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.
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 , 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 , and up to12.6% in parts of the south
often difficult, either due to their aggressive behaviour, for example
. 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 , Italy
Hepatitis C and lymphoma: a controversial
[12–15], Israel , Japan [17, 18], Romania , Turkey ,
Switzerland  and the USA . 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  and the
with an underlying bone marrow B-cell clonal proliferation .
USA , 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) .
Both Hodgkin's lymphoma and T-cell NHL consistently show
: 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: [email protected]
initial studies on HCV associations focused on lymphocytoplas-
2003 European Society for Medical Oncology
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. , 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. ,
B-cell NHL: 26/120 (22%)
USA (78% Hispanic)
haematological conditions: 7/154 (4.5%)
Montella et al. , Italy
High-grade B-cell NHL:
Intermediate-grade B-cell NHL:
General medical admissions:
Low-grade B-cell NHL:
Multiple myeloma: 13/41 (32%)
Vallisa et al. , Italy
NHL: 65/175 (37%)
‘Selected inpatients andoutpatient': 27/300 (9%)
Mizorogi et al. , Japan
B-cell NHL: 17/100 (17%)
Non B-cell NHL: 0/25 (0%)
Pioltelli et al. , Italy
B-cell NHL: 48/300 (16%)
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 . 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 . This mirrors the ability of the hepatitis virus to infect
geographical differences in viral genotype, population genetics or
these organs . 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 . 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 , and multiple
HCV is a member of the RNA flavivirus family. The virus lacks
small negative series from the UK , Canada [30, 31], Germany
reverse transcriptase, and hence is unable to integrate into the host
, Turkey , Thailand  and the USA  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 . 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
. The method of lymphomagenesis in this and the other
ability to transform mouse fibroblast cells in vitro
, 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 . 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 , 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 .
develop problems secondary to the HCV during or after treatment
There is evidence that HCV can induce clonal proliferation of
. 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 . 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-
gene . 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) , 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 . Actively
phoplasmacytoid lymphoma concurrent with eradication of the
replicating virus has been demonstrated in HCV-associated
virus with IFN-α . Further evidence to support this approach
lymphomas , 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 . 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
? 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 , 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
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