Oral diseases associated with hepatitis C virus infection. Part 1. sialadenitis and salivary glands lymphoma.

Abstract

Morbidity associated with hepatitis C virus (HCV) infection is due not only to the sequelae of chronic liver disease, but also to a variety of extraheaptic manifestations (EHM). Some of the most frequently reported EHM of HCV infection involves the oral region predominantly or exclusively and they are the topics of this 2-part review. The current part 1 discusses the evidences on the association of salivary glands disorders with HCV. HCV- infected patients may frequently have histological signs of Sjögren-like sialadenitis with mild or even absent clinical symptoms. However, the pathogenetic role of HCV in Sjogren Syndrome (SS) development and the characteristics distinguishing classic SS from HCV-related sialadenitis are still an issue. It is unclear if the virus may cause a disease mimicking primary SS or if HCV is directly responsible for the development of SS in a specific subset of patients. Notably, some patients may present a triple association between HCV, SS-like sialadenitis and salivary gland lymphoma and the virus may be involved in the lymphomagenesis. The risk of having a salivary gland lymphoma is particularly high in patients with mixed cryoglobulinemia. Little attention has been paid to the effects of anti-HCV treatment on sialadenitis or lymphoma development.

Full text

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HOT TOPIC
Oral diseases associated with hepatitis C virus infection.
Part 1. Sialadenitis and salivary glands lymphoma
M Carrozzo
Department of Oral Medicine, School of Dental Sciences, University of Newcastle upon Tyne, Newcastle upon Tyne, UK
Morbidity associated with hepatitis C virus (HCV) infec-
tion is due not only to the sequelae of chronic liver dis-
ease, but also to a variety of extraheaptic manifestations
(EHM). Some of the most frequently reported EHM of
HCV infection involves the oral region predominantly or
exclusively and they are the topics of this 2-part review.
The current part 1 discusses the evidences on the asso-
ciation of salivary glands disorders with HCV. HCV-
infected patients may frequently have histological signs of
Sjo ¨gren-like sialadenitis with mild or even absent clinical
symptoms. However, the pathogenetic role of HCV in
Sjogren Syndrome (SS) development and the character-
istics distinguishing classic SS from HCV-related sialade-
nitis are still an issue. It is unclear if the virus may cause a
disease mimicking primary SS or if HCV is directly
responsible for the development of SS in a specific subset
of patients. Notably, some patients may present a triple
association between HCV, SS-like sialadenitis and salivary
gland lymphoma and the virus may be involved in the
lymphomagenesis. The risk of having a salivary gland
lymphoma is particularly high in patients with mixed
cryoglobulinemia. Little attention has been paid to the
effects of anti-HCV treatment on sialadenitis or lym-
phoma development.
Oral Diseases (2008) doi: 10.1111/j.1601-0825.2007.01436.x
Keywords: hepatitis C virus; sialadenitis; Sjogren Syndrome;
lymphoma; cryoglobulinemia
Introduction
Hepatitis C virus (HCV) is an enveloped, RNA virus
that was isolated in 1989 from a chimpanzee chronically
infected by contamination with a human factor VIII
concentrate (Choo et al, 1989). The virus genome is a
linear, single-stranded RNA of ?9600 nucleotides,
which contains a single open reading frame (ORF)
encoding a polyprotein precursor of about 3000 amino
acids (Major and Feinstone, 1997). The ORF is
processed into structural (core, E1 and E2) and non-
structural proteins (NS2, NS3, NS4a, NS4b, NS5a and
NS5b) (Duibuisson, 2007). As HCV genome functions
as a messenger RNA for its polyprotein translation, it is
also referred to as the positive-strand RNA. The
replication of HCV RNA is believed to occur in the
cytoplasm, via its transcription into a complementary,
genomic-length RNA, alternatively known as negative-
strand HCV RNA. Moreover, during the replicative
process the double-stranded ?replicative form’ form
(consisting of the fully base-paired genomic- and neg-
ative-strand viral RNA’s) and NS proteins are synthe-
sized. Thus, while the mere detection of positive-strand
HCV RNA does not definitively prove replication, the
most important indicator of HCV genomic replication
within a given tissue is the production of negative strand
HCV-RNA (Negro et al, 1999; Blackard et al, 2006).
HCV has an extremely variable genome with six distinct
genotypes and multiple subtypes that have been identi-
fied (Le Guillou-Guillemette et al, 2007). Furthermore,
sequence variants forming a quasi-species may circulate
within an individual, possibly as a consequence of
ongoing immune surveillance and viral mutations (Toy-
oda et al, 1998). HCV is one of the major causes of
chronic liver disease worldwide. The overall estimated
prevalence of HCV infection is 2.2%, representing
approximately 130 million infected people worldwide
(Alter, 2007). The lowest prevalence of anti-HCV
antibodies (0.01–0.1%) has been reported in the UK
and Scandinavia, whilst the highest HCV prevalence has
been reported in Egypt (15–20%) (Alter, 2007). Inter-
estingly, different countries, including the US, Spain,
Italy and Japan, belonging to regions of the world with
similar overall average prevalences of HCV infection
(1.0–1.9%), have different patterns of age-specific
prevalence. In the United States, prevalence is highest
among persons 30–49 years old whereas in Spain, Italy
and Japan persons >50 years old account for most
Correspondence: Prof M Carrozzo, Department of Oral Medicine,
School of Dental Sciences, University of Newcastle upon Tyne,
Framlington Place, Newcastle upon Tyne, NE2 4BW, UK. Tel: +44
191 222 6797, Fax: +44 191 222 6137, E-mail: marco.carrozzo@
ncl.ac.uk
Received 29 August 2007; revised 4 October 2007; accepted 24 October
2007
Oral Diseases (2008). doi:10.1111/j.1601-0825.2007.01436.x
? 2008 The Author. Journal compilation ? 2008 Blackwell Munksgaard
All rights reserved
http://www.blackwellmunksgaard.com

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infections (Alter, 2007). An estimated 27% of cirrhosis
and 25% of hepatocellular carcinoma worldwide occur
in HCV-infected patients (Perz et al, 2006).
Morbidity associated with HCV infection is due not
only to the sequelae of chronic liver disease, but also to a
variety of extraheaptic manifestations (EHM) (Table 1).
Up to 74% of the HCV-infected patients might develop
at least one EHM during the course of the infection
(Cacoub et al, 1999, 2000). Because of the paucity of
specific symptoms and signs caused by HCV, EHM
could represent the first signal of this infection. More-
over, the extraheaptic tissues might act as reservoir for
HCV and this may have a profound effect on HCV
transmission, morbidity and treatment (Blackard et al,
2006). One approach used to study the pathogenesis of
HCV-EHM is to follow its replicative pattern in infected
tissue and to establish anatomo-clinical correlations. A
series of extraheaptic cell types possibly supporting
HCV replication has been proposed, including periph-
eral blood mononuclear cells, pancreas, thyroid, adrenal
gland, kidney, lung, spleen, gastric, brain, oral mucosa,
and skin cells (De Vita et al, 2000; Laskus et al, 2000;
Nagao et al, 2000). Nonetheless, laboratory confirma-
tion of extraheaptic HCV replication is complicated by
technical challenges and by the lack of in vitro system to
investigate non-hepatic replication. The association of
some EHM with HCV is very close, while for others it is
strongly suspected and in other cases only slightly
indicated by anecdotal data (Table 1). Some of the most
frequently reported EHM of HCV infection, involve the
oral region predominantly or exclusively. Some reviews
on non-hepatic diseases associated with HCV infection,
focused on its oral manifestations, are available (Lodi
and Porter, 1997; Roy and Bagg, 1999; Carrozzo and
Gandolfo,2003; Chainani-Wu et al, 2004; Nagao and
Sata, 2004). This current 2-part review focuses on
sialadenitis and salivary gland (SG) lymphomas (Part
1) and on lichen planus and other oral diseases possibly
associated with HCV infection (Part 2). Related issues
as the possible transmission of HCV by saliva (see
Ferreiro et al, 2005 for a comprehensive review) and the
influence of HIV-coinfection on oral manifestations of
HCV are beyond the aims of this review and are not
addressed.
Sjo¨gren-like Sialadenitis
Cryoglobulins are abnormal proteins that precipitate as
serum is cooled below core body temperature and
resolubilize when rewarmed (Dammacco et al, 2001).
They are detectable in up to 60% of HCV-infected
patients (Saadoun et al, 2007). Given the strong asso-
ciation between HCV infection and essential mixed
cryoglobulinemia (MC) (Ferri et al, 1991) and the high
prevalence of idiopathic Sjogren syndrome (SS) in
essential MC, an association between HCV infection
and the SS has been postulated (Gumber and Chopra,
1995). In 1992 a French study found that 57% of HCV-
associated chronic liver disease patients exhibited a
Table 1 Classification of extrahepatic manifestations of hepatitis C virus infection (modified from Zignego et al, 2007)
A: Association defined on the
basis of high prevalence and
pathogenesis
B: Associations defined on the
basis of higher prevalences than
in controls
C: Associations to be
confirmed⁄characterisedD: Anedoctal observations
Mixed cryglubulinemia B-cell non-Hodgkin lymphoma
Monoclonal gammopathies
Porphyria cutanea tarda
Lichen planus
Autoimmune thyroiditis
Thyroid cancer
Sialadenitis (Sjogren-like)
Alveolitis-lung fibrosis
Diabetes mellitus
Non-cryoglobulinaemic
nephropathies
Aortic atherosclerosis
Psoriasis
Peripheral⁄central neuropathies
Chronic polyarthritis
Rheumatoid arthritis
Polyartheritis nodosa
Bechet’s syndrome
Poly⁄dermatomyositis
Fibromyalgia
Chronic urticaria
Chronic pruritus
Kaposi’s pseudo-sarcoma
Vitiligo
Cardiomyopathies
Mooren corneal ulcer
Erectile dysfunctions
Necrolytic acral erythema
Erythema multiforme
Eythema nodosum
Malakoplakia
Still’s disease
Unilateral nevoid telangectasia
Disseminated superficial porokeratosis
Acquired epidermolysis bullosa
Pulmonary fibrosis
CRST (calcinosis cutis,
Raynaud’s phenomenon, sclerodactyly,
and telangiectasia) syndrome
Antiphospholipide syndrome
Oral carcinoma
Oral diseases associated with hepatitis C virus infection (Part 1)
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2
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grade 3 or 4 sialadenitis [according to Chisholm and
Mason’s classification, (Chisholm and Mason, 1968;
Haddad et al, 1992)]. A subsequent study noted that, in
contrast to SS, lymphocytic infiltration in HCV-infected
patients was pericapillary rather than periductal, with
no destruction of the SG ducts, and that lymphocytic
capillaritisresembledan
(Pawlotsky et al, 1994a). Further data (Almasio et al,
1992; Haddad et al, 1992; Guisset et al, 1993; Pawlotsky
et al, 1994a; Pirisi et al, 1994; Poet et al, 1994; Boscagli
et al, 1996; Taliani et al, 1997; Cacoub et al, 1999, 2000;
Verbaan et al, 1999; Coates et al, 2000; Ferreiro et al,
2001; Henderson et al, 2001; Loustaud-Ratti et al, 2001)
have shown that up to 80% of HCV-infected individuals
may have some salivary or lacrimal abnormality,
frequently represented by histological signs of mild
sialadenitis (Tables 2–3). However, clinical evidence of
dry mouth and mainly of dry eyes is often absent
(Table 3). Several studies seem indeed to indicate that
this sialadenitis may be significantly different from that
of SS. There is no female predominance, no specific
earlystage ofdisease
antinuclear [SS-A (anti-RO) and SS-B (anti-LA)] anti-
bodies, a frequent association with the HLA-DQB1*02
(Smyth et al, 2007) rather than with HLA-DR3 allele,
milder histopathology (with a CD8+ rather than a
CD4+ T-cell predominance), and apparently fewer
clinical symptoms (Pawlotsky et al, 1994a; Pirisi et al,
1994; Scott et al, 1997). Moreover, whereas in primary
SS there is a predominantly Th1 response, in HCV-
associated sialadenitis, the pattern of circulating cyto-
kines indicates a Th2 response (Ramos-Casals et al,
2002). HCV may be present in the saliva of 83% of
patients with HCV-associated sialadenitis (Jorgensen
et al, 1996) and is also detectable in tears in concentra-
tions higher than serum (Feucht et al, 1994). In contrast,
from 0% to 19% of patients with frank SS can be HCV-
infected, the frequency varying with the geographical
region, the HCV test used, and the inclusion criteria.
(Marson et al, 1991; Vitali et al, 1992; King et al, 1994;
Marrone et al, 1995; Porter et al, 1996; Roy and Bagg,
1999; Fox et al, 2000; Ramos-Casals et al, 2001).
Indeed, several authors have reported prevalence of
HCV antibodies in SS primary patients ranging from
3% to 75% using second-generation immunoenzymatic
(ELISA) tests, from 14% to 19% using third-generation
ELISA, and from 5% to 19% using second-generation
confirmatory immunoblot assay (RIBA) (Ramos-Casals
et al, 2001). Moreover, false-positive ELISA HCV tests
have been reported when hypergammaglobulinemia
(frequently observed in SS) is present (Marson et al,
1991; Vitali et al, 1992), and thus confirmatory tests are
clearly recommended so that bias can be avoided. The
problem of the diagnostic criteria used has been
highlighted by Loustaud-Ratti et al (2001), who re-
ported that the prevalence of SS in a cohort of 45
French HCV-infected patients increased from 8% to
38% according to the Fox and the 1996 European
criteria, respectively. In the recently reported American-
European classification criteria for SS the presence of
HCV is considered an exclusion criterion (von Bultzing-
slowen et al, 2007). However, the pattern of clinical
expression of HCV-related sialadenitis is still not well-
defined (Carrozzo, 2001) and the term of ?SS-secondary
to HCV’ has been proposed for those patients with
chronic HCV infection who fulfil the 2002 Classification
Criteria for SS (Ramos-Casals et al, 2005). However,
recent epidemiological studies report conflicting results.
An extremely large retrospective case-control USA
study in 2002 found no significant difference in the
prevalence of SS between 32.204 HCV-infected patient
and 136.816 randomly chosen controls whereas it found
a strong association between HCV infection and lichen
planus, porphyria cutanea tarda, cryoglobulimenia and
non-Hodgkin lymphoma (El-Serag et al, 2002). Simi-
larly, two other studies from dental units found no
significant hyposalivation and increased xerostomia in
HCV infected patients compared to healthy controls and
hepatitis B virus (HBV) infected patients (Ferreiro et al,
2001; Ubertalli Ape et al, 2006). Contrarily, a Japanese
study (Nagao et al, 2003) found a significantly higher
prevalence of SS in patients with chronic HCV infection
compared to patients with chronic HBV infection
Table 2 Prevalence of hepatitis C virus (HCV) infection in patients
with Sjo ¨ gren’s syndrome (SS)
Country Referencen
SS
diagnostic
criteria HCVve+a(%)
Francede Bandt, 1992
Loustaud-Ratti
et al, 1992
Mariette et al, 1993
Barrier et al, 1993
Vidal et al, 1994
Wattiaux et al, 1995
Boscagli et al, 1996
Jorgensen et al, 1996
Vitali et al, 1992
Szodoray et al, 2001
Wanchu et al, 2003
Aceti et al, 1992
Vitali et al, 1992
Frisoni et al, 1994
Masaki and
Hayashi, 1995
Garcia-Carrasco
et al, 1999
Coll et al, 1997
Fernandez-Campillo
et al, 1997
Selva-O’Callaghan
et al, 1999
Verbaan et al, 1999
Porter et al, 1996
King et al, 1994
Marrone et al, 1995
20
26
NA
NA
10
8
20
22
28
109
23
62
22
213
23
26
44
26
98
Fox Ib
Na
Fox Ib
European
NA
European
Vitali
European
European
Fox Ib
Vitali
NA
NA
10
9
14c
3
5c
19
5
6
4.4c
0
5
4
11c
Greece
Hungary
India
Italy
Japan
Spain90 European14
31
26
European
European
10
19c
98European7c
Sweden
UK
USA
USA
53
18
44
100
Copenhagen
European
NA
Fox IId
2
0c
0
1
NA, Not available.
aRIBA confirmed.
bFox et al (1986). In contrast to the Fox (San Diego) classification
system, the European-proposed (including Vitali and Copenhagen)
criteria can be fulfilled without a requirement for histologic or
serologic abnormality.
cELISA only.
dFox and Saito (1994). The last Fox classification excludes patients
with a history of pre-existing diseases such as hepatitis C, lymphoma,
sarcoidosis, or other causes of lymphocytic infiltrative disease.
Oral diseases associated with hepatitis C virus infection (Part 1)
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3
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Page 4

(25.9% vs 3.4%, respectively). However, the HCV group
was significantly older of the HBV one and the Authors
used the old European criteria, (Vitali et al, 1996)
probably overestimating the number of patients with
SS. There are also scanty and controversial data about
the eventual effect of hyposalivation on oral health of
HCV-infected patients. Whereas a UK study (Hender-
son et al, 2001), mainly including intravenous drug
users, suggested that patients with chronic HCV infec-
tion may have significant oral health needs, a more
recent Italian study found no significant differences in
oral health between patients with chronic HCV and
HBV infection (Ubertalli et al, 2006).
Pathogenesis of HCV-related sialadenitis
Viral factors such as genotype or viral load are not
apparently related to the onset of sialadenitis (Pawlot-
sky et al, 1994b; Loustaud-Ratti et al, 2001) even if it
has been reported that patients with HCV-RNA in the
saliva are more likely to complain of xerostomia (Roy
et al, 1998). However, the whole salivary flow is not
associated with the presence of the virus in the saliva
(Ferreiro et al, 2001). HCV is uncommon in SS patients
without MC (King et al, 1994; Verbaan et al, 1999).
Nevertheless, not all the HCV-positive patients with
evidence of SG abnormalities have detectable serum
cryoglobulinemia (Pawlotsky et al, 1994a; Loustaud-
Ratti et al, 2001). HCV is distantly related to flavivi-
ruses (Houghton et al, 1991), which are able to infect
the SGs of their arthropod vector. Unfortunately, the
available data on direct HCV replication of SGs are still
scanty and controversial. HCV antigens have been
immunohistochemically detected in SG epithelial cells
(De Vita et al, 1995) but not invariably (Verbaan et al,
1999). Whereas SGs of patients with chronic HCV
infection but without clinical and histological signs of
sialadenitis were not infected (Taliani et al, 1997),
positive- and negative-strand HCV-RNA has been
detected in minor SGs of patients with sialadenitis and
chronic hepatitis C by PCR and in situ hybridization
(Takamatsu et al, 1992; Biasi et al, 1995; Arrieta et al,
2001). In particular, HCV seems to infect and replicate
in epithelial cells of the SG acini. However, there is no
correlation between the percentage of infected SG
epithelial cells and the serum HCV-RNA titre, and the
infected cells did not show any differences with respect
to unaffected ones (Arrieta et al, 2001). A more recent
study using in situ hybridization, western blot and
immunohistochemistry reports negative results (Ohoka
et al, 2003). An animal model of transgenic mice
carrying the HCV envelope genes E1 and E2 has been
constructed (Koike et al, 1997). The mice developed an
exocrinopathy involving the SGs and lachrymal glands
Table 3 Lacrimal or salivary abnormality in patients with hepatitis C virus (HCV) infection (modified from Carrozzo and Gandolfo, 2003)
CountryReferencen
Xerostomia
(%)
Hyposalivation
(%)
Histological evidence
of sialadenitis (%)
Lacrimal
disturbs (%)
Australia
France
Coates et al, 2000
Haddad et al, 1992
Guisset et al, 1993
Pawlotsky et al, 1994a
Poet et al, 1994
Boscagli et al, 1996
Cacoub et al, 1999
Cacoub et al, 2000
Loustaud-Ratti et al, 2001
Almasio et al, 1992
Pirisi et al, 1994
Taliani et al, 1997
Salaffi et al, 1997
Ubertalli Ape et al, 2006
87
28
50
61
22
23
18.4
35.7
–
–
0
30.7
11
12
62
–
0
5
0
50.9
50a
–
–
–
–
13.4d
–
–
–
–
–
–
–
60.4
––
10010.3b
50c
26b
–
–
11e
12e
31e
14b,f
0b
–
0g
45.3e
30.2b
13.6e
24.7h
–
57b
–
–
49
20
60.8
–
–
80
–
77
0
47.2%
–
1614
321
45
22
32
20
36
51
Italy
Japan Nagao et al, 200381 27.223.4NA
Spain
Sweden
UK
Ferreiro et al, 2001
Verbaan et al, 1999
Henderson et al, 2001
74
21
40
8
5
8
16.6i
33d
NAl
–
11
–
NA, Not available.
aUnstimulated and stimulated whole sialometry.
bPositive Schirmer test.
cDetail of the test used not available.
dUnstimulated whole sialometry.
eXerophthalmia.
f45% of the patients had not further defined ?lacrimal dysfunctions’.
gNo evidence of xerophthalmia.
hDecreased tear secretion.
iPercentage of patients with hyposalivation measured by mean of the Salivette system not available; however, the salivary flow rates in HCV+ve
patients were significantly lower than those in healthy controls.
lStimulated whole sialometry; not significantly altered compared with healthy controls.
Oral diseases associated with hepatitis C virus infection (Part 1)
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(LGs) in 84% of cases. Initially, pericapillary lympho-
cytes were found, but soon focal infiltrates of small
lymphocytes appeared, closely resembling the Chisholm
and Mason grade 3 or 4 sialadenitis noted in humans
(Haddad et al, 1992). Nests of lymphatic infiltrates were
also noted in the LGs, but they occurred later and were
less extensive than those found in the SGs. This model
clearly suggests a direct role of the viral proteins in the
pathogenesis of HCV-related sialadenitis. Moreover,
because lymphocytic capillaritis preceded sialadenitis,
this may reflect the pathological sequence in Sjo ¨ gren-like
sialadenitis occurring in human patients. The model also
predicts that xerophthalmia, would be a late develop-
ment. The pathogenesis of this sialadenitis in transgenic
mice is unclear, but it seems unlikely to be induced by an
immune reaction against ductal cells expressing viral
antigens, as only one out of 20 transgenic mice showed a
weak antibody reaction to E1 protein. Alternative
explanations include the induction of interferon-c or
interleukin 2 by HCV proteins or the induction of an
immunological disturbance by the transgene. Human La
antigen (also called SS-B) is an RNA-binding protein of
50⁄52-kDa, which is predominantly localized within the
nucleus. Anti-La autoantibodies are characteristically
detected in SS patients although the implication of these
autoantibodies in disease pathogenesis is still unclear.
Nearly 70% of SS–HCV patients had positive anti-
nuclear antibodies (ANA) but two-thirds of these
ANA+ patients had negative Ro⁄La antibodies (Ca-
coub et al, 2000). Of note, a higher rate of anti-Ro⁄La
positivity has been recently reported when HCV+
patients with subjective and objective sicca manifesta-
tions were more strictly selected and anti-Ro⁄La+ were
investigated by means of both ELISA and immunoblot
assays (De Vita et al, 2002). Interestingly, it has been
shown that La protein specifically interacts with both
the 5¢- and 3¢-UTR of HCV RNA (Spangberg et al,
2001). La protein plays a functional role in internal
initiation of translation of the polyproteins of the HCV
RNA stimulating HCV internal ribosome entry site-
mediated translation (Ali and Siddiqui, 1997; Ali et al,
2000). La protein is a potent regulator and enhancer of
HCV replication (Honda et al, 2005) and the expression
of this autoantigen is significantly reduced after the
administration of interferon-a (IFN-a) in a dose-depen-
dent manner. However, there are no studies on the role
of La in HCV-related sialadenitis. The possible presence
of a common epitope between the HCV-E2 protein and
an antigenic protein in the SGs has been suggested
(Ohoka et al, 2003) but not substantiated further. On
the other hand, Cacoub et al (2002) did not observed
frank improvement in patients with sicca syndrome
under anti-HCV antiviral course, even after sustained
virological response and in an other small study more
than 50% of the patients with sicca-syndrome and HCV
develop severe immune-complication under IFN-a
treatment (Doffoel-Hantz et al, 2005). Sicca syndrome
was improved only in patients treated with IFN-a and
ribavirin but it is unclear if this improvement was due to
HCV eradication or ribavirin treatment (Doffoel-Hantz
et al, 2005).
Salivary gland lymphoma
B-cell non-Hodgkin’s lymphoma (NHL) is a complica-
tion of both SS and chronic HCV infection (Ferri et al,
1994; Luppi et al, 1996; Zuckerman et al, 1997; Ascoli
et al, 1998). In a recent meta-analysis, the pooled relative
risk (RR) of all NHL among HCV-positive individuals
was 2.5 (95% CI, 2.1–3.0), but substantial heterogeneity
was found between studies and by study design. The
strongest source of heterogeneity seemed to be the
prevalence of HCV among NHL-free study subjects.
RRs were consistently increased for all major B cells-
NHL subtypes, T cells-NHL, and primary sites of NHL
presentation (Dal Maso and Franceschi, 2006). Cases of
primary SG lymphoma in patients with HCV infection
have been reported (De Vita et al, 1995; Luppi et al,
1996; Ascoli et al, 1998; Ambrosetti et al, 2004; Ramos-
Casals et al, 2007), mainly associated with type II
cryoglobulinemia or SS. Most of the cases involved a
single SG, usually the parotid, but very rarely also the
submandibular and even minor SGs were affected
(Ambrosetti et al, 2004). Clinically, these patients may
present with frequent parotid enlargement and cryog-
lublins-related vasculitis (Ramos-Casals et al, 2007).
Lymphomas occurring in SS and HCV infection share
several characteristics, such as predominance of low-
grade, marginal zone histological type, frequency of
mucosal localization (mucosa-associated lymphoid tis-
sue [MALT] lymphomas), possible transformation into a
large B-cell lymphoma, association with asymptomatic
low-level cryoglobulinemia (De Vita et al, 1997; Mari-
ette, 2001). In a recent Italian multicentre study, the
estimated risk for lymphoproliferative disorders was
found to be 35 times higher in patients with MC than in
the general population (Monti et al, 2005). It has been
proposed that, in both diseases, the first event of
lymphomagenesis may be chronic stimulation of poly-
clonal B-cells capable of secreting rheumatoid factor
(RF) at the site of the disease (De Vita et al, 1997;
Mariette, 2001). In primary SS, lymphoma seems to be
triggered by RF-secreting B cells closely associated with
the 17109 and G-6 idiotypes (Tzioufas, 1996), while in
HCV-infected patients, a possible association with an
antibody response to the protein E2 of HCV has been
suggested (Starkebaum and Sasso, 2004). A predictive
value of RF for lymphoma developing in patients with
chronic HCV has been postulated but not demonstrated
(Ramos-Casals et al, 2007). The effectiveness of IFN-a in
inducing clinical remission of a MALT lymphoma of
both parotid and submandibolar SGs in a SS-HCV
patient has been reported (Caramaschi et al, 1999).
However, there are scanty available data on the effect of
anti-viral treatment in patients with HCV-related SSwho
developed a SG-lymphoma.
Conclusions
The pathogenetic role of HCV in SS development and
the characteristics distinguishing classic SS from HCV-
related sialadenitis are still an issue. It is unclear if the
virus may cause a disease mimicking primary SS or if
HCV is directly responsible for the development of SS
Oral diseases associated with hepatitis C virus infection (Part 1)
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in a specific subset of patients. Notably, some patients
may present a triple association between HCV, SS-like
sialadenitis and SG lymphoma and the virus may be
involved in the lymphomagenesis. The risk of having a
NHL is particularly high in patients with MC. Little
attention has been paid to the effects of anti-HCV
treatment on sialadenitis or lymphoma development
and specific trials are clearly warranted. The recent
development of new experimental animal models and
effective cell culture system (Duverlie and Wychowski,
2007) for HCV should enable to achieve a broad
number of applied studies on HCV pathogenesis
including further insight on the possible sialotropism
of this virus.
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