malt lymphoma | Helicobacter pylori and MALT Lymphoma

Helicobacter pylori and MALT Lymphoma


Department of Pathology and Laboratory Medicine, British Columbia Cancer Agency and the University of British Columbia, Vancouver, British
Columbia, Canada
Helicobacter pylori are gram-negative spiral microaerophilic
organisms that belong to the Campylobacterales
order, Helicobacteracea family. They are capable of
colonizing the harsh environment of the human stomach.
Over 50% of the world’s population carries this infection.1
H pylori have colonized the human stomach since
time immemorial.2 In virtually all infected individuals,
H pylori causes inflammation in the form of chronic active
gastritis, which progresses in 10%–20% of affected persons
to peptic ulcer disease, gastric adenocarcinoma,
and/or mucosa-associated lymphoid tissue (MALT) lymphoma.
However, only a very small minority (1%–2%)
of infected individuals will develop a malignant disease.3
One of the most distinctive features of H pylori is the
genetic diversity it displays between clinical isolates.4 H
pylori isolates are highly diverse, with evidence of a
constantly changing genome, primarily caused by point
mutations, substitutions, insertions, and/or deletions.5,6
Moreover, mixed infections are frequent and may lead to
exchange of DNA fragments between H pylori strains in
a single host. This suggests co-evolution of H pylori with
its human host and that disease may be caused both by
strain-specific properties that increase virulence and by
host susceptibility. Such strains possibly evolve through
exercising significant flexibility in gene content and gene
regulation. Among many of the host–pathogen interactions
that potentially could occur, some could prove
beneficial in which the co-evolved bacteria and the host
reach an almost symbiotic relationship. H pylori may not
be just a bad bug in all instances.
A large body of data have implicated H pylori in the
pathogenesis of gastric MALT lymphoma, including epidemiologic,
biological, and molecular genetic studies.
Interestingly, both H pylori and MALT lymphoma were
born almost simultaneously, when H pylori was described
by Marshall and Warren7 and MALT lymphoma was
recognized as a distinct entity by Isaacson and Wright.8
These latter investigators noted morphologic similarities
between the histology of the condition known as immunoproliferative
small intestinal disease, a subtype of primary
intestinal B-cell lymphoma, and primary low-grade
gastric B-cell lymphoma. Moreover, the histologic features
differed from that of comparable nodal low-grade
B-cell lymphomas in that the overall architecture and
cytology of these lymphomas bore a resemblance to
normal MALT tissue rather than recapitulating the
structure of lymph nodes. Roughly one third of all
non-Hodgkin’s lymphomas in adults are of extranodal
origin. MALT lymphomas, by definition arising at mucosal/epithelial
sites, collectively account for approximately
8% of all non-Hodgkin’s lymphomas, with gastric
MALT lymphoma being the most common
extranodal site.
This review summarizes the published data that support
a causative role for H pylori infection in the pathogenesis
of gastric MALT lymphomas. The epidemiology
of H pylori is discussed and its role in the pathogenesis,
including factors affecting the infectious organism and
the host. A major focus of this review addresses the
relationship between the immune response, H pylori, and
MALT lymphomas. This is followed by a description of
the morphology, phenotype, and unifying concepts of the
molecular genetics of MALT lymphomas. Treatment
strategies of gastric MALT lymphoma are not discussed
because these are beyond the scope of this review. Finally,
we conclude with a brief discussion of H pylori–negative
MALT lymphomas, preventative measures for reducing
infection, and the direction of future research into MALT
lymphomas.

Abbreviations used in this paper: Cabotaje, cytotoxin-associated antigen
Has CARD4, caspase recruitment domain; ICPM, CpG Island Methylator
Phenotype DC-SIGN, dendritic cell – specific intercellular adhesion molecule-3 –
grabbing Nonintegrin; DLBCL, diffuse large B-cell lymphoma;
DSB, double-strand DNA breaks; FOXP1, Forkhead box protein P1;
GST, glutathione S-transdone; IPA, inhibitors of apoptosis; IFN, interferon;
IGH, immunoglobulin heavy chain; He, interleukin; LEL, Lymphoepithelial
Lesion MALT, mucosa-associated lymphoid tissue; MHC
Major histocompatability complex; NF-B, nuclear factor b; NTx, Neonatal
thymectomized; PAI, Pathogenicity Island; PCR, polymerase
Chain Reaction; ROS, reactive oxygen species; SS, Sjögren's syndrome;
TH1, helper1 T cells; TH2, helper2 T cells; FRT, tumor necrosis factor –
Associated factor; Treg, regulatory T cells; TNF-, tumor necrosis
Factor-.
© 2005 by the American Gastroenterological Association
0016-5085/05/$30.00
DOI: 10.1053/J. Gastro. 2005.03.083
GASTROENTEROLOGY 2005; 128:1579 – 1605
Epidemiology
Infection with H pylori occurs worldwide and
Affects at least half the world's population, but the prevalence
varies greatly among countries and within individuals
In the same country. 3 The overall prevalence of H
Pylori infection is correlated strongly with socioeconomic
Status. 9 The prevalence among adults is approximately
80% in many developing countries and 50% in industrialized
Countries. Direct fecal-Oral transmission predominates
In industrialized countries where other
Transmission routes, such as contamination of water, may
Be more important in developing countries. 10 The Bacteria
is transmitted within families in early childhood. 11
Children often are infected by a strain with a genetic
Fingerprint identical to that of their parents, and they
Maintain this genotype even after moving to a different
Environment. Improved sanitation in industrialized
Countries reduced the rate of infection of H pylori over
Recent decades. In the United states, there has been a
Decrease in H pylori infection prevalence since the second
Half of the 19th century.
It has been known for some time that even though the
Genome of H pylori is extraordinarily diverse, strains fall
into distinct geographic groups. 2,12 By using DISTINCT
Patterns of polymorphic sites based on the nucleotide
Sequence of 8 genes in 370 H pylori strains from 27
Geographic and ethnic human populations, Falush and Al2
Identified 7 H pylori populations and subpopulations. By
Comparing human migratory flows with these H pylori
Populations, some of the apparent inconsistencies could
Be explained by known human migration patterns (eg,
The appearance of Helicobacter subpopulation West Africa
(HspW Africa) strains in African-Americans in the
United States as a result of the slave trade, and the
Isolation of H pylori East Asia strains from Native Americans
Introducing these strains into continental America
Some 12.000 years ago).
In adults, H pylori infection usually is chronic and will
Not heal without specific therapy. In Children, the elimination
Of the bacterium probably is relatively common,
Aided by the more frequent administration of antibiotics
Given for other reasons. 13 There currently is no evidence
For zoonotic transmission, although H pylori is found in
Some nonhuman primates and occasionally in other animals. 14
Undoubtedly, management of colonized individuals
Will continues to evolve as new knowledge emerges
and socioeconomic conditions change.
Gastric MALT lymphoma develops in only a very
Small percentage of patients. The Estimated incidence of
This lymphoma in the United states is between 1 per
30,000 – 80,000. Similar numbers are report in European
Countries, with recent report incidence rates of
.7 –. 8 per 100.000 population, except in England where
The incidence appears lower. 15 However, there are differences
Between populations within Europe, the United
States, and other countries. A higher incidence (13 per
100.000) has been reported in northeastern Italy, where
The prevalence of H pylori is also very high, being detected
In 80% of the adult population. 16 developing

Countries, not surprisingly, show higher incidences,
example, in Tunisia, with incidence rates of 6.3 and 3.8
Per 100.000, for men and women, respectively. 17
H pylori are not the only Helicobacter species infecting
Humans. Humans also can become infected with Helicobacter
Heilmannii, a tightly coiled spiral bacterium larger
than H pylori, found in dogs, cats, pigs, and nonhuman
Primates. The prevalence in humans is approximately
.5%. H heilmannii causes only mild gastritis in most
Cases, but it also can induce acquired MALT in the
Stomach and has been found in association with gastric
MALT lymphoma. 18
Evidence linking H pylori Infection
With Gastric MALT Lymphomas
The first study linking H pylori with gastric
MALT lymphoma occurred in 1991.19 These investigators
showed that H pylori infection significantly increased
The risk for gastric MALT lymphoma because the vast
Majority of gastric MALT lymphoma patients were infected
With H pylori. The normal stomach is devoid of
Organized lymphoid tissue. It was shown that lymphoid
Follicles develop in H pylori – infected persons and that the
lymphoid tissue formed in response is identical morphologically
to normal MALT. Moreover, Case-control studies
have shown an association between previous H pylori
Infection and the development of primary gastric lymphoma. 20
Direct evidence confirming the importance of H pylori
In the pathogenesis of gastric MALT lymphoma was
Obtained from studies that detected the Lymphoma B-cell
Clone in the biopsy specimens of chronic gastritis that
Preceded the development of lymphoma and from a series
Of in vitro studies showing that lymphoma growth could
Be stimulated in culture by H pylori strain-specific T cells
When crude lymphoma cultures were exposed to the
Organism. 21 Finally, Wotherspoon and Al22 in 1993, and
Subsequently several other groups, shown that eradication
of H pylori with antibiotics alone result in regression
of gastric MALT lymphoma in 75% of cases. Most
Of these patients whose lymphomas responded to antibiotic
Eradication therapy have shown sustained clinical
remissions. 23 These Landmark studies shown that a ma1580
FARINHA AND GASCOYNE GASTROENTEROLOGY Vol. 128, No. 6
Lignan tumor could be eradicated successfully by using
Antibiotic therapy alone. Moreover, very strong evidence
Based on Seroepidemiologic case-control studies
That infection with H pylori increased the risk for gastric
Carcinoma. Thus, in 1994, H pylori was classified as a
Type I (definitive) carcinogen by the International
Agency for Research on Cancer.

Pathogenesis
In contrast to infection with other mucosal pathogens,
Only a small percentage of persons carrying H pylori
Ever develop clinical sequelae. H pylori Induce gastric
Inflammation in virtually all hosts, and gastritis increases
The risk for gastric and odenal ulceration, distal gastric
Adenocarcinoma, and gastric mucosal lymphoproliferative
Disease of the MALT type. Recent investigations
Have emphasized that disease-specific mechanisms involve
Choreographed interactions between the pathogen
and host, which, in turn, are dependent on strain-specific
Bacterial factors and induced host effectors.

H pylori
Bacteria indigenous to the human body are numerus
and varied. They dwell in multiple niches on
Mucosal surfaces in various anatomic sites. Many of these
Sites are colonized persistently by several species. Such
Cohabitation Imfolds an equilibrium in which the biological
Cost of the colonization to the host is low. The
Different organisms compete for nutrients and the best
Rentals, and participate in a number of shared activities
such as waste management and genetic exchange. Colonization
Of the stomach by H pylori is an exception to
These generalities because it can persist for decades and is
Not disterred by competing microbes.

The H pylori genome (1,650,000 BP) codes for about
1500 proteins. 5, 6 H pylori research has benefited from
Genomic approaches more than any other bacterial pathogen.
It was the first bacterial species to have the complete
Genome of 2 unrelated clinical isolates (J99 and 26995)
Fully sequenced and compared. 5.6 Functional Genomics
has used the expression profiling of Messenger RNA to
Provide a condition-dependent and time-specific genome
Scale portrait of the Organism's transcriptome. 24 Comparison
Of the 2 completely sequenced H pylori organisms
Revealed a significant amount of genetic variation between
Genomes. The genome of strain J99 is smaller
(1,643,831 BP) than that of strain 26695 (1,667,867
BP). 5.6 They contain 52 and 110 strain-specific genes,
Respectively, approximately half of which reside within a
Locus termed the plasticity zone.

25 These 2 H pylori genome
Sequencing projects showed that many genes could
Be switched on and off by base mispairing – mediated
Mutagenesis. Proteins encoded by such genes include
Surface molecules responsible for control of entry of
Foreign DNA into the bacteria, and proteins affecting
Bacterial motility. Strains of H pylori have been shown to
Have a panmictic or freely recombining population structure
Over a period of years. The colonizing Populations has
Given host experience genetic variation as a result of
Point mutations or recombinant, which can involve
Exchanges across loci within a genome (intragenomic) or
Between differing organisms (intergenomic). 26 DNA Microarray
Analysis has been used to study H pylori genes
Within the same host who had refused eradication therapy
(9-year period). The genes of the later isolated strains
were related closely but not identical to either the earlier
Isolates or even each other. Each of 13 new isolates tested
Had a unique complement of genes. 27 Considering that a
Single gastric biopsy specimen represents only a small
Percentage of gastric mucosal cells, the amount of variation
Within the total population of H pylori must be
Enormous.
Thus, the genome of H pylori may change continuously
During chronic colonization of an individual host
By importing small pieces of foreign DNA from other H
Pylori strains during persistent or transient mixed infection. 28
These findings support microevolution of H pylori,
That is, gradual small changes in its genome as an
Adaptive mechanism, with marked plasticity and a trend
To adapt to the host. A Number of factors may
Impact this adaptation. These include PH levels within
Different gastric niches and their influence on the survival
of H pylori and its ability to grow under acidic conditions,
The distribution and viscosity of mucin glycoforms
In the gastric mucosa, the adherence of H pylori to gastric
Mucins, and host genotype and physiology affecting
Niche characteristics. 29,30 After being ingestured, the bacteria
Must evade the bactericidal activity of the gastric
Luminal contents and then enter the mucous layer. Urease
Production and motility are essential for this first step
of infection. Urease hydrolyzes urea into carbon dioxide
and ammonia, thereby allowing H pylori to survive in
This acidic medium. H pylori flagella have adapted similarly
to the gastric microenvironment.
Most strains of H pylori possess the cytotoxin-associated
Antigen (Cabotaje), a 120 – 145-Kilodalton protein. 31 It
is found in 60% – 70% of H pylori strains in the industrialized
World. 1 The cabotaje gene is localized at one end of
The CAG pathogenicity Island (CAG-PAI), a 37-kb genomic
Fragment containing 31 putative genes. Several of these
Genes encode components of a type IV secretion apparatus
That translocate the 120-to 145-Kilodalton Cabotaje
Protein into the host cell. 32 After Entering an epithelial