95% CI: 2.5-7), also with homogeneous results; OR increased up to 7.8 when subanalysis included only Italian studies. CONCLUSIONS HCV prevalence in patients with B-NHL is approximately 15%, higher than that reported not only in general population (1.5%) but also in patients with other hematologic malignancies (2.9%), suggesting a role of HCV in the etiology of B-NHL. The striking geographic variation in this association suggests that genetic and/or environmental factors are also involved in the pathogenesis of this disorder.
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Affiliation(s)
- Javier P Gisbert
- Gastroenterology and Hepatology Service, La Princesa University Hospital, Madrid, Spain.
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Paydas S, Kilic B, Yavuz S, Disel U, Tanriverdi K, Sahin B, Burgut R. Anti-HCV and HCV-RNA prevalence and clinical correlations in cases with non-Hodgkin's lymphoma. Am J Hematol 2003; 74:89-93. [PMID: 14508793 DOI: 10.1002/ajh.10386] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Hepatitis C virus (HCV) is an RNA virus in the Flaviviridae family. It displays lymphotropism in addition to hepatotropism and extrahepatic manifestations are very well known. There are many studies showing an association between HCV infection and non-Hodgkin's lymphomas (NHL). In this study the evidence for HCV infection was studied in cases with NHL. To this end, anti-HCV antibody and HCV-RNA were screened in serum samples of cases with NHL using third-generation ELISA and RT-PCR. Anti-HCV antibody was studied in 223 patients and was found to be positive in 18 cases (8.1%). Anti-HCV antibody positivity was compared with our blood bank/blood donor population. There was an important increased risk of HCV infection--the common odds ratio was 34.56 and corrected odds ratio was 19.07. HCV-RNA was studied in 67 of 223 serum samples. HCV-RNA was found to be positive in 21 of 67 samples (31.3%). When compared with clinico-demographic parameters for anti-HCV and HCV-RNA, including age, nodal status, and grade (in evaluable cases), except age in cases with or without HCV-RNA, we did not find an important correlation with HCV status and clinical findings (P=0.155; 0.442; 0.288 for anti-HCV and 0.027; 0,558; 0.126, respectively). These results suggest that HCV infection may be an important risk factor for lymphomagenesis and HCV-RNA is more useful for the detection of HCV infection in these immunosuppressed cases. Simultaneous detection of anti-HCV and HCV-RNA will be more informative in this population.
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Affiliation(s)
- Semra Paydas
- Department of Oncology, Cukurova University Faculty of Medicine, Adana, Turkey.
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Abstract
The association between the hepatitis C virus and B-cell non-Hodgkin's lymphomas is controversial. We review the epidemiological evidence behind the association, and look at the reasons behind the variation in study findings. There is increasing evidence of the pathogenesis of hepatitis C-associated lymphoma. Treatment of the hepatitis C virus with antiviral therapy may lead to the regression of some low-grade lymphomas. The management of other hepatitis C-associated lymphomas is similar to that of conventional lymphoma, although viral reactivation and subsequent immune reconstitution hepatitis can complicate chemotherapy.
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Affiliation(s)
- N C Turner
- Department of Clinical Oncology and Centre for Hepatology, Royal Free and University College Medical School, London, UK
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Abstract
This review considers in detail the descriptive and aetiological epidemiology of Hodgkin's disease and non-Hodgkin's lymphoma (NHL), with attention to histological subcategories when the literature allows. The aetiology of Hodgkin's disease remains only partially understood. There is evidence that Epstein-Barr virus (EBV) may be involved in the causation of some cases, and clinical immune deficiency is a risk factor for a few, but the evidence is not entirely consistent and other factors may also be important in causing the EBV-associated cases of Hodgkin's disease. The cause of EBV-unassociated cases remains obscure. For NHL, although it has been shown that some cases are related to immune deficiency and chronic antigenic stimulation, and especially to EBV in the context of immune deficiency, the causation of the majority of cases remains unknown. The increasing incidence of NHL, other than that related to AIDS, is also essentially unexplained. Epidemiological investigation of the aetiology of NHL and Hodgkin's disease is making steady progress, however, and there remain leads to be followed that may result in a better understanding and hence prevention.
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Affiliation(s)
- A J Swerdlow
- Section of Epidemiology, Institute of Cancer Research, Brookes Lawley Building, Sutton, Surrey, UK.
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Musto P. Hepatitis C virus infection and B-cell non-Hodgkin's lymphomas: more than a simple association. CLINICAL LYMPHOMA 2002; 3:150-60. [PMID: 12521391 DOI: 10.3816/clm.2002.n.021] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Several studies have reported that the prevalence of the hepatitis C virus (HCV) infection is significantly overrepresented in patients affected by non-Hodgkin's lymphoma (NHL), thus suggesting that besides the well-established link with essential mixed cryoglobulinemia, a possible role for HCV is determining the development of at least some types of B-cell NHL. Such an association, however, seems to be limited to geographic areas where the presence of HCV is more relevant or endemic. According to a multistep pathogenetic model based on a large series of clinical, immunological, histological, and molecular evidences, an HCV antigen-driven polyclonal B-cell lymphoproliferation could be the initial phase of a process leading, in a variable time, into a true clonal disease. Particular genetic and environmental backgrounds could play a role in the development of a malignant phenotype, while specific HCV genotypes do not seem to be relevant in this setting. Hepatitis C virus correlated with NHL often shows some distinctive clinicopathological features, such as older age, liver damage, presence of monoclonal gammopathy (often with no clinically relevant cryoglobulinemic and/or rheumatoid activity), increased rate of autoimmune disorders, extranodal localizations, and restricted histological subtypes. Overall, the clinical outcome of HCV-positive NHL does not seem to be different from that of NHL patients without HCV infection. However, the evidence of a significant hepatic injury may predict a worse prognosis in these subjects.
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Affiliation(s)
- Pellegrino Musto
- Unit of Hematology and Stem Cell Transplantation, IRCCS Casa Sollievo della Sofferenza, S. Giovanni Rotondo, Italy.
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Shaffer AL, Rosenwald A, Staudt LM. Lymphoid malignancies: the dark side of B-cell differentiation. Nat Rev Immunol 2002; 2:920-32. [PMID: 12461565 DOI: 10.1038/nri953] [Citation(s) in RCA: 275] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
When the regulation of B-cell differentiation and activation is disrupted, lymphomas and leukaemias can occur. The processes that normally create immunoglobulin diversity might be misdirected, resulting in oncogenic chromosomal translocations that block differentiation, prevent apoptosis and/or promote proliferation. Prolonged or unregulated antigenic stimulation might contribute further to the development and progression of some malignancies. Lymphoid malignancies often resemble normal stages of B-cell differentiation, as shown by molecular techniques such as gene-expression profiling. The similarities and differences between malignant and normal B cells indicate strategies for the treatment of these cancers.
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Affiliation(s)
- A L Shaffer
- Metabolism Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
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