American Journal of Hematology 64:95–100 (2000)

Hepatitis C Virus in Non-Hodgkin’s Lymphoma.

A Reappraisal After a Prospective Case-Control Study
of 300 Patients
Pietro Pioltelli,1* Livio Gargantini,2 Edmondo Cassi,3 Luca Santoleri,2 Giorgio Bellati,4
Enrico Massimo Magliano,5 and Enrica Morra,2 on Behalf of the Lombardy Study Group on
HCV-Lymphoma
1
Hematology Unit, Ospedale San Gerardo de’ Tintori, Monza, Italy
2
Department of Hematology, Ospedale Maggiore Niguarda/Ca’ Granda, Milano, Italy
3
Department of General Medicine, Ospedale Civile, Legnano, Italy
4
Department of Hepatology, Ospedale Maggiore Niguarda/Ca’ Granda, Milano, Italy
5
Laboratory of Microbiology, Ospedale Maggiore Niguarda/Ca’ Granda, Milano, Italy

It is widely thought, but not yet explained, that there might be a pathogenetic link between
the infection of hepatitis C virus (HCV) and the onset of B non-Hodgkin’s lymphoma
(NHL). We studied the prevalence of serum anti-HCV antibodies among 300 NHL com-
paring it with the prevalence among 600 age- and sex-matched non-neoplastic subjects
as controls, 247 patients with non-lymphomatous neoplasm, and 122 patients treated
with immunosuppressive agents. We found a prevalence of 0.16 among NHL and 0.085
among controls and non-lymphomatous patients. Although the difference was statisti-
cally significant (P < 0.001), the odds ratio was 2.049 and its confidence intervals included
the equality. The HCV prevalence was independent of NHL subset, and the genotypes
distribution was the same among NHL and controls. We disclosed a HBsAg prevalence of
0.077 in NHL versus 0.008 in controls (P < 0.001) with an odds ratio of 9.9. We do not
believe that these findings support the hypothesis of an HCV pathogenetic role in lym-
phomagenesis because (i) the risk of previous infection is marginally higher in NHL than
in controls, (ii) a typical genotype distribution is lacking, as is a NHL clinico-histological
feature associated with HCV, and (iii) the higher prevalence of viral infection is not spe-
cific as witnessed by the high HBsAg prevalence. Am. J. Hematol. 64:95–100, 2000.
© 2000 Wiley-Liss, Inc.

Key words: hepatitis C virus; hepatitis B virus; non-Hodgkin’s B cell lymphoma;

lymphomagenesis

INTRODUCTION The participants of the Lombardy Study Group on HCV-Lymphoma

are as follows: P. Pioltelli, E.M. Pogliani, Div. Ematologia Osp. S.
Gerardo Monza; L. Gargantini, E. Morra, L. Santoleri, Div. Ematolo-
Both the evidence of a strict association between hepa-
gia Osp Niguarda Milano; E. Magliano, F. Chiodo, Lab. Microbiologia
titis C virus (HCV) and mixed cryoglobulinemia (MC) Osp Niguarda Milano; E. Cassi, Div. Medicina Osp. Legnano; B.
[1,2], and the observation that sometimes MC can evolve Canesi, D.A. Filippini, Div. Reumatologia Osp. Niguarda Milano; A.
to low-grade lymphoma [3] suggest a possible role of Silvani, L. Cirasino, Div. Medicina Rizzi Osp. Niguarda Milano; G.
HCV in the pathogenesis of B-cell non-Hodgkin’s lym- Bellati, Div. Epatologia Osp. Niguarda Milano; L. Isa, Div. Medicina
Osp. Gorgonzola; A. Musaio, Div. Medicina Osp S. Biagio Clusone;
phomas (B-NHL) [4]. This hypothesis is supported by
L. Uziel, Patologia Medica Osp. S. Paolo Milano; L. Montalbetti, Div.
evidence of HCV lymphotropism [5,6] as well as by the Medicina Osp. Busto Arsizio; S. Gianelli, Oncologia Clinica S. Carlo
demonstration of HCV-specific genomic sequences in Paderno Dugnano; A. Frosi, Div. Medicina II Osp. Sesto S. Giovanni;
pathologic lymph node tissue [7]. At present, however, a and L. Tedeschi, F. Vinci, Div. Oncologia Osp S. Carlo Milano.
possible pathogenetic role of HCV in human lymphomas
*Correspondence to: P. Pioltelli, Ospedale San Gerardo de’ Tintori,
is based on epidemiological data only [8].
Sezione di Ematologia, Via Donizetti 106, 20052 Monza (Milano),
A high frequency of HCV infection among B-NHL Italy. E-mail: ppiolte@tin.it
patients (excluding chronic lymphocytic leukemia, hairy
cell leukemia, Waldenström’s macroglobulinemia and Received for publication 10 February 1999; Accepted 5 January 2000
© 2000 Wiley-Liss, Inc.
96 Pioltelli et al.
multiple myeloma) has been reported in Italy (451 HCV- This group did not include any patient with hematologi-
positive among 1715 B-NHL) [3,4,7–16], Japan (6 of 65 cal malignancies, overt liver diseases (cirrhosis or asci-
patients) [17], USA (32 of 130 patients) [18], and Ven- tes), solid neoplasms, autoimmune diseases, or any pa-
ezuela (7 of 94 patients) [19], while the frequency of tient who had been treated with corticosteroid or
HCV infection is quite insignificant in the United King- immunosuppressive agents.
dom (1 of 268 patients) [20–22]. (2) Neoplastic pathologies. This group included 247
To date, few studies have assessed the frequency of consecutive patients: 122 men, 125 women, median age
anti-HCV antibodies in a large series of B-NHL. These 62 years (27 to 89), with solid neoplasm (93/247 colon
studies, however, lack a cohort of healthy subjects carcinoma, 85/247 breast cancer, and 69/247 lung can-
matched for sex and age as controls, essential to deter- cer). They had recently undergone to surgical treatment.
mine the frequency of anti-HCV antibodies in a healthy The criteria for inclusion were the same as in group 1.
comparable population. (3) Autoimmune disorders. We consecutively re-
The aim of this study is to evaluate the frequency of cruited 122 unselected patients (14 men, 108 women,
serum anti-HCV antibodies positivity in a large series of median age 59.5 years, range 18–92), with systemic lu-
B-NHL and to compare it with those observed in a group pus erythematosus and rheumatoid arthritis, treated with
of healthy subjects, in a group of patients with non- immunosuppressive drugs or corticosteroid for at least
lymphoid malignancies and in a group of immunosup- one year. The criteria for inclusion were the same as in
pressed patients. groups 1 and 2.

PATIENTS AND CONTROLS MATERIALS AND METHODS

Study Population NHL Diagnosis
From 01/01/96 to 30/06/97, 300 consecutive patients NHL was diagnosed by pathological biopsy, according
with diagnosis of B-cell NHL (145 men, 155 women; to the Working Formulation (WF) for NHL and the Re-
median age 63 years, range 17–92) were included in the vised European American Classification of Lymphoid
study regardless of their performance status, stage, and neoplasm (REAL), and by the immunophenotypic analy-
grade of disease. sis of surface T and B lymphocyte markers.
They were Italian-born, human immunodeficiency vi-
rus negative, heterosexuals, with no history of intrave- Viral Assays
nous drugs or alcohol abuse. None of them had received
interferon treatment. All were newly diagnosed patients, We used ELISA (Ortho HCV 3.0) and RIBA (Chiron
observed at eleven institutions in Lombardy (Northern RIBA HCV 3.0) tests for the detection of antibodies to
Italy). Other B-cell neoplasms (B-cell chronic lympho- hepatitis C virus, RT-“nested” PCR (sensitivity 200 cop-
cytic leukemia, acute leukemia, multiple myeloma, Wal- ies/mL) for HCV-RNA and INNO-LiPA HCV II line
denström’s macroglobulinemia), T-cell and putative probe assay for the genotyping of HCV.
natural-killer-cell neoplasms, and Hodgkin’s disease For the detection of HBV surface antigen we used the
were not included. The study population excluded pa- ELISA, Organon-Technica test.
tients with previous or concomitant solid neoplasm, other
Statistical Evaluation
hematological malignancies, or autoimmune disorders.
According to the REAL classification there were 8/300 The study was planned as observational, multicenter,
(2.6%) with lymphoplasmacytoid lymphoma/ and prospective, according to the case-control model,
immunocytoma and 16/300 (5.2%) with MALT lym- with case/control ratio of 1/2 and matching for sex and
phoma. age. We evaluated the differences of sex and age distri-
bution among the patients with non-Hodgkin’s lym-
Control Groups phoma (NHL), non-lymphoid malignancies (NLM), or
(1) Internal and surgical diseases. This group in- autoimmune disorders (AD), and the differences of fre-
cluded 600 unselected patients age- and sex-matched quencies of anti-HCV antibodies and HBV surface anti-
with the study population: 290 men and 310 women; gen (HBsAg) between sexes, among groups of cases
median age 64 years (18 to 92). The cases were consec- (NHL, matched controls, NLM, AD), WF categories of
utively recruited during their routine visits at medicine, NHL and four age classes: younger than 21, from 21 to
surgery, or traumatology departments during the recruit- 40, from 41 to 60, and older than 60.
ment period of the study population. They were Italian- Among the NHL patients bearing anti-HCV antibodies
born, human immunodeficiency virus negative, hetero- we studied the distribution of WF categories and the
sexuals, with no history of intravenous drugs or alcohol presence of extranodal lymphoma or involvement of
abuse. None of them had received interferon treatment. stomach, liver, or bone marrow comparing these frequen-
 HCV in NHL: A Reappraisal 97
cies with those of the same features in the whole NHL In NLM the lower confidence limit for the risk of
group and in the non-HCV subset. HBsAg presence overlaps with the upper limit of con-
We estimated the differences of age distribution trols, and the upper limit of NLM overlaps with the lower
among groups and between sexes with one-way ANOVA limit of NHL; the AD series is too small for a sound
and performed the remaining evaluations by contingency evaluation of confidence interval for this feature.In the
tables and Pearson’s ␹2 using Cochran’s method to test series as a whole the anti-HCV frequency is similar be-
the linear trend for the proportions. tween the sexes (P < 0.34) and it is significantly higher
We applied the odds ratio method to estimate the rela- among the older subjects (P < 0.001).
tive risk of HCV infection or HBsAg presence between Among NHL patients, sex (P < 0.9), age classes (P <
NHL patients and controls. 0.24), anti-HCV (P < 0.1), and HBsAg (P < 0.63) fre-
We obtained two-sided 95% confidence intervals es- quencies are uniformly distributed among WF categories,
timates for the proportions from z values and two-sided as shown in Table I.
95% confidence intervals estimates for odds ratios from Differently from the whole series, the anti-HCV dis-
the natural log of their standard error. tribution does not differ among age classes (P < 0.33) but
We used BMDP Statistical Software package release 7 a linear trend between frequency and age classes shows
for statistical evaluations and nQuery package release 2 a weak significance (P < 0.06).
(Statistical Solution Ltd) for confidence interval assess- No link is found between HCV and the extra-nodal
ment and power study. lymphoma (P < 0.62) or the involvement of marrow (P <
0.4) or stomach (P < 0.71) but the liver involvement is
more frequent in the HCV group (P < 0.02), as reported
RESULTS
in Table II.
The power of our study ranks 0.88 for anti-HCV The distribution of WF categories does not differ be-
evaluation and 0.99 for HBsAg evaluation under an ␣ tween HCV-positive and -negative NHL patients (P <
error equal to 0.05. 0.86) nor does the frequency of MALT lymphoma (P <
The distribution between sexes is the same among 0.76).
NHL (M/F ⳱ 1/1.07) and NLM (M/F ⳱ 1/1.02), but HCV-RNA has been detected, allowing genotype
females occur more frequently among AD (M/F ⳱ identification, in the serum of 86% of HCV-positive
1/7.71) with a significant (P < 0.001) difference. NHL patients and in the one of 79% of HCV-positive
The difference in age distribution varies significantly controls. The HCV genotypes are uniformly distributed
(P < 0.012) among groups, the younger classes being between NHL patients and controls (P < 0.51): the 2a2c
more frequent in AD (median age ⳱ 59.5; C.I. 18–82) genotype is found more frequently both in NHL (0.55)
and the older in NLM (median age ⳱ 62.5; C.I. 27–89). and controls (0.46), genotype 1b shows a frequency of
We found anti-HCV antibodies in the sera of 48 NHL, 0.325 among NHL and 0.462 among controls, and other
51 controls, 15 NLM, and 6 AD. Among these anti-HCV genotypes (1a, 2, 3a, 4) are 0.125 in frequency in NHL
bearing persons, 7 NHL, 4 controls, and 3 NLM reported and 0.077 in controls.
previous transfusions, with a prevalence of 0.12 (C.I.
0.06–0.18) in the overall series of anti-HCV-positive
DISCUSSION
subjects.
Anti-HCV is more frequent in NHL (0.16; C.I. 0.119– Our results confirm the association already reported
0.201) than in controls (0.085; C.I. 0.063–0.107), NLM between NHL and HCV and are in accordance with the
(0.085; C.I. 0.031–0.091), and AD (0.049; C.I. 0.011– latest and larger series which state that the anti-HCV
0.087) (P < 0.001), and the confidence interval in NHL antibodies frequency among NHL ranges from 0.1 to 0.2
is clearly separate from other groups’ intervals which [12,23].
overlap. The presence of cryoglobulins is rarer in our series
A NHL patient shows a risk of bearing anti-HCV an- than in the others, possibly for lack of patients with pre-
tibodies 2.049 times higher (C.I. 0.701–27.027) than a vious cryoglobulinemic syndrome, this finding being
matched control. contemporary or closely connected with the NHL diag-
We found HBsAg in the sera of 23 NHL, 5 controls, 9 nosis.
NLM, and 2 AD, none of them had history of transfusion. We could not find a specific behavior of anti-HCV-
The HBsAg is significantly more frequent in NHL positive NHL for WF categories or for organ involve-
(0.077; C.I. 0.047–0.107) and NLM (0.036; C.I. 0.013– ment and the frequency of liver involvement has a weak
0.059) than in controls (0.008; C.I. 0.001–0.015) and AD significance, being very rare (Table II).
(0.016; C.I. limit below 0) (P < 0.001), and the risk of The genotype distribution pattern we have observed in
bearing this antigen is 9.9 times higher in NHL than in NHL differs from that reported in hepatitis patients [24],
matched controls (C.I. 3.7–26.2). but it mirrors what we found in the control group.
98 Pioltelli et al.
TABLE I. NHL Features

WFa Age median HCV Freq. HBsAg Freq.

categories No. M/F (min–max) (conf. int. 95%) (conf. int. 95%)

A, B, C 84 1/1.1 63 (29–89) 0.167 (0.087–0.247) 0.060 (0.009–0.101)

D, E, F 73 1/1.36 64 (17–92) 0.137 (0.058–0.216) 0.055 (0.003–0.107)
G, H, I, J 136 1/1.03 63.5 (19–92) 0.612 (0.100–0.224) 0.103 (0.052–0.154)
MALT 16 1/1.8 61.5 (50–75) 0.188b 0
a
WF classification is available for 293 patients.
b
Lower confidence limit below 0.

TABLE II. NHL Features Among HCV-Positive and HCV-Negative Patients

HCV-positive NHL (48) HCV-negative NHL (252)

Bearing Bearing
Feature (overall freq.) feature Freq. (conf. int. 95%) feature Freq. (conf. int. 95%)

Extranodal inv. (0.593) 30 0.625 (0.488–0.762) 148 0.587 (0.526–0.648)

Marrow inv. (0.283) 16 0.333 (0.200–0.466) 69 0.274 (0.219–0.329)
Stomach inv. (0.067) 2 0.042a 18 0.071 (0.039–0.103)
Liver inv. (0.030) 4 0.083 (0.005–0.161) 5 0.020 (0.003–0.037)
Cryoglobulins (0.033) 3 0.063a 7 0.028 (0.026–0.030)
Age to 20 (0.007) 0 0 2 0.008a
Age 21–40 (0.090) 2 0.042a 25 0.099 (0.062–0.136)
Age 41–60 (0.300) 12 0.250 (0.128–0.372) 78 0.310 (0.253–0.367)
Age >60 (0.603) 34 0.708 (0.579–0.837) 147 0.583 (0.522–0.643)
WF A, B, Cb (0.286) 14 0.304 (0.071–0.437) 70 0.283 (0.227–0.339)
WF D, E, Fb (0.248) 10 0.217 (0.098–0.336) 63 0.255 (0.201–0.309)
WF G, H, I, Jb (0.464) 22 0.478 (0.334–0.622) 114 0.462 (0.400–0.524)
MALT (0.053) 3 0.062a 13 0.052 (0.022–0.082)
a
Lower confidence limit below 0.
b
WF classification is available for 293 patients.

We found a prevalence of HBsAg significantly greater non-neoplastic controls and suggest that, from this point
in the NHL group than in nonmalignant controls, al- of view, chronic hepatitis patients are those who differ
though this difference is smaller if compared with the from the normal population [24].
NLM group. These findings are quite different from The lack of references to HBsAg indicates that the
those currently reported, but the published papers fre- published series are too small to allow judgment of a
quently refer to ill-chosen controls such as groups dif- possibly rare but significant finding.
ferent in size from the NHL group, or drawn from the The differences among anti-HCV frequency in NHL,
general population or from blood donors [12,25], without in NLM and in the group of patients treated with immu-
correction for the nonrandom differences existing among nosuppressive therapy are too small to prove the hypoth-
these populations and NHL patients. The studies rarely esis of a pathogenetic role of the virus for NHL. Many
report the power of the analyses, therefore an evaluation authors mention the possibility that HCV can induce
of their conclusions could be defective. NHL, but to date no study has demonstrated this
The link between the contact with HCV and some [4,11,12,16,23]. The lymphotropic behavior of this virus
histological subsets or with more aggressive behavior of and its ability to induce a activation of the immune sys-
the lymphoma is irregularly found [10,12,15,16,23,25– tem [30,31] make a lymphoma-inducing capacity likely
29] probably because of the unreliable size of the series. but not proven. The finding of viral RNA in lymphoma-
On the other hand, the reported differences in the tous material [7] is not enough to demonstrate this, be-
genotypes distribution pattern between NHL and patients cause its lymphotropism makes the HCV presence fore-
with chronic liver disease are useless to define their seeable in organs with high lymphocyte traffic, and in
pathogenetic role because these patients had active hepa- situ hybridization hardly ever has shown the virus geno-
titis and were selected for Interferon treatment after he- mic material inside the neighboring epithelial or lym-
patic biopsy: those with silent HCV infections or hepatic phoid cells [7,32] and very rarely inside the lymphoma
cirrhosis, and those over a certain age were excluded cells [28].
from this assessment. Our findings show that the geno- The epidemiological arguments advanced to support
type pattern of NHL patients is the same as the one in the lymphomagenic activity are weakened by the high
 HCV in NHL: A Reappraisal 99
variability of study populations. Being the virus endemic cannot be attributed to a generic malignancy or to a de-
in some areas and sporadic in others, the local virus pressed immune competence. The small difference
prevalence closely parallels the prevalence of the cryo- among these groups, the identical genotype pattern be-
globulinemic syndrome, in which the viral RNA is hardly tween NHL and controls and the contemporary finding of
ever present, but follows neither NHL prevalence nor the a similar increase in the HBV virus do not support the
prevalence of the low-grade categories within lympho- hypothesis that HCV plays a role in lymphomagenesis.
mas. This finding is in accordance with a model assum-
ing the HCV as inducer of cryoprecipitation, not as lym-
phomagenesis agent. On the contrary, the frequency of REFERENCES
anti-HCV antibodies among NHL mirrors the local 1. Ferri C, La Civita L, Longombardo G, Greco F, Bombardieri S. Hepa-
prevalence in the general population [17,21,33,34], as if titis C virus and mixed cryoglobulinaemia. Eur J Clin Invest 1993;
the lymphoma patients may act as a reservoir for a virus, 23:399–405.
common and easily growing in the lymphoid tissue in- 2. Cacoub P, Fabiani FL, Musset L, Perrin M, Franguel L, Leger JM,
Huraux JM, Piette JC, Godeau S. Mixed cryoglobulinemia and hepa-
dependently of its oncogenic power. This hypothesis is
titis C virus. Am J Med 1994;96:124–132.
supported by the prevalence of infection from HBV, 3. Pozzato G, Mazzaro C, Crovatto M, Modolo ML, Ceselli S, Mazzi G,
higher than in the control group and possibly more than Sulfaro S, Franzin F, Tulissi P, Moretti M, Santini GF. Low-grade
HCV prevalence itself, and by the observation that also malignant lymphoma, hepatitis C virus infection, and mixed cryoglob-
the HBV has a tropism to mononuclear blood cells [35– ulinemia. Blood 1994;84:3047–3053.
39]. 4. Ferri C, Caracciolo F, Zignego AL, La Civita L, Monti M, Longom-
bardo G, Lombardini F, Greco F, Capochiani E, Mazzoni A, Mazzaro
Occasional patients suffering from chronic hepatitis C, Pasero G. Hepatitis C virus infection in patients with non-
have been reported to develop NHL with exclusive liver Hodgkin’s lymphoma. Br J Haematol 1994;88:392–394.
involvement [19,40,41] and some series of patients with 5. Ferri C, Monti M, La Civita L, Longombardo G, Greco F, Pasero G,
HCV-related liver disease have been reported to have a Gentilini P, Bombardieri S, Zignego AL. Infection of peripheral blood
greater risk of developing NHL [42]. Liver involvement, mononuclear cells by hepatitis C virus in mixed cryoglobulinemia.
Blood 1993;82:3701–3704.
however, is not rare and the regular echographic moni-
6. Galli M, Zehender G, Monti G, Ballarè M, Saccardo F, Piconi S, De
toring in hepatopathic patients facilitates its early diag- Maddalena C, Bertoncelli MC, Rinaldi G, Invernizzi F, Monteverde A.
nosis and acts as a confounder if the unmonitored general Hepatitis C virus RNA in the bone marrow of patients with mixed
population is assumed as control. A confounder may cryoglobulinemia and in subjects with noncryoglobulinemic chronic
arise also in the evaluation of lymphoma prevalence hepatitis type C. J Infect Dis 1995;171:672–675.
among patients with chronic liver disease, when the gen- 7. Sansonno D, De Vita S, Cornacchiulo V, Carbone A, Boiocchi M,
Dammacco F. Detection and distribution of hepatitis C virus-related
eral population is assumed as control. The age-range in proteins in lymph nodes of patients with type II mixed cryoglobuli-
liver patients and the one observed in lymphoma patients nemia and neoplastic or non-neoplastic lymphoproliferation. Blood
largely overlaps, but the former is different from that 1996;88:4638–4645.
observed in the community. We found a significant re- 8. Luppi M, Ferrari MG, Bonaccorsi G, Longo G, Narni F, Barozzi P,
lation between HCV infection and the middle and old Marasca R, Mussini C, Torelli G. Hepatitis C virus infection in subset
of neoplastic lymphoproliferations not associated with cryoglobuline-
ages, the age groups with the highest lymphoma preva- mia. Leukemia 1996;10:351–355.
lence. Nevertheless this parallelism does not reveal a 9. Cavanna L, Sbolli G, Tanzi E, Romanò L, Cuardi G, Buscarini E,
causal link: even if the statistical significance is lost, the Vallisa D, Berté R, Rossi A. High prevalence of antibodies to hepatitis
same trend is present in the NHL group, meaning that the C virus in patients with lymphoproliferative disorders. Haematologica
linkage between HCV infection and age group could be 1995;80:486–487.
10. Luppi M, Longo G, Ferrari MG, Ferrara L, Marasca R, Barozzi P,
stronger than the linkage between HCV infection and
Morselli M, Emilia G, Torelli G. Additional neoplasms and HCV
lymphoma. infection in low-grade lymphoma MALT-type. Br J Haematol 1996;
The studies assuming control groups other than the 94:373–375.
general population can not confirm the finding of a re- 11. Musto P, Dell’Olio M, Carotenuto M, Mangia A, Andriulli A. Hepa-
lation between HCV infection and NHL; a retrospective titis C virus infection: a new bridge between hematologists and gas-
study revealed an increase of NHL in a group of patients troenterologists? Blood 1996;88:752–754.
12. Mazzaro C, Zagonel V, Monfardini S, Tulissi P, Pussini E, Fanni M,
with liver cirrhosis, but none of these had HCV-related Sorio R, Bortolis R, Crovatto M, Santini G, Tiribelli C, Sasso F,
liver disease [43]. Furthermore, in a large series of HCV- Masutti R, Pozzato G. Hepatitis C virus and non-Hodgkin’s lympho-
related chronic hepatitis the ratio of frequencies of NHL mas. Br J Hematol 1996;94:544–550.
and Hodgkin’s disease were similar to those found in the 13. Zignego AL, Ferri C, Innocenti F, Giannini C, Monti M, Bellesi G,
community [44]. Gentilini P. Lack of preferential localization of tumoral mass in B-cell
non-Hodgkin’s lymphoma associated with hepatitis C virus infection.
We conclude that among NHL the prevalence of HCV
Blood 1997;89:3066–3068.
infection is higher than in non-neoplastic people and in 14. Andriani A, Bibas M, Di Giacomo C. Liver involvement during HCV
patients with non-lymphoproliferative malignancies or infection in chronic lymphoproliferative diseases. Haematologica
receiving immunosuppressive treatment. This difference 1996;81:589–590.
100 Pioltelli et al.
15. De Vita S, Sacco C, Sansonno D, Gloghini A, Dammacco F, Crovatto with hepatitis C infection. Clin Immunol Immunopathol 1997;84:139–
M, Santini G, Dolcetti R, Boiocchi M, Carbone A, Zagonel V. Char- 144.
acterization of overt B-cell lymphomas in patients with hepatitis C 31. Franzin F, Efremov DG, Pozzato G, Tulissi P, Batista F, Burrone OR.
virus infection. Blood 1997;90:776–782. Clonal B-cell expansion in peripheral blood of HCV-infected patients.
16. Silvestri F, Barillari G, Fanin R, Pipan C, Falasca E, Salmaso F, Zaja B J Haematol 1995;90:548–552.
F, Infanti L, Patriarca F, Botta GA, Baccarani M. Hepatitis C virus 32. De Vita S, Dammacco F, Gloghini A, Crovatto M, Santini G, Cornac-
infection among cryoglobulinemic and non-cryoglobulinemic B-cell chiulo V, Carbone A, Ferraccioli G, Dolcetti R, Sansonno D. Hepatitis
non-Hodgkin’s lymphomas. Haematologica 1997;82:314–317. C virus within a malignant lymphoma lesion in the course of type II
17. Izumi T, Sasaki R, Miura Y, Okamoto H. B cell malignancy and mixed cryoglobulinemia. Blood 1995;86:1887–1892.
hepatitis C virus infection (letter). Leukemia Res 1996;20:445. 33. McColl MD, Hogg RB, Cumming RL, McNeil IR, Tait RC, Singer IO.
18. Zuckerman T, Zuckerman E, Douer D, Fong TL, Nathwani BN, The role of hepatitis C virus in the aetiology of non-Hodgkins lym-
Velankar M, Gutekunst K, Oian GD, Levine AM. Hepatitis C virus phoma: a regional association? Leuk Lymphoma 1977;26:127.
infection in patients with B-cell non-Hodgkin’s lymphoma. Blood 34. King PD, Wilkes JD, Diaz-Arias. Hepatitis C virus infection in non-
1996;88(Suppl):223. Hodgkin’s lymphoma. A A Clin Lab Haematol 1998;20:107–110.
19. Page RD, Romaguera J, Osborne B, Cabanillas F. Primary hepatic 35. Trippler M, Gerken G, Meyer zum Buschenfelde KH, Grimm B,
lymphoma and association of hepatitis C viral infection. Blood Knolle P, Spies U, Goergen B, Hampl H. Ligase chain reaction (LCR)
1996;88(Suppl):223. assay for semi-quantitative detection of HBV DNA in mononuclear
20. Thalen DJ, Reamaekers J, Galama J, Cooreman MP. Absence of hepa- leukocytes of patients with chronic hepatitis B. J Viral Hepat 1996;3:
titis C virus infection in non-Hodgkin’s lymphoma. Br J Haematol 267–272.
1997;96:880–881. 36. Nassal M, Schaller H. Hepatitis B virus replication: an update. J Viral
21. Brind AM, Bassendine MF, Proctor SJ, Wallis J, Kestevan P, Burt A, Hepat 1996;3:217–226.
Watson JP. Non-Hodgkin’s lymphoma and hepatitis C virus infection. 37. Pardoe IU, Michalak TI. Detection of hepatitis B and woodchuck
Leuk Lymphoma 1996;21:127–130. hepatitis viral DNA in plasma and mononuclear cells from eparinized
22. McCool MD, Campbell Tait R. Hepatitis C virus infection in patients blood by the polymerase chain reaction. J Virol Methods 1995;51:
with lymphoproliferative disorders. Br J Haematol 1996;92:771. 277–288.
23. Silvestri F, Baccarani M, Botta GA, Falasca E, Russo D, Infanti L, 38. Oesterreicher C, Muller C, Petermann D, Sunder-Plassmann G, Pfeffel
Fanin R, Zaja F, Barillari G, Pipan C. Prevalence of hepatitis C virus F, Koch U, Hammer J. HBV and HCV genome in peripheral blood
infection in patients with lymphoproliferative disorders. Blood 1996; mononuclear cells in patients undergoing chronic hemodialysis. Kid-
87:4296–4301. ney Int 1995;48:1967–1971.
24. Nousbaum JB, Pol S, Nalpas B, Landais P, Berthelot P, Brechot C. 39. Baischer W, Muller C, Lesch O, Leitner H, Hajji M, Pfeffel F, Brichta
Hepatitis C virus type 1b(II) infection in France and Italy. Collabora- A. Infection with hepatitis B or C virus of peripheral blood mono-
tive study group. Ann Intern Med 1995;122:161–168. nuclear cells in serologically negative chronic alcoholic patients. J
25. De Rosa G, Rotoli B, Matarazzo M, Picardi M, Chiurazzi F, Apuzzo Hepatol 1995;23:481.
A, Grimaldi M, Garofalo S, Notaro R, De Renzo A, Gobbo ML. High 40. Mohler M, Stremmel W, Goeser T, Kallinowski B, Gutzler F. Primary
prevalence of hepatitis C virus infection in patients with B-cell lym- hepatic high-grade non-Hodgkin’s lymphoma and chronic hepatitis C
phoproliferative disorders in Italy. Am J Hematol 1997;55(2):77–82. infection. Dig Dis Sci 1997;42:2241–2245.
26. Luppi M, Longo G, Ferrari MG, Ferrara L, Marasca R, Barozzi P, 41. Ellenrieder V, Adler G, Klatt S, Muller D, Beckh K. Intrahepatic
Morselli M, Emilia G, Torelli G. Prevalence of HCV infection and high-grade malignant non-Hodgkin lymphoma in a patient with
second neoplasms in marginal zone lymphomas. Br J Haematol 1997; chronic hepatitis C infection. Z Gastroenterol 1996;34:283–285.
96:873–874. 42. Ferri C, Zignego AL, Lombardini F, Longombardo G, Caracciolo F,
27. Luppi M, Longo G, Ferrari MG, Barozzi P, Marasca R, Morselli M, Cecchetti R, Giannini C, Monti M, La Civita L. Chronic hepatitis C
Valenti C, Mascia T, Vandelli L, Vallisa D, Cavanna L, Torelli G. and B-cell non-Hodgkin’s lymphoma. Q J Med 1996;89:117–122.
Clinico-pathological characterisation of hepatitis C virus-related B- 43. Lombardo L, Rota Scalabrini D, Vineis P, De La Pierre M. Malignant
cell non-Hodgkin’s lymphomas without symptomatic cryoglobuline- lymphoproliferative disorders in liver cirrhosis. Ann Oncol 1993;4:
mia. Ann Oncol 1998;9:495–498. 245–250.
28. Ohsawa M, Tomita Y, Hashimoto M, Kanno H, Aozasa K. Hepatitis C 44. Roffi L, Pioltelli P, Mascoli N, Scalori A, Panizzuti F, Pozzi M,
viral genome in a subset of primary hepatic lymphomas. Mod Pathol Minola E, Donada C, Del Poggio P, Rinaldi G, Paris B, Fornaciari G,
1998;11:471–478. Giusti M, Colloredo G, Riboli P, Morales R, Sangiovanni A, Bellia V,
29. Ascoli V, Lo Coco F, Artini M, Levrero M, Martelli M, Negro F. Marin R, Redaelli A, Mancia G. Mixed cryoglobulinemia and lym-
Extranodal lymphomas associated with hepatitis C virus infection. Am phoproliferative malignancies in HCV-RNA positive liver disease: a
J Clin Pathol 1998;109:600–609. survey on 1597 patients. International Association for the Study of the
30. Bansal AS, Powell EE, Prichard P, Hogan PG, Bruce J. Serum soluble Liver Biennal Scientific Meeting, Chicago, November 1998. Hepatol-
CD23 but not IL8, IL10, GM-CSF, or IFN-␥ is elevated in patients ogy 1998;28(Suppl):210a.