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Annals of Oncology 14: 1341–1345, 2003 Hepatitis C and B-cell lymphoma
N. C. Turner1, G. Dusheiko1 & A. Jones1* 1Department of Clinical Oncology and 2Centre for Hepatology, Royal Free and University College Medical School, London, UK Received 4 September 2002; revised 27 January 2003; accepted 14 March 2003 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.
Key words: hepatitis C, lymphoma, pathogenesis
cause of EMC 10 years ago, with antibodies to the virus found in84–98% [4, 5] of patients with EMC. EMC predisposed to develop- The number of viruses associated with lymphoma has increased ment of malignant lymphoma [6], prompting further studies on the over the last 20 years, and includes the Epstein–Barr virus (EBV), association between hepatitis C and lymphomas.
human T-cell lymphotropic virus 1 (HTLV1), human immuno-deficiency virus (HIV1 and 2) and human herpesvirus 8 (HHV8).
Some cause lymphoma by direct oncogenesis, for example EBV Studies with a positive association
and Burkitt's lymphoma. Others cause lymphoma in immuno- The epidemiological data supporting a general association of suppressed patients, for example HHV8 in primary effusion HCV and lymphoma remains controversial, with considerable lymphoma and Castleman's syndrome. Lymphomas in HIV discordance between reports. The majority of positive studies patients arise directly due to HIV action on lymphocytes and second- have originated in Italy, where the prevalence of HCV is parti- ary to AIDS, with up to 50% of these lymphomas associated with cularly high, with reported prevalences of up to 2.9% in parts of EBV. Successful treatment of virus-associated lymphomas is the north of the country [7], and up to12.6% in parts of the south often difficult, either due to their aggressive behaviour, for example [8]. The lymphoma with the clearest link to HCV is lymphoplas- Burkitt's lymphoma, or due to the inadequate dose intensity or macytoid lymphoma, an overt B-cell lymphoma that can compli- development of infection associated with chemotherapy in cate EMC, with up to 30% of cases associated with hepatitis C patients who are already immunosuppressed.
[9, 10]. These initial studies compared the rate of HCV antibodies Hepatitis C virus (HCV) has only recently been recognized as a in retrospective cohorts of lymphoma patients with the healthy potential cause of B-cell lymphoma. The management of these background population as control. It was not until larger case– lymphomas is also complicated by the presence of the underlying control studies were performed that a more general association chronic HCV infection [1, 2]. We discuss the available evidence with other B-cell malignancies was found.
on the epidemiology of HCV and lymphoma, recent insights into There has been a recent proliferation of papers on the associ- the pathogenesis, and the management of HCV during treatment.
ation between HCV and NHL. A general association of HCV andB-cell NHL has been reported in studies from Brazil [11], Italy Hepatitis C and lymphoma: a controversial
[12–15], Israel [16], Japan [17, 18], Romania [19], Turkey [20], Switzerland [21] and the USA [22]. Some of these studies haveused inappropriate control groups, such as healthy blood donors, The potential association of HCV and non-Hodgkin's lymphomas which potentially confound interpretation, and those studies are (NHL) was first recognized while studying patients with essential not discussed here. Studies that have used more appropriate control mixed cryoglobulinaemia (EMC), a chronic autoimmune disease groups, including those from Italy [13–15], Japan [18] and the with an underlying bone marrow B-cell clonal proliferation [3].
USA [22], have found a general association of B-cell NHL and Chronic hepatitis C infection was recognized as the principle chronic infection with HCV (Table 1). A further paper from Italyhas produced equivocal results (Table 1) [23].
Both Hodgkin's lymphoma and T-cell NHL consistently show *Correspondence to: Dr A. Jones, Department of Clinical Oncology, no association with HCV. There may be an association of myeloma Royal Free and University College Medical School, Pond Street, London with HCV, in addition to B-cell lymphomas (Table 1). Although NW3 2QG, UK. Tel: +44 207-472-6395; Fax: +44-207-794-3341; E-mail: alison.jones@royalfree.nhs.uk initial studies on HCV associations focused on lymphocytoplas- 2003 European Society for Medical Oncology Table 1. Selected case–control studies demonstrating the association of HCV infection with B-cell NHL and B-cell lymphoproliferative disorders
HCV infection rates in HCV infection rates Odds ratio (95% CI) for HCV infection De Rosa et al. [14], Italy T-cell NHL or Hodgkin's disorders: 59/263 (22.4%) lymphoma: 1/52 (1.9%) B-cell NHL: 26/91 (23.1%) Zuckerman et al. [22], B-cell NHL: 26/120 (22%) USA (78% Hispanic) haematological conditions: 7/154 (4.5%) Montella et al. [13], Italy High-grade B-cell NHL: Hodgkin's lymphoma: 11.5 (4.2–32.2) Intermediate-grade B-cell NHL: General medical admissions: Low-grade B-cell NHL: Multiple myeloma: 13/41 (32%) Vallisa et al. [15], Italy NHL: 65/175 (37%) ‘Selected inpatients andoutpatient': 27/300 (9%) Mizorogi et al. [18], Japan B-cell NHL: 17/100 (17%) Non B-cell NHL: 0/25 (0%) Pioltelli et al. [23], Italy B-cell NHL: 48/300 (16%) Age-/sex-matched controls: CI, confidence interval; NHL, non-Hodgkin's lymphoma; NS, not significant.
Chronic infection with HCV indicated by the presence of HCV antibodies, and confirmed by HCV RNA detection by RT–PCR in references [13–15, 22, 23].
macytoid lymphoma as the principal HCV-associated lymphoma interpretation would be that there is no association between [9, 10], this lymphoma is not prominent in many later series. In lymphoma and HCV. Many positive studies are well conducted, some series, low grade histologies predominate [12, 14, 21], but in however, and other reasons are likely to explain the discrepancies other series the association is with intermediate- or high-grade between studies. At best, only a small minority of HCV carriers lymphomas [13, 16, 18]. It is unclear if this simply represents will develop lymphoma, otherwise countries with a high preva- ascertainment bias, reflecting local referral practices and different lence of HCV carriage would be overwhelmed by cases of lym- case mixes, or is a more significant finding.
phoma. An accurate assessment of the exact risk could only come The presentation of NHL associated with HCV differs from from a large cohort study, and no such studies have been reported.
standard NHL. Lymphomas associated with HCV more commonly Many of the negative studies have been small, and hence lacking present as primary extra-nodal lymphomas, especially liver, adequate power, or have studied populations with a low preva- spleen and salivary glands [13, 24, 25]. Indeed, as many as 65% of lence of HCV carriage, and hence have only been able to identify diffuse large B-cell lymphomas associated with HCV may present a weak association [28]. It is also possible that there may be a as primary extra-nodal lymphomas, compared with 19% of con- geographical variation in the association, with cofactors such as trols [24]. This mirrors the ability of the hepatitis virus to infect geographical differences in viral genotype, population genetics or these organs [26]. Cryoglobulinaemia is more commonly found in environmental factors underlying the differences between studies.
HCV-associated lymphomas, especially lymphoplasmacytoid There is, however, no direct evidence to support or refute these lymphoma [10]. Retrospective studies of patients whose infection possibilities. From the available evidence it appears that HCV is date can be accurately determined, suggest the mean latency from only an important risk factor for B-cell malignancies in areas with acquiring the virus to presentation with lymphoma is 15 years [22, a high prevalence of HCV carriage.
Studies showing no association
Potential mechanisms of pathogenesis of
hepatitis C-associated lymphoma

The finding of an association is not universal in the literature, witha recent large case–control study from France [28], and multiple HCV is a member of the RNA flavivirus family. The virus lacks small negative series from the UK [29], Canada [30, 31], Germany reverse transcriptase, and hence is unable to integrate into the host [32], Turkey [33], Thailand [34] and the USA [35] failing to find genome and does not encode for any known oncogenes. The an association. In contrast to the Japanese studies supporting the pathogenesis of hepatocellular carcinoma associated with HCV association discussed above, a further Japanese study found little has been much studied, but still remains largely unknown. There evidence of a significant association [36]. Why might these is increasing evidence that HCV-encoded proteins may contribute studies have failed to find an association? Clearly one possible to the pathogenesis of hepatocellular carcinoma. HCV proteins can interfere with signal transduction, growth regulation and HCV lack any evidence of a background low-grade malignancy apoptosis. HCV proteins, for example the Core protein, have the [24]. The method of lymphomagenesis in this and the other ability to transform mouse fibroblast cells in vitro [37], and trans- associated B-cell malignancies is unknown. Indeed, in these lym- genic mice expressing HCV core proteins have, in some studies, phomas HCV may come to be regarded as a cofactor rather than a developed liver tumours.
HCV infection becomes chronic in up to 86% of cases of sero- conversion [38]. Although the virus excites an active immune Management of the lymphoma
response, the virus evades the immune system by unknownmechanisms. Possible methods of evasion include escape muta- In areas of high background HCV prevalence, screening for HCV tions in HCV genes [39], defects in antigen recognition, and in at diagnosis of all new B-cell malignancies is important to help addition the virus can infect B lymphocytes, which act as a sanctuary direct future management, and to predict which patients may site protected from immune attack by T cells [40].
develop problems secondary to the HCV during or after treatment There is evidence that HCV can induce clonal proliferation of [49]. Patients positive for HCV antibodies should be assessed for B-cells in patients carrying the virus chronically, with molecular HCV viraemia by RT–PCR, although there is no evidence linking alterations in the lymphocytes that may subsequently play a role in baseline viral load and subsequent outcome of treatment. The the multi-step process of malignant lymphocyte transformation.
degree of hepatitis or underlying cirrhosis should be determined, Lymphocytes in intra-hepatic follicles in livers of patients with by liver biopsy, in viraemic patients with abnormal liver function chronic HCV undergo an oligoclonal proliferation [41]. Circu- tests before therapy is commenced, especially with high-dose lating lymphocytes in patients with chronic HCV, but without evidence of frank lymphoma, overexpress the anti-apoptotic pro- The majority of lymphomas presenting concurrently with HCV tein bcl-2, with a high incidence of t(14;18) translocations involving carriage should be managed in a similar manner to their HCV- the bcl-2 gene [42]. There is also a high incidence of circulating negative counterparts. For certain low-grade lymphomas there is monoclonal B cells, as evidenced by populations of lymphocytes increasing evidence that treatment of the HCV with antiviral therapy expressing the same immunoglobulin heavy chain (IgH) rearrange- can lead to remission of the lymphoma. The underlying B-cell ments. bcl-2 and IgH rearrangements can be cleared from the monoclonal proliferation associated with EMC can be cleared blood by antiviral therapy, concurrent with suppression of the when the HCV is treated with interferon-α (IFN-α) [50], and there HCV, possibly eliminating the early monoclonal proliferation and are case reports of long-lasting complete remission of frank lym- preventing subsequent transformation to lymphoma [43]. Actively phoplasmacytoid lymphoma concurrent with eradication of the replicating virus has been demonstrated in HCV-associated virus with IFN-α [51]. Further evidence to support this approach lymphomas [44], a finding that although important does not comes from a recent case series of patients with splenic lymphoma necessarily imply a causative role of HCV.
with villous lymphocytes, with associated HCV infection andcyroglobulinaemia [52]. In this series, treatment of the HCV withIFN-α and ribavirin was followed by a complete response of the If HCV is lymphomagenic, how could the virus
lymphoma in the majority of patients. Patients with the same lead to malignant transformation?
lymphoma who were not infected with HCV did not respond to the Does the presence of the virus in B lymphocytes somehow initiate IFN-α therapy. It is not clear if this approach would be applicable cellular changes that predispose to the development of a malignant to other lymphomas. There are no data on the relative effective- lymphoma? It is well recognized that HCV can infect B lymphocytes ness of the treatment, or of the prognosis, or of other subtypes of as discussed above. In theory, the presence of HCV proteins in lymphoma when associated with HCV, and they should be managed infected lymphocytes could initiate growth dysregulation and pre- in a manner similar to their HCV-negative counterparts.
dispose the lymphocyte to the development of further molecularchanges, leading eventually to malignant lymphoma. No studies, Management of hepatitis C during treatment
however, have specifically studied the effects of the expression ofHCV proteins in lymphocytes. Alternatively, does the chronic The pathogenesis of liver damage secondary to HCV is poorly antigenic stimulation of persistent HCV infection drive lymphocyte understood and is a subject of substantial ongoing research. It is proliferation, eventually leading to the development of a malignant possible that hepatitis and liver damage is mediated in part by lymphoma in a similar manner to that hypothesized for mucosa- effects of HCV proteins, and in part by the immune response associated lymphoid tissue (MALT) lymphomas and Helicobacter directed against the virus. The immunosuppression associated pylori [45]? The HCV E2 envelope protein has been identified as a with chemotherapy upsets the balance that occurs in every chroni- potential antigen that may drive the development of lymphoma cally infected patient between viral proliferation and host immune response. During periods of lymphopenia, secondary to chemo- Lymphoplasmacytoid lymphomas originating from the back- therapy or steroids, the virus can proliferate or ‘reactivate'. After ground bone marrow proliferation of EMC preferentially express treatment is completed the immune system reconstitutes, leading certain immunoglobulin gene combinations [48], implying that to a drop in viral load, and under some circumstances this is this type of HCV-associated lymphoma is antigen driven. How- accompanied by hepatitis. This contrasts with the hepatitis that ever, the majority of diffuse B-cell lymphomas associated with can occur at the end of HCV antiviral therapy, which is commonly associated with a rise in viral load. Recovery of the immune system appears to be important in the pathogenesis of liver 1. Zuckerman E, Zuckerman T, Douer D et al. Liver dysfunction in patients damage secondary to chemotherapy-induced reactivation of HCV, infected with hepatitis C virus undergoing chemotherapy for hematologic as biochemical hepatitis usually only becomes apparent after chemo- malignancies. Cancer 1998; 83: 1224–1230.
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