Review Article
Hepatitis C virus and non-Hodgkin's lymphoma 10 years later

https://doi.org/10.1016/j.dld.2005.01.003Get rights and content

Abstract

Hepatitis C virus is associated with chronic liver disease as well as with lymphoproliferative disorders such as mixed cryoglobulinemia and, likely, non-Hodgkin's lymphomas. The association between hepatitis C virus infection and B-cell lymphoma is controversial since it shows a strong regional variation. In fact, the prevalence of hepatitis C virus infection in non-Hodgkin's lymphoma shows a prevalence ranging between 7.4 and 37.0%. However, the intimate pathogenetic mechanism involved in hepatitis C virus-associated lymphomas remains considerably unknown. Hepatitis C virus may exert its oncogenic potential via an indirect mechanism or utilise other pathways directly. It is reasonable to assume that several different pathogenetic mechanisms operate in the wide spectrum of hepatitis C virus-related lymphoproliferative disorders, which include the intermediate to high-grade lymphoma, and the more common indolent, low-grade lymphoma, preceded by long standing symptomatic mixed cryoglobulinemia Type II. In this review, the etiopathogenetic role of hepatitis C virus in non-Hodgkin's lymphoma is discussed on the basis of molecular, clinical and epidemiological considerations.

The management of hepatitis C virus-associated non-Hodgkin's lymphoma is similar to that of conventional lymphoma, although viral reactivation or the underlying chronic liver disease can complicate chemotherapy. Whether to treat low-grade hepatitis C virus-related lymphomas with anti-viral therapy is still debatable, but encouraging data emerge from some recent studies.

Introduction

Ten years ago (1984), several papers were published, almost simultaneously, in Blood and other journals [1], [2], [3], [4] concerning the possible relationship among hepatitis C virus (HCV) infection, mixed cryoglobulinemia (MC) and non-Hodgkin lymphoma (NHL). Those papers were the pathfinders for several observations addressing the same topic coming from all over the world, and often showed results in complete disaccord with initial findings. In these 10 years, the problem has been studied not only from an observational or epidemiological point of view, but also a pathogenetic interpretation of the initial findings is now possible. In this review, we revisited this topic of the most recent clinical and biological observations, thus offering the opportunity to better understand the complex relationship between HCV and haematological monoclonal diseases.

Section snippets

HCV and the immune system

At present, nearly all aspects of HCV replication are well known, and the role of its marked genetic variability has been widely studied [5], [6]. Though some viral genotypes are associated with a better prognosis and a better response to anti-viral therapy, no clear association has been found among some genotypes and specific diseases including lymphoproliferative disorders.

The main characteristic of the HCV-related liver disease is a slow progressive clinical course, but some patients show a

HCV and MC

MC is a lymphoproliferative disorder characterised by the presence of variable levels of cryoglobulin (immunoglobulins (Ig) insoluble at 4 °C) in the serum, and the involvement of several organs and tissues [35]. The histological lesions are secondary to vasculitis, which is caused by the deposition of immuno-complexes in small and medium sized blood vessels. It is often associated with multiple organs involvement, such as chronic liver disease, peripheral neuropathy and glomerulonephritis [36].

HCV and clonal B-cell proliferation

While there are no doubts that Type I MC is a malignant B-cell neoplasm, Types II and III MC were, in the past, considered as rheumatic diseases; but since cryoglobulin production is associated with B-cell monoclonal or polyclonal expansion, MC should be considered as a lymphoproliferative disease. Also from a historical point of view, the first cases of MC reported by Meltzer et al. [49] and by Brouet et al. [37] were considered as malignant lymphoproliferative disorders, given the presence of

HCV and NHL

The first observational studies, most from Italy, recorded the prevalence of anti-HCV antibodies in large unselected series of patients affected by NHL. These studies indicated a very strong association between HCV infection and NHL, while the viral infection in the patients with other haematological malignancies was similar to that observed in the general population [61], [62]. These initial studies were able to compare the prevalence of HCV infection in the NHL patients with the results of a

HCV and NHL: a lesson from epidemiology

The first epidemiological data supporting the association of HCV and NHL originated from Italy, where the prevalence of HCV is particularly high, especially in the South (up to 12%) [78], [79], [80]. Since these findings were not confirmed by other researchers, the possibility of ascertainment bias, reflecting local referral practices and/or different enrolment modalities was likely. In addition, the clinical presentation of HCV-NHL is generally different from standard NHL, since these present

Conclusions

In the last few years, there is increasing evidence that a large fraction of diseases are due to infectious factors. In the field of haematology, many malignant disorders are now related to infectious agents: Epstein–Barr Virus (EBV) in Burkitt's lymphoma, Human T Lymphocyte Virus I (HTLV-I) in T-cell leukaemia–lymphoma, Helicobacter pylori in gastric B-cell lymphoma, human herpes virus (HHV-6, -7, -8) in Kaposi's sarcoma and Castelman's disease and, perhaps, parvovirus B19 in pure red cell

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