Hepatitis C virus-related B cell subtypes in non Hodgkin's lymphoma.

Abstract

To evaluate if indolent B cell-non Hodgkin's lymphoma (B-NHL) and diffuse large B-cell lymphoma (DLBCL) in hepatitis C virus (HCV) positive patients could have different biological and clinical characteristics requiring different management strategies.
A group of 24 HCV related B-NHL patients (11 indolent, 13 DLBCL) in whom the biological and clinical characteristics were described and confronted. Patients with DLBCL were managed with the standard of care of treatment. Patients with indolent HCV-related B-NHL were managed with antiviral treatment pegylated interferon plus ribavirin and their course observed. The outcomes of the different approaches were compared.
Patients with DLBCL had a shorter duration of HCV infection and a higher prevalence of HCV genotype 1 compared to patients with indolent B-NHL in which HCV genotype 2 was the more frequent genotype. Five of the 9 patients with indolent HCV-related B-NHL treated with only antiviral therapy, achieved a complete response of their onco-haematological disease (55%). Seven of the 13 DLBCL patients treated with immunochemotheraphy obtained a complete response (54%).
HCV genotypes and duration of HCV infection differed between B-NHL subtypes. Indolent lymphomas can be managed with antiviral treatment, while DLBCL is not affected by the HCV infection.

Full text

Page 1

Adriano M Pellicelli, Massimo Marignani, Valerio Zoli, Mario Romano, Aldo Morrone, Lorenzo Nosotti, Giuseppe
Barbaro, Antonio Picardi, Umberto Vespasiani Gentilucci, Daniele Remotti, Cecilia D'Ambrosio, Caterina Furlan,
Fabrizio Mecenate, Ettore Mazzoni, Ignazio Majolino, Roberto Villani, Arnaldo Andreoli, Giorgio Barbarini
BRIEF ARTICLE
Hepatitis C virus-related B cell subtypes in non Hodgkin's
lymphoma
Online Submissions: http://www.wjgnet.com/1948-5182office
wjh@wjgnet.com
doi:10.4254/wjh.v3.i11.278
World J Hepatol 2011 November 27; 3(11): 278-284
ISSN 1948-5182 (online)
© 2011 Baishideng. All rights reserved.
November 27, 2011|Volume 3|Issue 11|
WJH|www.wjgnet.com278
Adriano M Pellicelli, Cecilia D'Ambrosio, Roberto Villani,
Arnaldo Andreoli, Liver Unit, Azienda Ospedaliera San Camillo
Forlanini, Circonvallazione Gianicolense 87, 00149 Rome, Italy
Massimo Marignani, Department of Digestive and Liver Disease,
Azienda Ospedaliera Sant’Andrea, Via Grottarossa 1035/1039,
000189 Rome, Italy
Valerio Zoli, Ignazio Majolino, Hematology and Bone Marrow
Transplantation, Azienda Ospedaliera San Camillo Forlanini,
Circonvallazione Gianicolense 87, 00149 Rome, Italy
Mario Romano, Liver Unit, Ospedale Sandro Pertini, Via dei
Monti Tiburtini 385, 00157 Rome, Italy
Aldo Morrone, Azienda Ospedaliera San Camillo Forlanini, Cir-
convallazione Gianicolense, 87, 00149 Rome, Italy
Lorenzo Nosotti, Medicine of Migration, National Institute for
Migrant Health and Poverty, Via di S. Gallicano 25/a, 00153
Rome, Italy
Giuseppe Barbaro, Department of Medical Pathophysiology,
University of Rome “La Sapienza”, Viale del Policlinico 155,
00161 Rome, Italy
Antonio Picardi, Umberto Vespasiani Gentilucci, Liver Unit,
Campus Biomedico University, Via Álvaro del Portillo 21, 00128
Rome, Italy
Daniele Remotti, Histopathology Unit, Azienda Ospedaliera
San Camillo Forlanini, Circonvallazione Gianicolense 87, 00149
Rome, Italy
Caterina Furlan, Department of Infectious and Tropical Dis-
ease, University of Rome “La Sapienza”, Viale del Policlinico
155, 00161 Rome, Italy
Fabrizio Mecenate, Liver Unit, Ospedale Villa Betania, Via
Niccolò Piccolomini 27, 00165 Rome, Italy
Ettore Mazzoni, Liver Unit, Policlinico Casilino, Via Casilina
1049, 00169 Rome, Italy
Giorgio Barbarini, Infectious and Parasitic Diseases, Policlinico
San Matteo P.zzale Golgi 2, 2710 Pavia, Italy
Author contributions: Pellicelli AM provided the concept,
design, manuscript editing, literature search, collection of all
materials, definition of intellectual concept and interpretation of
data; Marignani M contributed the concept, manuscript review
and definition of intellectual concept. Zoli V did the data acquisi-
tion and literature search; Romano M and Nosotti L did the data
acquisition and manuscript review; Morrone A contributed the
concept; Barbaro G performed the statistical analysis and inter-
pretation of data; Picardi A and Vespasiani Gentilucci U provided
the data acquisition; Remotti D provided the data acquisition and
histopathology analysis; D'Ambrosio C and Villani R provided
the data acquisition and review of the literature; Andreoli A,
Barbarini G and Majolino I contributed the concept, manuscript
editing and review of the literature; Furlan C, Mazzoni E and
Mecenate F has provided the manuscript preparation and data
collection.
Correspondence to: Adriano M Pellicelli, MD, Liver Unit,
Azienda Ospedaliera San Camillo Forlanini,Via Terni 97, 00182
Rome, Italy. adriano.pellicelli@tiscali.it
Telephone: +39-06-58704369 Fax:+39-06-58704667
Received: March 12, 2011 Revised: October 8, 2011
Accepted: November 8, 2011
Published online: November 27, 2011
Abstract
AIM: To evaluate if indolent B cell-non Hodgkin’s lym-
phoma (B-NHL) and diffuse large B-cell lymphoma (DL-
BCL) in hepatitis C virus (HCV) positive patients could
have different biological and clinical characteristics re-
quiring different management strategies.
METHODS: A group of 24 HCV related B-NHL patients
(11 indolent, 13 DLBCL) in whom the biological and
clinical characteristics were described and confronted.
Patients with DLBCL were managed with the standard
of care of treatment. Patients with indolent HCV-related
B-NHL were managed with antiviral treatment pegylated
interferon plus ribavirin and their course observed. The
outcomes of the different approaches were compared.
RESULTS: Patients with DLBCL had a shorter dura-
tion of HCV infection and a higher prevalence of HCV
genotype 1 compared to patients with indolent B-NHL
in which HCV genotype 2 was the more frequent geno-
type. Five of the 9 patients with indolent HCV-related

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Pellicelli AM et al. HCV and Non Hodgkin’s Lymphoma
November 27, 2011|Volume 3|Issue 11|
WJH|www.wjgnet.com
279
B-NHL treated with only antiviral therapy, achieved a
complete response of their onco-haematological disease
(55%). Seven of the 13 DLBCL patients treated with
immunochemotheraphy obtained a complete response
(54%).
CONCLUSION: HCV genotypes and duration of HCV
infection differed between B-NHL subtypes. Indolent
lymphomas can be managed with antiviral treatment,
while DLBCL is not affected by the HCV infection.
© 2011 Baishideng. All rights reserved.
Key words: Hepatitis C virus infection; Diffuse large B
cell lymphoma; Indolent lymphoma; Pegylated inter-
feron; Lymphomagenesis
Peer reviewer: Marta Rodriguez Romero, PhD, Department of
Biochemistry and Molecular Biology, University of Salamanca,
National Biomedical Research Centre for the Study of Liver and
Gastrointestinal Diseases, Campus Miguel de Unamuno, ED-
LAB129, 37007 Salamanca, Spain
Pellicelli AM, Marignani M, Zoli V, Romano M, Morrone A,
Nosotti L, Barbaro G, Picardi A, Vespasiani Gentilucci U ,
Remotti D, D'Ambrosio C, Furlan C, Mecenate F, Mazzoni E,
Majolino I, Villani R, Andreoli A, Barbarini G. Hepatitis C virus-
related B cell subtypes in non Hodgkin's lymphoma. World J
Hepatol 2011; 3(11): 278-284 Available from: URL: http://www.
wjgnet.com/1948-5182/full/v3/i11/278.htm DOI: http://dx.doi.
org/10.4254/wjh.v3.i11.278
INTRODUCTION
The relationship between lymphoproliferative disorders
and infectious agents has been studied for many decades.
Epidemiological studies have linked hepatitis C virus
(HCV) infection to B-cell non Hodgkin’s Lymphomas (B-
NHL)[1,2]. The majority of these studies were conducted
in Italy, where the prevalence of HCV infection is par-
ticularly high[3-5]. However, studies conducted in countries
with a lower prevalence of HCV infection also found a
possible positive association between HCV and risk of
developing B-NHL[6]. In a large pooled analysis of com-
bined data from several countries, de Sanjose et al[7] dem-
onstrated that presence of HCV infection was linked not
only to marginal zone lymphoma, considered an indolent
course B-NHL, but also to diffuse large B-cell lymphoma
(DLBCL), a high-grade B-NHL. However, the strongest
argument for a causative role of HCV infection in lym-
phoproliferative disease derives from interventional stud-
ies where antiviral regimen directed to HCV were success-
ful in achieving the cure of HCV-related B-NHL[8-11].
In our study, the authors have analyzed and compared
the biological and clinical features of HCV-related indo-
lent B-NHL versus DLBCL. Furthermore, the authors
have evaluated the outcomes of the different treatment
approaches used in the management of these two types
of B-NHL, and evaluated the influence of HCV infection
on disease course.
MATERIALS AND METHODS
Patients
One hundred and twenty-five consecutive patients with
B-NHL referred to our institution between January 2008
and January 2009 were included in the study and analyzed
retrospectively. The diagnosis of lymphoma was estab-
lished according to the 2008 World Health Organization
(WHO) classification of tumours of haematopoietic and
lymphoid tissues[12]. Total body computed tomography
(CT) scan, bone marrow biopsy (BOM), lesion biopsies
and physical examination were used to assess the stage
and extranodal involvement according to Costwolds
modification of the Ann Arbor classification[13]. Indolent
B-NHL was defined by the 2008 WHO classification of
Tumours of haematopoietic and lymphoid tissue[12] and
included: marginal zone lymphoma (nodal, splenic and
extranodal), lymphoplasmocytoid lymphoma and follicu-
lar lymphoma. Clinically, indolent course lymphoma was
also defined as having a lesion doubling time greater than
1 year, no B symptoms and no masses > 10 cm (bulky
disease). The study was approved by the local institutional
review board.
Laboratory analysis
Enzyme-linked immunosorbent assays were used to deter-
mine anti-HCV antibodies in the 125 patients. All patients
anti-HCV antibodies positive, underwent HCV-RNA
testing [reverse transcription polymerase chain reaction
(RT-PCR); detection limit <15 UI/mL)]. HCV-RNA
determination was performed at disease diagnosis and
subsequently at one, three, six and twelve months during
antiviral treatment, and at six and twelve month after the
its completion. HCV genotyping was performed in all
viremic HCV patients (Immunogenetics Line Probe As-
say, INNO-lipa HCV, Innogenetics, Ghent, Belgium). All
HCV patients were tested for the presence of cryoglobu-
lins. In all HCV-positive patients alanine aminotransferase
(ALT) plasma levels were determined and expresses as
UI/L. All HCV positive patients were tested for hepatitis
B virus (HBV) antibodies and HBsAg (AxSYM, Abbott
Laboratories, North Chicago, IL, United States), and for
antibodies to human immunodeficiency virus (HIV) using
an HIV-1 third-generation assay (AxSYM HIV 1/2, Ab-
bott Laboratories). Presence of Bcl2 and Bcl6 were evalu-
ated in biopsy samples or peripheral and medullary blood
mononuclear cells using immunohistochemistry in all cas-
es of HCV related B-NHL. The presence of HBV, HIV
infection or concomitant neoplastic diseases excluded
patients from the study. In HCV positive patients, demo-
graphic information such as periods of first and last ex-
posure to injecting drug use or blood transfusion, tattoos
and occupational exposure, needlestick injuries were re-
corded and considered as valid surrogate timepoints to de-
fine duration of HCV infection, expressed as mean + SD.
Liver Biopsy
Fifteen of the 24 patients with HCV-related B-NHL gave
informed consent to perform liver biopsy. Histologic

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evaluation was carried out according to the Ishak score[14].
Antiviral treatment
Patients with indolent HCV-related B-NHL were offered
treatment with antiviral therapy on the basis that previous in-
terventional studies had demonstrated the efficacy of this
approach in inducing a complete response of onco-hema-
tological diseases (CR)[8-11]. In detail, pegylated interferon
alpha 2a (180 μg) was administered subcutaneously once
a week. It was combined with oral ribavirin: 800 mg/d
when the patient weighed < 65 kg, 1000 mg/d when the
weight was between 65 and 85 kg and 1200 mg/d when
the patient was > 85 kg. Treatment was scheduled for 1
year if the patient had HCV genotype 1 or 4, and for 6
mo if the genotype was 2 or 3. Epoetin alfa was given at
the dosage of 40 000 IU/week subcutaneously if haemo-
globin levels (Hb) decreased by more than 2 g/100mL
as compared to baseline in the first 4 wk of treatment,
or when Hb was below 10 g/100 mL during treatment.
Toxicity of antiviral treatment was evaluated according
National Cancer Institute Common Terminology Criteria
for Adverse Events; treatment dose was reduced in the
case of grade 2 development, or withheld in the case of
grade 3 toxicity (until toxicity had resolved to grade 2).
Treatment was stopped in the case of grade 4 toxicity.
Sustained virologic response (SVR) was defined as HCV-
RNA negativity (< 12 IU/mL) 24 wk after stopping
antiviral treatment. Patients were categorized as non-
responders if HCV-RNA was positive after three months
from the beginning of antiviral treatment. Relapser status
was defined as the reappearance of HCV-RNA after anti-
viral treatment stoppage.
Haematologic Response
Antiviral treatment: In lymphoma patients managed
with the antiviral treatment, haematological response was
evaluated at the end of antiviral therapy, and every 3 mo
thereafter.
Immunochemotheraphy: Immunochemotherapy was
reserved for patients with DLBCL, an aggressive form of
lymphoma. The multi-drug regimen used in all patients
was Cyclophoshamide, Doxorubicin, Vincristine and
Prednisone associated with Rituximab (CHOP-R).
The haematological response was evaluated by means
of physical examination, biochemical evaluation, CT scan
and BOM when indicated according to standard response
criteria[13]. CR was defined as no evidence of lymphoma.
In patients with marginal splenic lymphoma, CR was de-
fined as resolution of splenomegaly, absence of periph-
eral circulating villous lymphocytes, and normalization
of platelet and white blood cells counts. When the BOM
was initially positive, a negative BOM evaluation was an
additional required criterion for confirming CR. Partial
haematological response (PR) was defined as a ≥ 50%
decrease in the size of all measurable lesions. The criteria
for progressive haematological disease (PD) was a > 25%
size increase in a previously documented lesion or the ap-
pearance of new lesions[15].
Statistical analysis
Continuous data were expressed as mean and standard
deviation, and analysed using the t-test for independent
samples with 95% confidence intervals. Categorical data
were analysed using the χ
and the Fisher’s exact test. The significance level was set
at a two-tailed P value < 0.05.
2 test, with Yates’s correction
RESULTS
Of 125 consecutive patients presenting with B-NHL,
24 patients were HCV antibody positive, and all were
viremic. The prevalence of HCV-related B-NHL in our
population was 19.2%. Of these patients, 13 (54%) had
DLBCL, while 11 (46%) had an indolent, HCV-related
B-NHL (Table 1).
As compared to the indolent HCV-related B-NHL
group, the DLBCL group had significantly more male
patients, had a short duration of HCV infection, and a
preponderance of patients with HCV genotype 1 infec-
tion. No differences in HCV-RNA titres, ALT levels, and
histologic grading and staging between the two group
of B-NHL were detected (Table 2). All DLBCL patients
were treated with immunochemotherapy. Antiviral treat-
ment was proposed to all 11 patients with indolent HCV
related B-NHL. Nine out of 11 (81%) agreed to be treat-
ed with the antiviral treatment.
Antiviral treatment outcome
During antiviral treatment, 4 patients experienced grade 2
anaemia and were treated with epoetin alfa. One patient
developed depression, and treatment with sertraline (50
mg/d) was started. However, all nine indolent, HCV-
related B-NHL patients treated with antiviral treatment
completed the scheduled course. All the patients had an
end treatment response. Six months after antiviral treat-
ment completion, 7 patients had a SVR, while 2 patients
had a relapse of HCV infection (Table 3).
Haematologic outcome in patients treated with antiviral
treatment
Complete response of onco-hematological diseases was
obtained in 5 of the 7 patients with SVR (71%), while
the remaining 2 patients with SVR had a PR. The two pa-
tients not responding to antiviral treatment developed PD.
After a median of (14.2 + 2) mo, the 5 patients originally
obtaining SVR were still in CR (Table 3).
Haematological outcome in patients treated with immuno-
chemotherapy
Thirteen patients with DLBCL were treated with immu-
nochemotherapy as first line therapy. A CR was observed
in 7 patients. In 2 of the 13 DLBCL patients treated with
chemotherapy, there was an increase in ALT value (>
1.5 normal value) during treatment. None of the HCV-
positive DLBCL patients had to stop treatment because
of liver related events.
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DISCUSSION
In accordance with de Sanjose et al[7], we found a high
prevalence of HCV-positives (19%) among DBLC and
indolent lymphoma patients. We observed that DLBCL
patients had a history suggestive of a short duration of
HCV infection, and a higher prevalence of genotype 1, as
compared to patients with indolent, low-grade B-NHL,
who had a higher prevalence of genotype 2. Various clini-
cal studies failed to demonstrate an association between
B-NLH and specific HCV genotypes, although the pos-
sible association between specific HCV genotypes and
particular subtypes of B-NHL was not considered in
these studies[3,9,16].
Several studies have demonstrated differences between
infection due to HCV genotypes 1 and 2[17,18]. In HCV
genotype 2 infection, HCV-RNA titre was lower, there
were more patients with normal ALT values, and the
patients had a longer duration of HCV infection as com-
pared to genotype 1 patients.Conversely, chronic HCV
hepatitis progression appears to have a more rapid and
severe course in genotype 1 as compared to genotype
2[17]. Because HCV genotype 2 is associated with a longer
duration of viral infection, it can be speculated that over
time it might induce a persistent immunostimulation of
B cells. Zignego et al[19,20] have found that type Ⅱ mixed
crioglobulinemia and bcl-2 expression in HCV genotype 2
patients was the more frequent cause of a prolonged im-
munostimulation of the B cell exerted by HCV over time.
In our study HCV genotype 2 was detected in 5 out of
8 patients who had bcl-2 positivity and in all the patients
where a long duration of HCV infection was found. We
believe that bcl-2 expression in indolent lymphoma, such
as, follicular lymphoma and marginal zone lymphoma,
is the expression of a chronic B cell proliferation in re-
sponse to antigenic stimulation or polyclonal activation in
genotype 2 patients with and without cryoglobulins.
It has been demonstrated that the HCV envelope
Table 1 Clinical and biological characteristics of 24 hepatitis C virus patients with low and high grade B cell-non Hodgkin’s lymphoma
Sex Age
(yr)
HCV RNA
log10 (UI/mL)
HCV
genotype
Duration of HCV-
infection (mo)
Ishak
(grading)
Ishak
(staging)
Type of lymphomaStage Extranodal Cryoglobulin Bcl2/
Bcl6
1
2
3
4
5
6
7
8
9
10
11
F
F
F
M
F
F
F
F
M
F
F
70
69
64
36
72
65
70
55
67
59
78
5.90
5.40
nd
nd
6.00
nd
5.90
5.07
6.80
nd
nd
2a/2c
2a
2
2
1b
2a/2c
2
2a/2c
2a
2
2a
21
19
25
7
22
nd
nd
31
30
20
30
4
12
nd
6
8
nd
8
17
6
16
nd
0
6
Marginal extranodal (MALT)
Marginal extranodal (MALT)
Marginal extranodal (MALT)
Splenic marginal
Splenic marginal
Splenic marginal
Marginal nodal
Follicular lymphoma
Follicular lymphoma
Follicular lymphoma
Lymphoplasmocytoid
lymphoma
DLBCL
DLBCL
DLBCL
DLBCL
DLBCL
DLBCL
DLBCL
DLBCL
DLBCL
DLBCL
DLBCL
DLBCL
DLBCL
Ⅳ
Ⅳ
Ⅳ
Ⅳ
Ⅲ
Ⅳ
Ⅳ
Ⅲ
Ⅳ
Ⅲ
Ⅳ
Orbit/BM
Parotid/BM
Orbit/BM
Spleen/BM
Spleen
Spleen/BM
BM
None
Liver/BM
None
BM
Positive
Positive
Positive
Negative
Negative
Negative
Positive
na
Negative
Negative
Positive
+/-
-/-
na
-/-
-/-
-/-
-/-
+/+
+/-
+/+
na
nd
1
2
nd
1
6
0
6
nd
12
13
14
15
16
17
18
19
20
21
22
23
24
M
M
M
M
M
F
F
M
M
M
M
M
F
61
29
66
62
56
55
59
65
46
51
49
78
74
nd
7.80
6.70
6.90
5.1
5.4
6.4
5.8
nd
6.3
5.9
6.2
5.0
1b
1a
1b
1a
1b
1b
18
4
nd
10
nd
nd
nd
11
6
15
15
19
16
5
6
12
nd
nd
nd
nd
10
8
10
nd
10
10
2
0
6
Ⅳ
Ⅱ
BM
None
nana
+/+
na
na
na
na
+/+
+/+
+/+
-/-
-/-
+/+
-/-
Negative
na
na
na
na
na
Negative
Negative
Negative
Negative
Negative
Negative
Liver, Lung
BM
BM
Liver
Lung/BM
Lung
Liver
Lung/BM
Gastric
None
Palatine
Tonsil/BM
nd
nd
nd
nd
2
1
2
nd
1
4
Ⅳ
Ⅳ
Ⅳ
Ⅳ
Ⅳ
Ⅳ
Ⅳ
Ⅳ
Ⅲ
Ⅳ
1a/1b
1b
1b
1b
3
2a/2c
1
DLBCL: Diffuse large B cells lymphoma; nd: Not determined; Extranodal: Extranodal involvement; BM: Bone marrow; na: Not available; MALT: Mucosal
associated lymphoid tissue; HCV: Hepatitis C virus.
Table 2 Comparison of biological, virological and clinical
characteristics of hepatitis C virus-related low vs high grade B
cell-non Hodgkin’s lymphoma
DLBCL
(n = 13)
Indolent B-NHL
(n = 11)
95% CIP value
Age ( yr)1
Sex (M/F)
Duration of HCV
infection (yr)1
ALT value (UI/L)1
Genotype 1/not 1
HCVRNA log10
(UI/mL)1
Ishak (grading)1
Ishak (staging)1
57 ± 12
10/3
12 ± 5
64 ± 11
2/9
-16.8 to 2.8
-
-15.1 to -4.9
0.153
0.014
< 0.001 22 ± 7
58 ± 40
10/3
6.1 ± 0.6
40 ± 27
2/9
5.8 ± 0.3
-11.5 to 47.5
-
-0.11 to 0.71
0.219
0.014
0.147
8.4 ± 2.1
1.5 ± 1.2 2.75 ± 2.7
9.3 ± 5.0-4.05 to 2.25
-2.97 to 0.47
0.560
0.146
1Means ± SD; HCV: Hepatitis C virus; B-NHL: B cell-Non Hodgkin’s lym-
phoma; DLBCL: Diffuse large B cells lymphoma; CI: Confidence interval.
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glycoprotein E2 interacts with a specific B cell receptor
associated with the CD19/CD21/CD81 complex. This
interaction lowers the threshold for B cell activation and
induces the proliferation of benign B cells. However, this
prolonged exposure to stimuli may render B cells at risk
for additional events leading to malignant transforma-
tion[21]. This mechanism may offer a clue to interpreting
lymphomagenesis in genotype 2 patients affected by indo-
lent HCV-related B-NHL in whom a prolonged exposure
to immunostimulation of the B-cell compartment seems
to be a characteristic.
On the contrary, in our study direct lymphocyte trans-
formation could be hypothesized in HCV genotype 2
patients on the basis of the shorter duration of HCV
infection. Furthermore we found positivity of bcl-6 in
five DLBCL patients, while bcl-6 negativity was found in
only three patients. Positivity of bcl-6 in DLBCL is found
in typical DLBCL and not in DLBCL transformed from
indolent lymphoma. We believe that this data reinforces
the hypothesis of a direct lymphomagenesis of HCV in
DLBCL[22]. B cell receptors can bind HCV and efficiently
internalize the virus, possibly causing genomic instabil-
ity[21,23-25]. This mechanism might be involved in a possible
scenario of direct lymphomagenesis. Direct lymphocyte
transformation has been demonstrated for Epstein-Barr
virus, human herpes virus 8, and human T lymphotropic
virus 1. However this mechanism, even if intriguing, has
not been conclusively demonstrated for HCV[26].
Because the etiopathogenetic mechanisms underly-
ing HCV-related low and high-grade B-NHL may differ,
the optimal management approach also differs. Indolent,
HCV-related B-NHL is a subset of neoplasms character-
ized by an unrelenting course that requires chemotherapy
only if an aggressive behaviour develops. In this subset
of lymphomas, antiviral treatment alone may eradicate
the HCV infection and stop the chronic antigen-driven
lymphoproliferation. Clinical studies have demonstrated
the efficacy of antiviral treatment in these patients[9-11]. A
systematic review of Gisbert et al[8] has shown that in 65
HCV infected patients with lymphoproliferative disorders
treated with antiviral regimen, CR was achieved in 75% of
cases. In contrast, HCV negative patients did not respond
to interferon, indicating that CR in HCV positive patients
was not merely due to the antiproliferative action of inter-
feron.
Our study confirms that combined antiviral therapy is
effective in inducing CR in indolent, HCV-related B-NHL,
and that reaching SVR seems to be crucial in maintaining
it. In our studies most patients reaching SVR achieved
a CR, while 2 patients relapsing after treatment had a
progression of haematologic disease. However, two of
the HCV positive, indolent B-NHL reaching SVR had a
PR, suggesting that other mechanisms may intervene in
determining CR. Obviously, the high percentage of SVR
obtained in this group is also associated to the elevated
prevalence of genotype 2, a well known easier-to-treat
genotype. However, antiviral therapy of HCV-positive in-
dolent B-NHL is an attractive therapeutic option, even if
SVR is the objective.
For HCV-positive DLBCL, immunochemotherapy
is necessary. A recently published paper observed that
HCV-positive status is a risk factor for the development
of hepatitis flare in patients treated with rituximab-con-
taining regimens. In this retrospective study none of the
HCV-negative lymphoma patients receiving rituximab–
containing therapy developed hepatitis flares as compared
with a significant percentage in the HCV positive group.
However, even if no liver-related deaths deriving from the
hepatitis flare were observed in this paper, it was impos-
sible to define the exact mechanism of toxicity[27]. In our
Table 3 Results of antiviral treatment in patients with low grade B cell-non Hodgkin’s lymphoma
Sex Age
(yr)
HistologyStageHCVRNA
log10 (UI/mL)
Genotype Staging
(Ishak)
Treatment Treatment
duration
(mo)
Response to
treatment
Remission lymphoma
1F70Marginal
extranodal
Marginal
extranodal
Marginal
extranodal
Marginal
splenic
Marginal
splenic
Marginal
splenic
Marginal
nodal
Follicular
lymphoma
Follicular
lymphoma
Ⅳ
5.92a/2c0Peg 180 μg/wk + RBV 800 mg/d6 SVRComplete
hematological response
Complete
hematological response
Progressive disease
2F69
Ⅳ
5.42a6Peg 180 μg/wk + RBV 800 mg/d6SVR
3F64
Ⅳ
5.61bndPeg 180 μg/wk + RBV 1000 mg/d 12Relapser
4M 36
Ⅳ
5.521Peg 180 μg/wk + RBV 800 mg/d6SVR Partial response
5F 72
Ⅲ
6.0 1b2 Peg 180 μg/wk + RBV 1000 mg/d 12 SVR Partial response
6F65
Ⅳ
5.62a/2c ndPeg 180 μg/wk + RBV 1200 mg/d6 SVRComplete
hematological response
Complete
hematological response
Progressive disease
7F 70
Ⅳ
5.922 Peg 180 μg/wk + RBV 800 mg/d6SVR
8F55
Ⅲ
5.0 2a/2c6Peg 180 μg/wk + RBV 800 mg/d 6Relapser
9M67
Ⅳ
6.8 2a0Peg 180 μg/wk + RBV 800 mg/d6SVR Complete
hematological response
MU: Million of units; RBV: Ribavirin; SVR: Sustained virological response.
Pellicelli AM et al. HCV and Non Hodgkin’s Lymphoma

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WJH|www.wjgnet.com 283
study we treated all HCV-positive DLBCL patients with
CHOP-R regimen, and CR was obtained and maintained
over the period in 7 of 13 patients despite the persistence
of HCV infection. Hepatotoxicity, expressed by an in-
crease in transaminases and bilirubin, was noted in 2 pa-
tients, with liver biopsy showing cirrhosis in both (patients
14 and 24). However, in our study none of the patients
had to stop or modify treatment because of liver-related
complications.
In conclusion, indolent HCV-related B-NHL and
DLBCL have different biological and clinical features: the
former is associated with a higher prevalence of HCV
genotype 2 and a longer exposure to HCV infection,
whereas the latter more frequently shows infection with
genotype 1 and a shorter duration of HCV exposure.
These characteristics and the differential response of
indolent HCV-related lymphomas to antiviral treatment
suggest that these two groups might follow different
pathways of lymphomagenesis. Thus, we strongly believe
that antiviral treatment should be the first line of treat-
ment to be offered in these patients. As far as the treat-
ment of DLBCL patients is concerned, we observed that
liver-related complications can develop in HCV-positive
cases, but these are marginal and do not require modifica-
tions to the onco-hematological treatment schedule, thus
not affecting the opportunity of obtaining CR. Further
studies are needed to determine the utility of antiviral
treatment as consolidation therapy after cytostatic treat-
ment for high-grade B-NHL.
COMMENTS
Background
Non Hodgkin’s Lymphoma (NHL) is the hematologic malignancy with the highest
prevalence worldwide. Among the risk factor for NHL are primary and acquired
immune deficiency as well as several infectious agents such as hepatitis C virus
(HCV). A positive association between HCV and NHL has been confirmed in a
large number of studies. It has been reported that clearance of HCV infection by
antiviral treatment led to regression of the tumor burden in indolent HCV-related
NHL, while the therapeutic approach for HCV-related high grade NHL could be
different. In this study the authors have analyzed and compared the biological
and clinical features of HCV-related indolent B cell-non Hodgkin’s lymphoma
(B-NHL) vs HCV-related high grade lymphomas, such as diffuse large B cell lym-
phoma. Furthermore, the authors have evaluated the outcomes of the different
treatment approaches used in the management of these two types of B-NHL, and
evaluated the influence of HCV infection on disease course.
Research frontiers
HCV-related lymphomagenesis could be due to different immunopathologic
mechanisms. While in indolent HCV-related lymphoma an indirect role of HCV
in lymphomagenesis is hypothesized, in HCV-related high grade lymphoma a
direct mechanism could be possible. A deep understanding of the mechanism of
HCV lymphomagenesis is essential for the development of further therapeutic
approaches.
Innovations and breakthroughs
This is the first study that has analyzed and compared the biological and clinical
features of two subtypes of HCV-related B cell NHL. Characteristics of HCV infec-
tion such as viral genotype, duration of HCV infection, and histopathology could
be of fundamental importance to understand the different treatment approaches
used in the management of these two subtypes of HCV-related B cell NHL.
Applications
The observations could have clinical importance for future therapeutic approach-
es in HCV-related B cell NHL.
Terminology
HCV-related B cell NHL is a lymphoma that is linked to HCV infection
Peer review
This is a study that analyzes the mechanism of HCV-related lymphomagenesis
and then the rationale of therapeutic approaches.
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Pellicelli AM et al. HCV and Non Hodgkin’s Lymphoma