Carcinogenesis and Infection with Helicobacter pylori

Carcinogenesis and Infection with Helicobacter pylori 

GIANINA MICU 1 , FLORICA STĂNICEANU 1,2 , SABINA ZURAC 1,2 , ALEXANDRA BASTIAN 1 , ELIZA GRAMADĂ 1 , 

LUCIANA NICHITA 1,2 , CRISTIANA POPP 1 , LIANA STICLARU 1 , R. ANDREI 1 , C. SOCOLIUC 1 

1 “Colentina” Clinical Hospital, Department of Pathology, Bucharest, Romania 

2 

“Carol Davila” University of Medicine, Bucharest, Romania 

It was accepted several years ago that, in the carcinogenesis process of human cancers, 

biologic agents, especially the viruses, are playing an etiologic role. This is the case of lymphomas 

(retroviruses), hepatocarcinoma (hepatic viruses) and cervical carcinoma (papilloma viruses). Helicobacter 

pylori is the first bacteria recognized as a first class carcinogen for gastric cancer. Nevertheless, 

comparing with the most validated human carcinogens, the activity of H. pylori is very little studied. 

As a consequence, at this moment, in its case, explanation of carcinogenesis mechanism is more or 

less hypothetical. 

Key words: Helicobacter pylori, CagA, VacA, carcinogenesis, epithelial premalignant lesions, 

lymphoid malignities. 

THE EPIDEMIOLOGICAL PERSPECTIVE 

In the last fifty years we witnessed a significant 

decrease of gastric cancer incidence in the developed 

countries population. An important contribution to 

this decrease was brought by the Japanese school of 

gastroenterology [1] [3] by healing of early gastric 

cancers in over 90% cases. Even so, at a world 

level, this terrible disease continues to be a frontrunner 

among cancer-caused deaths (2 nd place) and it 

is considered the world’s 14 th cause of mortality [1]. 

Until H. pylori (Fig. 1) to become known as a 

direct carcinogen [2], the association of the H. pylori 

gastric infection with different gastric lesions was 

considered a facilitating (and not inductive) factor 

for carcinogenesis through the induction of intestinal 

metaplasia, glandular atrophy and hypochlorhydria 

followed by the accumulation of N-nitrous carcinogenic 

components, through the free radicals-generating 

inflammatory reaction and excessive cellular 

proliferation. 

Afterwards it was demonstrated that bacteria 

not only favour, but also produce malign modifycations 

at the level of the gastric mucosa: both 

histological variants of antral gastric adenocarcinoma 

(the intestinal type and the diffuse type, according 

to the Lauren classification) and the gastric lymphoma, 

without being implicated in eso-cardial 

junction cancers. Cardial lesions appear in patients 

with a significant gastro-oesophageal reflux, and in 

this case H. pylori infection can have a protective 

role [4]. 

Recently, sero-epidemiological studies approximate 

that at least 70% of diagnosed gastric 

carcinomas have Helicobacter pylori as a determining 

cause [3] [4], and the serologic presence of HP 

antibodies was demonstrated at least ten years before 

the disease was diagnosed. 

The arguments belong to descriptive epidemiology 

that presents a geographical distribution [3][5] 

of the gastric cancer overlapped by that of 

Helicobacter pylori infection. In countries with a 

high presence of gastric cancer, the incidence of 

Helicobacter pylori infection is also high. These 

observations are also sustained by the conclusions 

of the epidemiological studies that show a high 

frequency of the gastric cancer in patients that 

belong to economically disadvantaged classes, 

subjects that also proved to have a significantly 

high incidence of the infection [1] [6]. 

Epidemiological paradoxes 

From the researchers in epidemiology point 

of view there are still several unsolved paradoxes: 

– Why, even if H. Pylori infection affects about 

half of the planet’s population, only very 

few subjects develop a gastric cancer? [7] 

Explanations for this situation are probably 

in the role of genetic and diet factors. 

– On the other hand, even if H. pylori infection 

has a relatively even distribution in 

both sexes, why does the gastric cancer affect 

mainly men? [4] [7] 

ROM. J. INTERN. MED., 2010, 48, 4, 299–306

300 

Gianina Micu et al. 2 

– How come there are areas where the 

infection’s prevalence is very high (around 

100%), but the gastric cancer’s prevalence 

is almost null? [1] [5] [7]. 

But, with or without clarifying the epidemiological 

paradoxes that, one fact remains certain: the 

risk of developing gastric cancer by a person with 

H. pylori infection is under 1% and seems to 

depend on the interaction between the virulence 

factors of the infecting bacteria strain and the host’s 

genetically-determined immune response [8]. 

The implications of H. pylori in carcinogenesis 

are sustained by epidemiological studies as 

well as by animal models and researches made for 

clarifying the molecular mechanisms involved in 

gastric carcinogenesis. Most gastric cancers are 

preceded by premalignant lesions that evolve for 

decades. Atrophic gastritis perturbs the secretion of 

gastric acid by increasing the pH, allowing gastric 

colonization with anaerobe bacteria. These bacteria 

produce reductase, implicated in the formation of 

N-nitroso carcinogenic components [8] [9]. 

PATHOGENIC MECHANISMS OF INDUCTION IN 

GASTRIC CARCINOGENESIS 

H. pylori induces carcinogenesis both directly 

through his virulence factors, as well as indirectly 

through the induction of the inflammatory response 

from the host [7–9]. 

A. DIRECT FACTORS – VIRULENCE FACTORS OF 

HELICOBACTER PYLORI 

The direct carcinogenetic action of Helicobacter 

pylori: Helicobacter pylori’s virulence factors 

are produced due to its endowment with a series of 

structural factors or the bacteria’s secretion products, 

among which the most significant are urease, 

phospholipase A, proteolytic enzymes, adhesins – 

common to all Helicobacter pylori strains–, as well 

as the cag cytotoxin, present in 60–70% of the 

strains and the vacuolisant protein vacA, present in 

60–65% of Helicobacter pylori strains [10] [11]. 

Helicobacter pylori genome is heterogenic, 

with some strains playing a more significant role in 

developing malignity. This gene group bears the 

name of pathogen islet CagA (PAI) and is made of 

31 genes. While the positive CagA types are 

proved to imply a high risk of gastric cancer in the 

Western population, in Asian population this 

correlation is poorly supported. The vacuolisant 

cytotoxin vacA is responsible for the lesion of 

epithelial cells associated with carcinogenesis – 

genotypes vacA s1 and vacA m1 have a high 

malignnant potential. The carcinogenetic action of 

both CagA and vacA was expressed experimentally 

through their inoculation in Mongolian gorillas, 

which determined intestinal metaplasia and gastric 

cancer. On the other hand, the development of B cells 

gastric lymphoma was recently associated with 

virulent forms of H. pylori, such as HopZ [11–13]. 

Oxidative stress. Gastritis is associated with 

the increase in production of nitric acid (NO). The 

nitroso components are recognized as gastric carcinogens 

in experimental milieus. 

Among the host’s response factors to Helicobacter 

pylori infection, interleukin 1 and the necrotic 

tumoral factor (TNF–A–308) present a high risk 

for gastric cancer. 

B. INDIRECT FACTORS – CHRONIC INFECTION AND 

ITS CONSEQUENCES ON GASTRIC MUCOSA CELLS 

The inflammation of the gastric mucosa 

infected with H. pylori implicates cytokines, gamma 

interferon, TN-α, IL-1b, IL-6, IL-8, IL-12 and IL-17. 

The expression of cytokines is secondary to the 

activation of the transcriptional factor NF-kB, 

activation induced in epithelial cells through the 

translocation of the cagA gene. The intensity of the 

gastric inflammation depends on the host’s hereditary 

factors [12] [13]. Some H. pylori strains induce a 

severe inflammatory reaction while others are not 

at all accompanied by inflammation. This difference 

of the inflammation degree is parallel to the 

balance of pro- and anti-inflammatory cytokines. 

H. pylori is capable of modulating the cytokines’ 

response. The bacteria’s genomic recombination 

seems to play a very important role in perpetuating 

the bacteria in spite of the inflammatory response. 

The bacteria can survive about 24 h the macrophages’ 

phagosomes, the bacteria’s lipopolysaccharides 

inhibiting the macrophages’ apoptosis. On 

the other hand, the vacuolisant toxin vacA permits 

the survival in an acid milieu through the formation 

of intercellular vacuoles containing ammonia which 

is freed when the bacteria come into contact with 

the cell’s apical pole. Thus, the bacteria’s virulence 

factors allow it to survive in spite of host’s immune 

response [14]. 

I. CARCINOGENESIS ON THE EPITHELIAL LINE 

THE CARCINOGENIC CASCADE 

The carcinogenic cascade triggered by H. pylori 

infection, as it was proposed by Correa et al in

3 Carcinogenesis and infection with H. pylori 301 

1975, goes through several important stages [1] 

[11] [17]: 

fundic and corporeal infection with Helicobacter 

pylori → chronic gastritis → glandular atrophy → 

intestinal metaplasia → dysplasia → adenocarcinoma 

PREMALIGNANT LESIONS ON 

THE EPITHELIAL LINE 

The initial lesion is constituted by chronic 

gastritis together with the decrease of peptic acid 

secretion and of the intragastric ascorbic acid concentration, 

a substance recognised as having protective 

role against cancer (Fig. 2). The absence of H. pylori 

in the areas of intestinal metaplasia, areas where 

the neoplastic transformation originates, suggests a 

distant carcinogenic influence through the bacteria’s 

products, as well as through the inflammatory 

response generated by the infection [9] [10] [19]. 

Intestinal metaplasia associated to cancer is 

the incomplete type, either 2 or 3, and it is distributed 

diffusely, antro-fundic, or along the lesser curvature, 

from the cardia to the pylorus [18] – Fig. 3. 

As far as the atrophy associated with cancer 

is concerned, recent studies confirm that it can be 

continuous or multifocal, located most often antral 

and fundic. German researchers have put forward 

the hypothesis that the gastric cancer risk is higher 

in subjects with fundic-located gastritis if the level 

of activity is equal to the antral one. Japanese 

studies confirm the fact that the predominance of 

gastritis at the gastric fundus, as well as severe 

atrophy and intestinal metaplasia are risk factors 

for gastric cancer [17] [19]. Atrophy is defined by 

a glandular depletion, probably a consequence of a 

fault in the replacement of cells through apoptosis 

(Fig. 3). The histopathologic examination highlights 

the abundance of inflammatory cells and apoptotic 

epithelial cells at the level of the neck glands, 

which is precisely where there are epithelial strain 

cells. The multi factorial analysis done on patients 

with adenocarcinoma, duodenal ulcer or gastritis 

indicates the association between genotype s1 and 

m1 cag and the density of the inflammatory infiltrate, 

the mucosa’s degree of atrophy and the type of 

intestinal metaplasia. A role in the appearance of 

the gastric mucosa atrophy seems to be also played 

by the auto-antibodies through the activation of the 

local immune system and the induction of a cellular 

mediated reaction followed by the destruction of 

parietal cells by cytotoxic lymphocytes [18–20]. 

Apoptosis. Among the carcinogenesis 

mechanisms there is also the maladjustment of the 

apoptotic ways. Apoptosis is a form of geneticallyprogrammed 

cellular death in view of regulating 

the number of epithelial cells of the digestive tract. 

Both the presence of inflammatory mediators and 

the secretion product of H. pylori can intervene 

directly in the enzyme cascade that forms the base 

of the molecular mechanisms of the apoptosis [19]. 

As a consequence, modifications of the cellular turnover 

appear. The ways through which H. pylori can 

induce the acceleration of the apoptosis’ rhythm in 

the gastric epithelial cells belong to two main 

categories: 

a) Direct pathway, through the bacteria’s 

virulence factors, especially cagA, cagE 

and the vacuolisant cytotoxin vacA, which 

is confirmed by the absence of an accelerated 

apoptosis in infections with H. pylori strains 

with the above-mentioned virulence factors. 

b) Indirect pathway, via the inflammation’s 

mediators: the gamma interferon (IFN-γ) 

and TNF-α amplify the apoptosis induced 

by H. pylori through a mechanism that 

implies the over-expression of the Fas 

receptor at the level of gastric epithelial cells. 

This increases the susceptibility of gastric 

epithelial cells towards T-cells. Apoptosis is accelerated 

by a series of bacterial elements: ammonia, 

urease, ceramide [7] [18]. 

In cell cultures the over expression of Bak 

(correspondent of the Bcl-2 protein, inductor of the 

apoptosis) was also noticed. At the present moment 

there are two theories regarding the significance of 

apoptosis in H. pylori infection. According to the 

first one, the induction of apoptosis stimulates the 

cellular proliferation, explaining the hyper prolixferative 

response of the host epithelium associated 

to the infection. The second theory affirms that, on 

the contrary, apoptosis could be the answer to 

epithelial hyper proliferation in view of preventing 

tissue hypertrophy [23]. 

In vivo the apoptosis’ mechanisms depend 

significantly on the level of pro inflammatory 

cytokines (IL-8, IL-6, gamma interferon and TN-α). 

These induce apoptosis through the induction of 

synthetase nitrogen monoxide. NO has a degrading 

effect on the DNA, the increase in the production 

of NO can determine irreversible lesions of the 

genome and the appearance of pro carcinogenic 

mutations. The free radicals and NO induce the 

expression of the P53 protein, that repairs DNA’s 

lesions or produces cells’ apoptosis [20] [22].

302 


Epithelial proliferation – Fig. 4. In the 

gastric mucosa infected with H. pylori there is a 

concomitance between the accelerated apoptotic 

process and the cellular proliferation. When the 

balance between these two opposed effects processes 

is broken in favour of the proliferative factors, the 

evolution leads to cancer. Cellular proliferation is 

secondary to the inflammation induced by the 

H. pylori bacteria. The central role in its production 

seems to be played by cyclooxygenase Cox-2 and 

nitrogen monoxide (NO), both expressed at an 

increased level in gastric adenocarcinoma. Excessive 

cellular proliferation decreases significantly after 

the eradication of H. pylori infection [20]. On the 

other hand, one must note its increase in the 

absence of a parallel increase of the apoptosis, of 

genetic (genetic mutations) or epigenetic (modifycations 

of the gene’s expression) alterations. Genetic 

modifications seem to be more precocious in the 

diffuse-type cancer than in the intestinal type, even 

if in the latter’s case precancerous lesions such as 

intestinal metaplasia can be described. Somatic 

mutations of gene E-cadherine or a hypermethylation 

of one of these gene’s promoters are 

characteristic to the diffuse type of adenocarcinoma, 

while for the intestinal type the mutations frequently 

affect gene p53. Mutations of the APC and betacatenina 

genes are much rarer. All these genetic 

modifications can be induced by the oxidative 

stress produced by H. pylori [20] [22] [24]. 

H. pylori interferes in angiogenesis through 

the induction of a vascular factor for endothelial 

growth – A (VEGF – A). Other growth factors 

induced through H. pylori’s virulence include the 

epidermal growth factor (EGF), the heparin growth 

factor (EGF-like) and amphiregulin. Through the 

CagA protein it also activates the c-Met growth 

factor. 

There are numerous studies that describe 

cellular and genetic modifications in malignant 

gastric cells: the affection of the intercellular adhesion 

owing to the mutations E-cadherin, alpha and betacatenins, 

as well as to the increase in the activity of 

telomerase and the instability of microsatellites. 

The most common genetic abnormalities are 

connected to p53, as well as to the activation of the 

oncogenes c-Med and Her2/Neu, while the K-raz 

mutations occur less and less frequently. It was 

demonstrated that some of these genetic modifycations 

can appear even before intestinal metaplasia is 

installed [20] [25]. 

Intraepithelial neoplasia (“dysplasia”) represents 

a renewal and tissue-development process; 

it is frequently associated to chronic gastritis and 

can recede under treatment. It appears at the level 

of the normal gastric mucosa and is signalled by a 

foveolar hyper-proliferation and/or intestinal metaplasia. 

Cytoarchitectural alterations start at the level 

of the glands’ neck, where glands appear grouped 

in small “packages”. It can be plane/polypoid/ 

depressed from a macroscopic point of view, with a 

microscopic tubular/tubulo-villous/ villous or 

papillary pattern [20–22] [25] – Fig. 5. 

Microscopic criteria of considering the gastric 

intraepithelial neoplasia are: 

– structural disorganisation: deformation of 

the crypts, the appearance of epithelial 

intraluminal buds, the relation between the 

epithelial tissue and the conjunctive one, 

modified in favour of the former. 

– the presence of cellular atypia, predominantly 

nuclear: polymorphism, hyperchromasia, 

loss of nuclear polarity, stratification, presence 

of an increased number of mitoses. 

– anomalies of differentiation: modification 

of the secretion, increase of the number of 

non-differentiated cells. 

According to these criteria two types of intraepithelial 

neoplasia can be described, comprising 

the three degrees of epithelial dysplasia formerly 

described: low degree intraepithelial neoplasia 

(light and medium epithelial dysplasia) and high 

degree intraepithelial neoplasia (severe epithelial 

dysplasia); the cases which lack of criteria for a 

certain definition are classified in the indefinite 

intraepithelial neoplasia category (OMS) [1] [25]. 

In the low degree intraepithelial neoplasia, 

the mucosa’s architecture is slightly modified, and 

it presents tubular ramified/ budded structures, with 

elongated crypts, cystic dilatations, glands covered 

by large-size, low-Muncie columnar cells; pseudo 

stratified vesiculous round-ovoid nuclei. 

In the case of high degree intraepithelial 

neoplasia visible architectural distortions appear; 

the tubes gain an irregular, ramified shape; the 

glandules become crowded and one can identify 

visible cellular atypical situations; there is no 

stromal invasion; the mucus secretion is either 

minimal or absent; the nuclei become pseudo 

stratified, pleomorphic, hyperchromatic, cigar-shaped 

with prominent, amphophilous nucleoli. 

THE PROGRESSION OF INTRAEPITHELIAL 

NEOPLASIA TOWARDS CARCINOMA 

Over 80% of intraepithelial neoplasia cases 

progress towards invasion. The carcinoma diagnosis 

is imposed when the tumour invades lamina 

propria (intramucous carcinoma) or the muscularis 

mucosae [24] [27].


N.B.: the association of extensive lesions of 

intestinal metaplasia with lesions of intraepithelial 

neoplasia in the presence of the sulphomucinesecreting 

phenotype has a high risk of evolving 

towards carcinoma – Figs. 6, 7. 

PHYSIOPATHOLOGICAL AND CLINIC 

MODIFICATIONS: GASTRITIS, 

HYPOCHLORHYDRIA AND THE RISK OF 

ADENOCARCINOMA 

The chronic infection with H. pylori can lead 

in time to the appearance of pan gastritis when 

inflammatory lesions at the level of the fundic 

mucosa lead to the decrease of the acid secretion. 

From a physiopathological point of view, hypochlorhydria 

is partly caused by the decrease in the 

secretion of histamines by the ECL cells; on the 

other hand, the parietal cells’ acid secretion is 

inhibited by TN-α and IL1β [26]. 

H. pylori infection induces an immune reaction 

from the organism, whose first stage is the alteration 

of gastric epithelium through the presence of the 

bacteria in the mucosa that covers cells’ apical pole. 

The consequence is secretion of numerous chemotactic 

factors, of cytokines and the stimulation of 

lymphocytes. Even if sometimes it is spontaneously 

eliminated by local defence mechanisms, in most 

cases the infection continues to persist. In time, it 

appears a local inflammatory reaction that provokes 

the acceleration of the cellular turn-over and, 

sometimes, genomic lesions that can lead to cancer 

if lesions of the DNA-repair mechanisms appear. 

Chronic inflammation can also induce hypochlorhydria 

in patients with a pre inflammatory genotype 

of interleukins. Convergence of bacterial virulence 

factors with the host’s immune response can generate 

varied diseases, from ulcer to the atrophy of the 

mucosa and afterwards the development of cancer 

[26] [27]. 

applied by Wong and his team) suggest the fact 

that the eradication of H. pylori reduces the 

incidence of gastric cancer only in patients that did 

not present gastric atrophy and/or intestinal metaplasia. 

But even in the case where these lesions’ 

point of no return has been surpassed, eradication 

of H. pylori seems to stop their evolution. The 

regression of precancerous lesions is thought 66% 

possible for patients that become H. pylori negative 

after treatment and only 14% possible for patients 

that stay positive after treatment [1] [26]. 

According to some studies, non-atrophic 

gastritis is completely reversible after the eradication 

of the H. pylori infection. Others, in contrast 

[19] [28], have demonstrated that both atrophic 

gastritis and intestinal metaplasia could be reversible, 

even if these studies have noticed a decrease in the 

incidence of gastric cancer; this was though related 

to the decrease of cellular proliferation after 

eradication of active infection [27]. 

Some researchers [20] [26] mentioned the 

existence of a stage of pre-atrophic gastritis in 

which the parietal epithelial cells have disappeared, 

but the glandular architecture was conserved and 

the strain cells were also not affected. At least 

theoretically, at this stage the lesions are reversible. 

To conclude, the real amplitude of the role 

played by H. pylori’s eradication in the prevention 

of gastric cancer remains still a subject for study. 

As long as after the eradication of H. pylori 

precancerous lesions stop evolving and, sometimes, 

they even regress, the practical decision imposes 

itself: the infection’s treatment must be applied 

even without the evidence of pre neoplasia modifications. 

Another important, but theoretical idea, is 

that of the existence of the point of no-return, beyond 

which bacteria-induced genetic modifications make 

atrophy and intestinal metaplasia irreversible, in 

spite of the elimination of the carcinogen agent 

(H. pylori) [25–27]. 

ERADICATION OF H. PYLORI AND PREVENTION 

OF GASTRIC CANCER 

The major problem with gastric cancer prevention 

strategies derives at this moment from the 

fact that we do not know exactly at which stage 

gastritis, atrophy, intestinal metaplasia or intraepithelial 

neoplasia become irreversible. Random, 

prospective studies and placebo (like the one 

REVERSIBILITY OF PRECANCEROUS LESIONS 

At the present moment there are still few 

studies concerning the role that the infection’s 

eradication can have in the prevention of the gastric 

cancer through the reversibility of pre neoplasia 

modifications: atrophic gastritis, intestinal metaplasia 

and the intraepithelial neoplasia of different 

degrees [16] [25] [26].

304 


II. PATHOGENESIS OF H. PYLORI-INDUCED 

LYMPHOID MALIGNITIES 

As far as the malign transformation on a 

lymphoid line is concerned, the pathogenic sequence 

described above at this moment is the following: 

Gastric infection with Helicobacter pylori→ 

lymphoid hyperplasia → clone abnormalities at 

the level of B lymphoid population → low degree 

MALT lymphoma dependent on the Helicobacter 

pylori infection’s level→ (possibly via the 

t translocation (1;14) → low degree MALT lymphoma 

independent of the level of Helicobacter 

pylori infection→ (possibly via the p53 mutation) 

→ high degree MALT lymphoma. 

EPIDEMIOLOGY 

Epidemiological studies, as well as the 

detection of the H. pylori infection in most gastric 

lymphomas have proved the tight connection 

between these and the bacteria. The regression and 

even healing of some lymphomas following the 

antibiotic treatment aimed at H. pylori infection 

also come in support of this idea [1] [21]. 

The carcinogenetic steps in this case begin 

with the activation of T cells in the presence of the 

chronic H. pylori infection, starting towards cells 

that further on activate the population of polyclonal 

B lymphocytes. In time, a proliferation of monoclonal 

B cells with the possible accumulation of 

genetic mutations takes place. Because the lymphoma 

appears in the lymphoid tissue associated to the 

mucosa (MALT), they are called MALT-oms. B-cells 

that proliferate come from the lymphoid follicle’s 

peripheral area, which explains this tumour’s other 

name, that of marginal area lymphoma [1] [21] [24]. 

Even if the first studies concerning the low 

degree MALT lymphoma launched the idea of the 

presence of Helicobacter pylori infection among 

the etiologic factors up to 98%, more recent studies 

keep the bacteria in the fore-group, but decrease its 

incidence at 62–77%. It was proven that lymphoma 

is preceded by a H. pylori infection, but there are 

still controversies concerning this theme, especially 

because a series of serious studies have published 

partially contradicting results. For example, some 

studies mention the association between high degree 

lesions and positive cagA strains and the nonassociation 

of this strain with low degree lymphoma 

[21]. 

THE MALT LYMPHOMA CONCEPT 

The term MALT was proposed by Isaacson et 

al. for the immune system’s components developed 

at the level of the gastrointestinal tract’s mucosa; 

these contain lymph ganglions (which in ileum form 

the Payer paches), the lymphocyte and plasmocytes 

in lamina propria and the intraepithelial lymphocytes. 

These immune components of the MALT 

system have distinct morph functional traits, as well 

as the lymphoma developed from them (MALT). It is 

considered that, in order to develop a tumour from 

this tissue, an important role is played by H. pylori, 

the latter’s eradication leading to the lymphoma’s 

remission [1] [28]. 

Between the lymphoid follicles there are 

variable sized lymphoid cells, without mitosis, 

frequent immunoblasts, post-capillary venules and 

sometimes plasmocytes – Fig. 8. 

The specific immunohistochemical markers 

are: CD19, CD20, CD21, CD35, bcl-2, sometimes 

CD43. 

LYMPHOID HYPERPLASIA 

Lymphoid hyperplasia, named until recently 

“pseudo-lymphoma”, represents a reactive condition 

that appears frequently in association with ulcerations/ 

gastric erosions and who is accompanied by an 

extensive fibrosis and a vascular proliferation. At a 

microscopic level, one can describe the presence of 

reactive germinal centres in a polymorph inflammatory 

population (including mature lymphocytes and 

plasmocytes). 

Initially, the pseudo-lymphoma was considered 

a benign reactive inflammatory process. Later on, it 

was recognised as a pre-malignant lesion. At the 

present moment, thanks to data provided by immunohistochemical 

studies and molecular biology, that 

can make the difference between monoclonal (neoplasia) 

and polyclonal (reactive) lymph proliferations, 

the term of pseudo-lymphoma is not longer used 

[1] [23]. 

MAIN CHARACTERISTICS OF MALT 

GASTRIC LYMPHOMA 

Over 95% of gastric lymphoma is non-Hodgkin 

type. Most of them are B cells lymphoma, T cells 

being reported fewer than 8%.


Lesions appear at the level of the mucosa’s 

junction with the submucosa, making difficult at 

this stage a diagnosis through endoscopic biopsy. 

Also difficult is the differentiation of the low-degree 

malignity lymphoma from benign inflammatory 

infiltrates at the level of endoscopic biopsies. In 

early or borderline cases there can be significant 

confusions with follicular gastritis. In these cases it 

is necessary to have a immunohistochemical and 

molecular confirmation of the monoclonality of 

B cells [1] [21] [23]. 

THE TUMORIGENIC ROLE OF H. PYLORI 

IN MALT-TYPE GASTRIC LYMPHOMA 

It was demonstrated (Isaacson et al. 1984, 

Wyatt et al. 1988, Worth Erspool, 1991) that chronic 

H. pylori infection determines the stimulation of 

the lymphoid tissue in the gastric mucosa. The 

presence of lymphoid follicles at this level is 

pathognomonic to the long-term infection with H. 

pylori; the appearances of lymphoepithelial lesions 

definitely mark the development of a MALT 

lymphoma. The chronic infection with Helicobacter 

pylori determines the recruitment of B and T cells 

in gastric mucosa as an immune response. The 

proliferation of B cells is secondary to the specific 

activation of T cells by the bacteria and cytokines. 

Because gene alterations of the malign clone are 

not sufficient for insuring autonomy in relation to 

cellular death, the MALT lymphoma can regress 

the anti-Helicobacter pylori treatment. In time, the 

malignant clone can accumulate varied gene 

alterations (t (1; 14)), inactivation of the p53 gene 

or the p16 gene) that determine acquiring of an 

autonomous proliferation capacity and/or apoptosis 

inhibition. As a consequence, the low degree MALT 

lymphoma that would have responded to the 

antibiotic treatment become high degree lymphoma 

that do not respond to the antibiotic treatment 

anymore and tend to lead to metastasis. 

TUMOUR CELLS E RESPONSE OF 

TO H. PYLORI INFECTION 

Tumour B cells are not directly stimulated by 

the bacteria. H. pylori stimulate the intratumoral 

T cells that, in their turn, favour the proliferation of 

tumour cells. It was demonstrated that the same 

patient’s spleen T cells do not respond to H. pylori, 

which implies that the population of T cells 

responsive to the bacteria is a local one. This is one 

of the explanations for the fact that the MALT 

gastric lymphoma at least initially remains localized, 

the lymphoma being dependent on the activated 

T cells present in great number in H. pylori produced 

gastritis [24]. 

It is necessary for the progenitors of the 

malign B cells clone to have certain properties, a 

possible genetic alteration or the ability to recognise 

antigens that allow their uncontrolled proliferation 

in the presence of T cells. The MALT lymphomatous 

cells present a genetic instability, genetic 

anomalies and respond to a variety of auto antigens. 

In 2000, De Jong proposed a model of oncogenesis 

for the MALT-type gastric lymphoma. 

H. pylori → chronic gastritis → gastric lymphoma 

Non H type MALT, low malignity → gastric 

lymphoma Non H type MALT, high malignity. If 

the passage from chronic gastritis to the low degree 

MALT lymphoma is regulated through immunological 

processes, the passage to the high degree 

lymphoma is achieved through an autonomous 

proliferation [23] [26]. 

REGRESSION OF THE MALT GASTRIC LYMPHOMA 

AFTER ERADICATION OF H. PYLORI 

Antibiotic therapy for the MALT gastric 

lymphoma is efficient only in low degree lymphoma 

and the extension is limited to the mucosa and/or 

the submucosa [23] [25] [28]. 

__________________________________________________________________ 

În procesul carcinogenezei cancerelor umane au fost acceptaţi de mulţi ani 

agenţi biologici cu rol etiologic, în special virusurile. Acesta este cazul limfoamelor 

(retrovirusurile), hepatocarcinomului (virusurile hepatitice) şi cancerului de col 

uterin (papiloma virusurile). Helicobacter pylori este prima bacterie recunoscută 

ca şi carcinogen de clasa I, fiind demonstrat epidemiologic ca agent cauzal pentru 

cancerul gastric. Totuşi, prin comparaţie cu cei mai mulţi carcinogeni umani 

validaţi, acţiunea carcinogenetică a H. pylori este încă puţin experimentată. În 

consecinţă, la momentul prezent, în cazul său, explicarea mecanismelor carcinogenezei 

este încă mai mult sau mai puţin una ipotetică. 

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Correponding author: Gianina Micu 

Colentina Clinical Hospital, Department of Pathology 

19–21 Şos. Ştefan cel Mare, Bucharest 

E-mail: dr_geanina@yahoo.com 

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Received July 24, 2010

Fig. 1. – Numerous H. pylori organisms in the mucus at the 

apical pole of the surface epithelium, Giemsa stain, ob. 40×. 

Fig. 2. – Antral gastric mucosa showing chronic gastritis with 

high grade of activity, presenting marked polymorph 

inflammatory infiltrate including lymphocytes and numerous 

neutrophils in lamina propria and intraepithelial, focally 

destroying the glandular epithelium; regenerative changes 

in the epithelium; HE stain, ob.20×. 

Fig. 3. – Inactive chronic gastritis with moderate glandular atrophy 

and limited areas of intestinal metaplasia; HE stain, ob.20×. 

Fig. 4. – Marked pseudopolypoid hyperplasia of the surface 

epithelium; HE stain, ob.10×.

Fig. 5. – Epithelial dysplasia – low and moderate grade (low 

grade intraepithelial neoplasia) with loss of the nuclear polarity 

and hyperchromatic nuclei, areas with pseudostratification of 

the glandular epithelium; Giemsa stain, ob.20×. 

Fig. 6. – Gastric adenocarcinoma – intestinal type (Lauren), 

tubulo-papilar; Giemsa, stain, ob.10×, respective ly signet ring 

carcinoma diffuse Lauren type. 

Fig. 7. – Gastric adenocarcinoma – intestinal type (Lauren), 

tubulo-papilar; Giemsa, stain, ob.10×, respective ly signet ring 

carcinoma diffuse Lauren type. 

Fig. 8. – Antral non-Hodgkin MALT type lymphoma; HE 

stain, 0b.10×.

Carcinogenesis and Infection with Helicobacter pylori

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