Salvatore Perrone, Gianna Maria D’Elia, Giorgia Annechini and Alessandro Pulsoni
Division of Hematology, Department of Cellular Biotechnologies and Hematology, “Sapienza University” Rome, Italy.
Published: January 1, 2016
Received: Agust 7, 2015
Accepted: November 16, 2015
Mediterr J Hematol Infect Dis 2016, 8(1): e2016006, DOI 10.4084/MJHID.2015.006
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Marginal zone lymphomas have been
associated with several infectious agents covering both viral and
bacterial pathogens and in some cases a clear aetiological role has
been established. Pathogenetic mechanisms are currently not completely
understood. However, the role of chronic stimulation of the host immune
response with persistent lymphocyte activation represents the most
convincing explanation for lymphoproliferation. Gastric MALT lymphoma
is strictly associated with Helicobacter pylori infection
and various eradicating protocols, developed due to increasing
antibiotic resistance, represent the first line therapy for gastric
MALT. The response rate to eradication is good with 80% of response at
1 year; this finding is also noteworthy because it recapitulates cancer
cured only by the antibacterial approach and it satisfies the Koch
postulates of causation, establishing a causative relationship between
Hp and gastric MALT lymphoma. Patients with chronic HCV infection have
5 times higher risk to develop MZL, in particular, an association with
splenic and nodal MZL has been shown in several studies. Moreover,
there is evidence of lymphoma regression after antiviral therapy with
interferon+ribavirin, thus raising hope that newly available drugs,
extremely efficient against HCV replication, could improve outcome also
in HCV-driven lymphomas. Another case-study are represented by those
rare cases of MZL localized to orbital fat and eye conjunctivas that
have been associated with Chlamydophila psittaci
infection carried by birds. Efficacy of antibacterial therapy against
C. psittaci are conflicting and generally poorer than gastric MALT.
Finally, some case reports will cover the relationship between primary
cutaneous B-cell Lymphomas and Borrelia Burgdorferi.
Marginal zone lymphoma (MZL) is a heterogeneous group of low-grade,
B-cell, non-Hodgkin lymphomas comprising three distinct diseases:
extranodal MZL (EMZL) of mucosa-associated lymphoid tissue (MALT),
splenic MZL (SMZL), and nodal MZL (NMZL). In recent European
studies, MZL has been reported in 12% of new lymphoma diagnoses,
while a lower incidence of 3% was reported in the United States from
Surveillance, Epidemiology, and End Results (SEER) registries.
Various contributing factors have been defined in terms of
pathogenesis, including autoimmune diseases (mainly Sjögren syndrome
and chronic autoimmune thyroiditis) while also several infectious
agents are known or simply suspected to cause MZL. Mainly three
mechanisms linking infections to MZL have been hypothesized:
lymphocyte-transforming viruses can infect lymphocytes inducing
dysregulation of normal cell functions and promotion of cell division
(Epstein–Barr virus, Human Herpesvirus 8, Human T-lymphotropic virus
2) induction of immune suppression through progressive
depletion of CD4+ T-lymphocytes, as in AIDS (Human immunodeficiency
virus) or in patients submitted to therapeutic immunosuppression;
3) stimulation of chronic immune response and persistent lymphocyte activation (Helicobacter pylori, Hepatitis C virus, Chlamydophila psittaci, Borrelia burgdorferi, Campylobacter jejuni).
Specific organisms have been implicated in the aetiology of MZL involving particular anatomic sites: Helicobacter pylori for the stomach, Chlamydophila psittaci for the ocular adnexa, Borrelia burgdorferi for the cutis, Campylobacter jejune for the small intestine, Mycobacterium spp.
For the bronchus, Hepatitis C virus (HCV) for splenic and nodal MZL.
However, a robust association is present only in gastric MALT lymphoma
with Helicobacter pylori (Hp),
where 90% of cases are Hp+. Moreover, Hp eradication therapy is
effective in gastric MALT Hp+ lymphoma with a remission rate around
80%[8,9] and also long-term results are excellent. The studies on Hp
and gastric MALT lymphoma have profoundly influenced our understanding
of the pathogenesis of lymphomas and modified our management, because,
for the first time in the history of medical oncology, cancer has been
cured by antibiotic therapy.
This review focuses on the role of
pathogens and development of MZL, with implication on the therapeutic
option to target the implied infectious agents.
Gastric MALT Lymphoma
The clinical presentation of gastric involvement by MALT lymphoma is
variable and not specific with abdominal pain being the most common
symptom, followed by dyspepsia, vomiting, nausea and anorexia; weight
loss is common; gastric bleeding occurs as presenting symptom in
20%–30% of patients, while gastric occlusion and perforation are less
common. Diagnosis is made after histopathological evaluation of
gastric biopsy, generally after esophagogastroduodenoscopy, and rely on
the morphologic demonstration of the “hallmark” of MALT lymphoma: the
lymphoepithelial lesion that results from invasion by atypical
lymphocytes of epithelial mucosa and invasion of the glandular
epithelium, as well as reactive lymphoid follicles. Paradoxically,
the stomach is the commonest site of MALT lymphoma, despite MALT tissue
is not normally present in gastric mucosa. However, differentiation
from other indolent lymphomas (Follicular lymphoma, Mantle-cell
lymphoma) and aggressive lymphoma (Diffuse large B-cell lymphoma and
Peripheral T-cell lymphoma) is not always straightforward, and a
minimum immunohistochemistry panel including CD20, CD10, CD5 and cyclin
D1 is recommended. Since the diagnosis should be made according to
the WHO criteria, it should be reviewed by an expert
hematopathologist. Since the first discovery in 1982 by the Nobel
prize-winning authors, B. Marshall and R. Warren Helicobacter pylori has
become critical for treating and studying gastric disease like peptic
ulcer, MALT lymphoma and gastric cancer. Hp identification mainly
relies on histology (HE and modified Giemsa staining) and culture or
invasive molecular tests. In the case of negativity, serology
should be performed to identify truly negative gastric MALT
lymphomas, in fact, Hp mucosal colonisation is not uniform, but in
patches; therefore, the infection can go undiagnosed if biopsy
involves a non-colonised area. In addition, it is believed that
extensive mucosal lesion secondary to lymphoma may reduce the density
of the infection to even undetectable levels.[21,22]
Role of H. Pylori in MALT Lymphoma. Helicobacter species are the indigenous biota of mammalian stomachs, and H. pylori is the human-specific inhabitant, there is evidence that H. pylori has
been present in humans at least since ancestors of Amerindians migrated
from Asia more than 11,000 years ago. In this long time span, Hp
has adapted to human gastric environment establishing an interaction
that can be interpreted as both commensalism and long-term
parasitism. Extensive allelic diversity and genetic variability are
hallmarks of this microaerophilic gram-negative bacterium,
resulting from the combination of a high mutation rate and frequent
exchange of genetic material during mixed strains infections. That
extraordinary capacity of adaptation to human host (resembling a
quasispecies) is the key to the success for this microorganism to
infect more than one-half of the human population. H. pylori has been established by International Agency for Research on Cancer
(IARC) to be definitive bacterial carcinogen for humans and is
estimated to be responsible for 5.5% of all human cancer cases, about
592.000 new gastric cancer. Spectrum of H. pylori infection
is wide with most carriers remaining asymptomatic while patients with
duodenal ulcer have antral predominant gastritis with little mucosal
atrophy and hyperacidity; patients with gastric ulcer almost invariably
have corpus predominant gastritis and hypoacidity with various degree
of mucosal atrophy, the latter condition is associated with gastric
cancer. Moreover, the case of gastric MALT lymphoma is a rarer
condition, accounting for <5% of primary gastric neoplasms. The
epidemiological data raise the question why some people develop gastric
cancer (also MALT lymphoma), and others do not? For example, what is
the possible answer to the ‘African enigma’ where ubiquitous H. pylori infections
is not associated with gastric cancer but only gastritis? On the
other hand, in the setting of a developed Country like the Nord-East of
Italy, where there is a higher prevalence of HP infection there is a
concomitant high incidence of gastric lymphoma.
some simulations indicate that Hp seems to have spread from East Africa
around 58,000 years ago following human migrations, we could
hypothesize that in Africa, where H. pylori have interacted for more time with its human host, it could have reached a better symbiotic state with a decreased virulence.
Pathogenesis of Helicobacter Pylori-Induced Gastric MALT Lymphoma. There are several known mechanism that Helicobacter exploits to interact with the host mucosa. Actually, H. pylori strains
can be broadly categorized into strains that express multiple factors
that interact with host tissue (CagA, s1-VacA, BabA, OipA) and strains
that lack these factors. In 1989, CagA was firstly identified
and is now recognized as a marker for strains that confers increased
risk for peptic ulcer disease and gastric cancer. The Cag Type
IV secretion system (T4SS) is the primary virulence determinant and is
responsible for injecting macromolecules, in particular, CagA, inside
epithelial cells. CagA is then tyrosine-phosphorylated by the host
cell Src kinase; once phosphorylated, CagA interacts with SHP-2, a
tyrosine phosphatase, which affects spreading, migration, and adhesion
of epithelial cells. Moreover, CagA protein interacts with Grb2 and
activates the Ras/MEK/ERK pathway, leading to the phenotypes of cell
scattering and proliferation. In addition, tyrosine-phosphorylated
CagA binds and activates C-terminal Src kinase (Csk) via its SH2
domain, which in turn inactivates the Src family of protein-tyrosine
kinases. Since this signalling may induce apoptosis, the Csk pathway
may attenuate the other CagA interactions. In conclusion,
attenuation of CagA activity by Csk may enable CagA-positive HP
to infect the human stomach persistently for decades while avoiding
excessive CagA toxicity to the host. There is also evidence that
CagA can be directly injected by T4SS inside B-lymphocytes. The
delivered CagA induces the activation and stimulation of B cells
(mediated by intracellular SHP-2 and phosphorylation of ERK and P38
MAPK), and could initiate the first step of transformation, also
upregulating anti-apoptotic proteins BCl-2 and BCl-XL. Moreover,
Kuo and colleagues have demonstrated the presence of the bacterial
protein CagA inside malignant B cells of MALT lymphoma and that those
patients tend to respond faster to HP eradication.
The vacuolating cytotoxin VacA, a high–molecular weight multimeric pore-forming protein is one of virulence factors produced by Hp
and is responsible for epithelial cells by both apoptosis and
programmed cell necrosis. VacA forms a pore that permeabilizes the
epithelial cell plasma membrane to urea, that is an essential
substrate for the H. pylori’s
urease to mitigate acid gastric environment. More importantly, VacA
determines immune suppression by blocking phagosome maturation in
macrophages, inhibiting antigen presentation in T cells,
blocking T cell proliferation with down-regulation of Th1 effects
through interaction with calcineurin to block intracellular
Chronic H. pylori infection
can trigger inflammation and immunological responses that stimulate
lymphoid infiltration displaying features of classic MALT
architecture. It is suggested that H. pylori
infection results in T-cell-dependent responses through the classic
germinal centre reaction, with generation of reactive B and T cells;
the H. pylori-specific T
cells then migrate to the marginal zone/tumour area and provide
non-cognate help to auto-reactive neoplastic B cells, which may involve
stimulation of CD40 and other surface receptors by soluble ligands and
Host polymorphisms are also a crucial determinant of the interaction with H. pylori and
could elucidate why only rarely MALT lymphoma develops. Determinants of
host immune response variability have been extensively reviewed by
Datta De and mainly consist in variation in an inflammatory gene
like IL-1 (RN 2/2 genotype), glutathione S-transferase T1 null phenotype and a negative association with HLA-B35.
An important proof of concept of the association of Hp
with Gastric MALT were the first report by Wotherspoon of MALT
regression after successful eradication of Hp. Those data have been
corroborated by other studies,[8,10] thus fulfilling Hill’s criteria of
Gastric MALT Beyond Helicobacter Pylori. After a clonal expansion of B-cell H. pylori-driven
has established in gastric mucosa, other mutational events can explain
the gain of independence from the infection itself. Three chromosomal
translocations are the most frequently detected
t(11;18)(q21;q21)/API2-MALT1, t(1;14)(p22;q32)/BCL10-IGH, and
t(14;18)(q32;q21)/IGH-MALT1, all converging to activation of nuclear
factor kappa-B (NF-κB). Translocation t(11;18)(q21;q21), occurring
in approximately 30% of cases, fuses the N-terminus of the API2 gene to
the C-terminus of the MALT1 gene and generates a functional API2-MALT1
fusion product,[57,58] the other two translocations involve
translocation to immunoglobulin gene loci, and consequently increased
expression, of BCL10 and MALT1 genes. Gastric MALT lymphomas
carrying the t(11;18) are more aggressive with spread to local lymph
nodes and, most importantly, rarely respond to HP
eradication.[60,61] Therefore, its detection can influence the clinical
management and is easily feasible with a commercial MALT1 dual-colour
break-apart probe and an API2-MALT1 dual-colour dual-fusion probe for
FISH, or by rt-PCR of the API2-MALT1 fusion mRNA transcripts. Not
translocated cases frequently carry trisomies of chromosomes 3, 12 and
Gastric MALT lymphoma H. Pylori Negative. Another interesting setting is represented by gastric MALT lymphoma, H. pylori negative that responded to antibiotic treatment in 15.5% of cases, despite H. pylori triple negativity test.[64,65] Those data have been interpreted by authors in light of a limited accuracy of H. pylori
detection (false negative) or the possible presence of other
unidentified bacteria implicated in MALT pathogenesis. Nowadays,
given the limited toxicity, low costs and risk of low-grade lymphoma
progression, antibiotic therapy is also recommended in H. pylori- cases.
Antibiotic Treatment. As previously discussed, targeting H. pylori seems a logical first line approach for gastric MALT lymphoma. Several effective schemes are available for the treatment of H. pylori infection.[67-69] The antibiotic choice should be based mainly on the epidemiology of Hp resistance
to clarithromycin. Therefore, in countries with a prevalence >15%
(That is the case of Europe, with the exception of Northern States)
antimicrobial susceptibility testing could be useful. The most
commonly used regimen is triple therapy: a proton pump inhibitor
(omeprazole) in association with amoxicillin and
clarithromycin. Metronidazole can be substituted to amoxicillin in
penicillin-allergic individuals. An alternative is represented by the
Sequential treatment, which includes a 5-day period with
PPI+amoxicillin, followed by a 5-day period with
PPI-clarithromycin-metronidazole. For failure of the first line
therapy or for clarithromycin-resistant isolated strains, it is
available a bismuth-based quadruple therapy with omeprazole, bismuth
salts, metronidazole and tetracycline (OBMT), an RCT using a
combination of PPI and a single three-in-one capsule tablet showed
improved eradication in comparison with standard triple therapy.
Finally, in case of failure of the second-line treatment
(bismuth-containing quadruple regimen), it is recommended to use the
PPI-levofloxacin-amoxicillin regimen,[76,77] always considering the
rise in epidemiologic H. pylori resistance to levofloxacin.
MALT lymphoma response to H. pylori
eradication is about 80%. However the length of time necessary to
obtain a remission can span from few months to more than 12 months.
Anti-Lymphoma Directed Treatment.
In cases not responding to antibiotic treatment, a control of localised
disease can be achieved with radiation therapy alone with moderate-dose
involved-field radiotherapy (24–30 Gy) to the stomach and perigastric
Patients with the symptomatic systemic disease
should be considered for systemic treatment that encompass the
association of rituximab + chemotherapy. Rituximab in combination with
chlorambucil has been proven in a randomised study by International
Extranodal Lymphoma Study Group (IELSG)-19 where an excellent
event-free-survival was achieved, superior to chlorambucil alone,
although no overall survival benefit has been shown. Aggressive
anthracycline-containing regimens (CHOP-like) are not usually necessary
and should be reserved for cases with transformation to high grade.
Marginal Zone Lymphoma and HCV
A heterogeneous group of lymphoproliferative disorders have been
long suspected to be associated with HCV infection. HCV-related Mixed
cryoglobulinemia (MC) is considered as a low-grade B-cell
lymphoproliferative disorder, characterized clinically by arthritis,
cutaneous vasculitis (palpable purpura), and, occasionally associated
with glomerulonephritis and by the presence of circulating
cryoprecipitable immune complexes of more than one immunoglobulin
class. MC is defined by laboratory findings: the presence of serum Ig
that precipitate at low temperatures (<37°C) and can solve by
warming serum, that are produced by the lymphoproliferation of B-cells
clones secreting pathogenic IgM with rheumatoid factor activity. MC can
evolve into an overt B-cell NHL in approximately 8–10% of cases after a
MZLs, in particular splenic (SMZL) and nodal MZL
(NMZL), and other extranodal-MZL are the iNHL subtypes most frequently
described as being HCV-related.[80-82] SMZL is an indolent and rare
entity, separately recognised by WHO,[1,83] usually presenting with
symptomatic splenomegaly, cytopenias, autoimmune phenomena, and serum
monoclonal paraprotein; in some patients a leukemic phase characterized
by circulating lymphocytes with villous projections defines the
so-called Splenic lymphoma with villous lymphocytes (SLVL). SMZL,
albeit rare, in a population-based study, has been reported with an
incidence between 2001 and 2008 of 0.13 per 100,000 person-years,
accounting for 0.6% of all NHL cases and is the most common primary
splenic lymphoma. SMZL incidence is higher among older (median age
is 65 years), white and male (male-to-female ratio of 1.2:1)
population, in the United States.
NMZL is a distinct
clinical-pathological subtype of MZL characterized by exclusive primary
lymph node localization in the absence of extranodal or splenic
disease. NMZLs represent only 1.5% to 1.8% of all lymphoid
neoplasms; the most frequent clinical presentation is a generalized or,
less frequently, localized lymphadenopathy.
Recently, Paulli et
al. have reported a new subset of patients with extranodal HCV-related
MZL characterized by a primary ‘lipoma-like’ subcutaneous presentation
and an indolent clinical course.
Role of HCV in iNHL.
Hepatitis C virus (HCV) is an enveloped, RNA virus of the Flaviviridae
family; it comprises six major genotypes, whose prevalence varies among
different population and countries. HCV is not only hepatotropic,
causing infection of hepatocytes associated with hepatitis, liver
cirrhosis and hepatocellular carcinoma (HCC), but is also responsible
for other extrahepatic manifestations, of whose the most frequent is
Models of Pathogenesis in HCV-Induced Lymphoproliferation.
The mechanisms underlying B-cell lymphoproliferation possibly induced,
directly or indirectly, by HCV chronic infection are yet not fully
understood. However, few experimental data suggest some clues to
explain this phenomenon and have been reviewed elsewhere.[89,90]
first observation derives from the HCV chronic antigenic stimulation
leading to continuous stimulation and selection of reactive B-clones.
HCV-associated NHLs derive from B cells activated during HCV infection,
with some of these B cells being specific for the protein HCV-E2, which
is the primary target of antibody responses against HCV. Moreover,
the monoclonal IgM component of type II MC is often encoded by the same
set of Variable region genes, VH1-69, and Vk3-A27 and similarly the
same genes can be demonstrated to be involved in some cases of
HCV-related NHL.[92,93] The burden of these data suggests that
HCV-associated lymphomas are derived from clonally expanded B cells
stimulated by HCV-E2 protein.
HCV is a positive, single-strand RNA
virus, lacking a DNA intermediate in its replicative cycle. Thus,
insertional mutagenesis in infected B-cells seems not possible.
Moreover, there is conflicting evidence about the demonstration in
B-cells of the negative RNA viral strand, which would be consistent
with active viral replication. In fact, in a Japanese study
negative-strand HCV RNA was detected in B cells only in 4 of the 75
(5%) patients while no replicative intermediates were detected in
another study. In addition, B-cells could be not suitable for virus
entry because claudin-1, a membrane co-receptor required for HCV
infection is not present in peripheral blood cells.
more robust data exist supporting a direct B-cell stimulation by the
engagement of CD81 on their surface by a combination of HCV-E2 and
anti-CD81 antibodies leading to polyclonal activation of naïve, CD27-
Since 1990, several Epidemiologic studies suggested an association
between hepatitis C virus (HCV) infection and B-cell NHL, although with
geographical heterogeneity due to the different prevalence of HCV
seropositivity.[98-102] Nevertheless, many of these studies suffered
from methodologic restrictions such as their retrospective nature, the
consideration of prevalent instead of incident cases, missing or
inappropriate controls. In 2003, the GIMEMA group published an Italian
case-control study performed with adequate epidemiologic methods that
demonstrated a clear association between HCV infection and various
types of B-NHL. Recently a larger case-control study of InterLymph
NHL Subtypes Project hepatitis confirmed the increased risk of MZL in C
virus seropositive patients (EMZL OR=5.29, 95% CI=2.48 to 11.28).
In 2002, Hermine et al. reported the first series of nine patients with
SLVL in which a complete regression of lymphoma was obtained with
antiviral treatment (AT) consisting of interferon (IFN) +/-
ribavirin. As a control, the authors reported 6 pts. with the same
disease, but without HCV infection, not responding to the same
treatment. This argument suggested for the first time that viral
eradication and not the direct anti-proliferative effect of IFN was
responsible for HCV-related NHL regression. Many single cases
subsequently confirmed this observation, although, due to the rarity of
HCV-related NHL, very few prospective studies have been published. In
20 patients, Vallisa et al. demonstrated a complete response to
antiviral treatment of different subtypes in 70% of indolent
i-NHL. Recently a multicenter study of Fondazione Italiana Linfomi
(FIL) recorded more than 700 patients with i-NHL and HCV
seropositivity, demonstrating that AT used in the first line in 100 pts
produced 44 CR and 33 PR. A French prospective study of 116
HCV-positive patients with B-NHL revealed that within the MZL subgroup
(n=45 pts.), 84% (n=38) received AT and 61% (n=23) achieved a Sustained
Virological Response. Moreover, outcome analysis showed a
favourable association between OS and AT in MZL patients (P =
0.04). From these experiences, AT is, to date, considered the
first-line approach for the cases of HCV-related indolent lymphoma, not
requiring immediate chemo-immunotherapy. The recent introduction of
new, highly active, antiviral treatments could clarify whether a pure
antiviral approach,[109-111] free from the confounding role of
interferon, is equally or even more efficacious against lymphoma.
Ocular Adnexa MALT Lymphoma
Ocular adnexa MALT lymphoma (OAML), although uncommon, is the third
most frequently involved site of MZL with an incidence rate of
1.4/1,000,000 person-years, with a median age of 65 years,6 thus
accounting for 50-78% of all ocular lymphomas in Western
Countries. Moreover, Danish and American SEER data from
surveillance registries have reported an increase in the incidence of
OAML.[114,115] Clinical presentation of orbital fat lymphomas
involvement (75% of OAML) includes exophthalmos (27% of cases),
palpable mass (19%), eyelid ptosis (6%), diplopia (2%), eyelid nodule,
orbital oedema, epiphora and a variable degree of impaired ocular
motility, while the most common sign for conjunctival lymphomas (25% of
OAML) is the characteristic ‘salmon red patch’. OAML is an
indolent lymphoma with a favourable clinical outcome emphasized by a
10-year overall survival of 81%, with no deaths from lymphoma for the
patients treated with radiotherapy and 94% for the patients
managed with ‘watch and wait’. Microscopically neoplastic cells
are monocytoid, centrocytic-like or lymphoplasmocitoid and their
immunophenotype is similar to that of other MALT lymphomas: CD20+,
CD79a+, usually IgM+ with light-chain restriction, PAX5+, bcl-2+,
TCL1+, CD11c+/-, CD43+/-,CD21+/-, CD35+/-, and IgD2, CD32, CD52, CD102,
CD23-, cyclin D1-, bcl-6-, MUM1-. Frequent chromosomal alteration
encompasses trisomy 3 in 62% of cases and trisomy 18 in 47% of
cases. In addition, the most common translocations in ocular
adnexal MALT lymphomas are the t(11;18)(q21;q21)/API2-MALT1 and the
t(14;18) (q32;q21)/IGH-MALT1. The immunoglobulin heavy-chain gene
rearrangement is clonal in 55% of cases and shows somatic
hypermutation in two-thirds of these, with a majority of selected
genes commonly implicated in the assembly of autoantibodies, hence
supporting the view that OAML represents a clonal expansion of
post-germinal-centre memory B-cells, where selection may have occurred
driven by antigen stimulation. Moreover, in OAML a possible
infectious association has been long proposed, Chlamidophila spp.
and, to a lesser extent, H. pylori and HCV have been proposed as
causative agents. Although the association with Hp is
controversial, a more robust evidence is available for the role of
Role of C. Psittaci in Ocular Adnexa MALT Lymphoma. Chlamydophila psittaci (CP)
is an obligate intracellular bacterium responsible for
psittacosis/ornithosis in birds and in humans after zoonotic infection
through inhalation of aerosolized bacteria when exposed to infected
birds or handling contaminated feathers, faecal material or
carcasses. CP infection is commonly asymptomatic with repeated
infection cycles in humans but mainly involves the respiratory tract.
CP has been reported as a potential trigger for OAML, and Ferreri et
colleagues firstly showed the efficacy of antibiotic treatment. In
this work CP DNA was found in lymphoma samples from 32 of the 40 (80%)
case-patients analysed, thus revealing a strong association between
OAML and CP infection, also in light of the low seroprevalence in
general population studies varying between 0 and 49% (median:
5–10%). Moreover, Ponzoni et al. reported the presence ofCP in
74% OAML specimens by different techniques such as
immunohistochemistry, immunofluorescence and laser-capture
microdissection-assisted PCR inside infiltrating
monocytes/macrophages. Nevertheless, significant variability in CP
association with OAML has been reported in different geographical
areas, ranging from 47% in Germany to 35% in the East Coast of the USA,
29% in the Netherlands, 13% in Italy, 12% in UK and 11% in Southern
China, while no evidence of CP infection was found in cases from
the South Florida and Japan. To sum up, the overall
prevalence of CP infection in
423 cases of OAML reported in 14 different papers is 19%. In
conclusion, the possible role of methodological pitfalls and other
interpretation bias or confounding factors should be carefully
considered when interpreting the bacteria–lymphoma association, also
focussing on the potential role for C. psittaci infection in lymphomagenesis.
OAML is a rare indolent lymphoma, for its treatment no consensus is
available because no prospective clinical trials have been conducted to
define the optimal treatment approach for these patients. However,
patients managed by a watch & wait for approach have a 10-years OS
of 94%. Moreover, limited toxicity and costs associated with
antibiotic treatment should suggest the opportunity to target the
possibly correlated infection by C. psittaci,
in analogy with gastric MALT lymphoma and Hp eradication. A single
antibiotic course of oral doxycycline at a dose of 100 mg, given twice
a day, for 3 weeks is the most popular regimen. In the first
prospective trial of doxycycline, 20 of the 27 patients were
progression free at 2 years; interestingly also 6 CP DNA–negative
patients of the 16 treated experienced lymphoma regression. A
subsequent international prospective phase II trial was performed by
IELSG: the prevalence of Cp positivity in OAML was 89%; in these naïve
patients, after CP eradication, lymphoma regressed with an ORR of 65%,
with 6 complete and 16 partial responses. A larger Korean
prospective trial, enrolling 90 patients, showed an ORR of 27%.
Actually, a new prospective study (IELSG 39) is enrolling patients (http://www.ielsg.org/trialsonfr.html).
On the contrary, another retrospective study did not show any
response, even if the short median follow-up of 9 months could
have hampered the proper assessment of response. Altogether, in 9
studies identified in the literature by Kiesewetter and Raderer, 131
patients were treated with doxycycline resulting in an ORR of 45%, with
CR achieved in 23 patients (18%) and PR achieved by 36 pts. (27%).
An interesting Italian work by Govi et al. showed the efficacy of
administration of 500 mg clarithromycin, twice a day, for 6-months, in
relapsed/refractory EMZL after treatment with doxycycline. Over
the anti-bacterial effect on unidentified pathogens, clarithromycin
could exert a direct anti-proliferating effect on OAML. Patients who
fail to respond to doxycycline therapy can be successfully salvaged
with chemotherapy and/or radiotherapy.
Anti-Lymphoma Directed Treatment.
Standard treatment is based on surgical resection of the single lesion.
Radiotherapy is known as a treatment modality with a high local control
rate for primary OAML.[140,141] However, orbital irradiation can induce
complications such as cataracts, keratitis, dry eye syndrome, and
retinopathy. Even if no universally accepted radiation schedule is
available, National Cancer Center Network guidelines recommend
radiotherapy of 20 to 30 Gy for initial treatment of early-stage
non-gastric MZL of all sites and reirradiation for locally recurrent
Only limited data on chemotherapy for patients with OAML
suggest different association and schedule. The oral agent chlorambucil
is the most frequently used chemotherapy agent and has an extremely
favourable toxicity. Complete responses are observed in 67% to 100% of
patients; however, long-term outcome data suggest that local recurrence
occurs in up to 29% of patients.[143-146] Only a few cases of OAML have
been treated with rituximab as single-agent, demonstrating high
activity in both newly diagnosed and relapsed disease, although early
recurrence is common.[147-150] Also, the association of rituximab and
chlorambucil has been tested with encouraging results. CNS
prophylaxis is not recommended since OAML rarely recurs to CNS.
Role of Borrelia Burgdorferi in Primary Cutaneous B-cell Lymphomas
MZL of the skin has an incidence rate of 1.1/1,000,000 person-years and is predominant among males across all ages. B. burgdorferi (Bb)
infection has been associated with skin MZL in some cases in Europe,
but not in the U.S., Asia and some parts of Europe, thereby challenging
the aetiological role of this agent.[153,154] In particular, in Bb
endemic areas such as the Scottish Highlands or Austria,
cutaneous MZL patients have demonstrated Borrelia infection in up to
40% cases, while no association was detected in two Italian case
series.[157,158] However, in a nonendemic region like France, Bb DNA
was found in 19% of 16 cases with primary cutaneous MALT lymphoma.
infection might be associated with chronic antigen-driven
lymphomagenesis in the skin, which is the port of entry of this
gram-negative spirochete, through a bite from Ixodid tick and is also
the infectious agent of Lyme borreliosis.[5,160] Moreover, in late Lyme
borreliosis, lymphocytes may infiltrate the dermis and produce the
characteristic borrelia “lymphocytoma”, a cutaneous B-cell
pseudolymphoma characterized by ‘top-heavy’, mixed-cell lymphoid
infiltrate, usually accompanied by the formation of lymphoid follicles
with germinal centres. Lyme disease and primary cutaneous lymphoma
may represent a continuous spectrum of pathological states viewed as a
multistep progression from lymphocytoma to “pseudolymphoma” eventually
leading to primary cutaneous B-cell Lymphoma, where evidence of B-cell
monoconality may help distinguish between the different stages of the
Discordant data exist about cutaneous MZL recession
after antibiotic treatment of Bb infection (generally consisting of
cephalosporins +/- tetracyclines) and are based on case reports.
In conclusion, Bb and its association with cutaneous MZL are currently
the object of investigation, even if an antibiotic treatment may be
attempted given the indolent nature of the disease.
Marginal zone lymphoma is a
fascinating clinical setting in which it has been clearly shown in
several trials (see Table 1) that several therapies targeting the
putative oncogenic infectious agent can induce steady lymphoma
regression. It represents the proof of concept that a chronic stimulus
on the immune system induced by an infectious agent, under particular
host predisposition, may lead to the selection of abnormal B-clones and
a more selection may result in overt lymphoma development. For gastric
and the ocular adnexa MALT lymphomas the compelling evidence, to date,
provides a rationale to implement actively antibiotics regimens that
can be an effective first-line treatment due to the peculiar indolent
course of the disease and the high therapeutic index of these drugs.
Indeed, international guidelines state that “Helicobacter pylori
eradication therapy must be given to all gastric MALT lymphomas,
independently of stage”. Conversely, in OAML and MZL of the skin
antibiotic treatment remains investigational, given the questionable
results of the former and the paucity of data for the latter clinical
With the recent availability of new direct-acting
antiviral agents for HCV infection, that promise a rapid and sustained
virological response, there is increasing interest in their employment
to treat HCV-related SMZL and NMZL; however, further studies are needed
to assess this strategy. In conclusion, we hope new evidence can
improve our understanding of the pathogenesis of lymphoma mediated by
antigen-dependent infectious agents, thus enabling the availability of
other alternative and efficacious anti-lymphoma treatments.
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