Falk Symposium 149Highlights in

Gastrointestinal OncologyBerlin, October 1-2, 2005

Helicobacter pylori and risk ofgastric cancer and lymphoma

W. FischbachAschaffenburg, Germany

Helicobacter pylori

Peptic ulcer

MALT lymphoma gastric cancer

dyspepsiaExtragastricdiseases

Helicobacter pyloriis a crucial factor in the pathogenesis

of gastric cancer

Helicobacter pyloriis a group I carcinogene

WHO 1994

Helicobacter pylori and gastric cancerEvidence for an association

• Epidemiology• Induction of gastritis, atrophy, IM• Ascorbin acid• Hyperproliferation• O2-radicals, NO• Hypochlorhydria, hypergastrinemia• Animal studies• Observational studies• Interventional studies

Hp and risk of gastric cancerMetaanalysis of prospective case-control-studies

Danesh, Aliment Pharmacol Ther

Further increase of risk by 1.6 in case of cagA +Huang, Gastroenterology 2003

Population based case-control study

More than 2/3 of non-cardia cancerare attributable to Helicobacter pylori

Ekstrom, Gastroenterology 2001

Hp and risk of gastric cancer

case-control study with rigorous exclusion criteria

OR of non-cardia cancer:3.7 18.3 for any Hp5.7 28.4 for CagA +

Brenner, Am J Epidemiol 2004

Hp and risk of gastric cancerFamilial cancer risk and Hp

German Health and Nutrition Survey1351 male and female, age 30-74 years

0

10

20

30

40

50

60

70

%

familial cancer no cancer

Hp prevalence

Brenner et al., Gastroenterology 2000

Hp is an independent risik factor(RR 2.7)

Familial risk of gastric cancer:due to intrafamilial clustering

of Hp infection ?

Familial cancer risk and Hp

Hp cagA positive individuals with a family historyof gastric cancer have

8-fold increased risk for gastric cancer16-fold increased risk for non-cardia cancer

Independent risk factors

BackgroundFamilial history of gastric cancer:

Is it a consequence of a clustering of Hp infectionor are Hp and familial history independent risk factors ?

Brenner, Cancer 2000

Gastric cancerGenetic disposition and Hp

Hypothesis

Hp Gastritis

risk gastritisrisk of cancer

Genetic disposition

Cytokine genetic polymorphismsare associated with an increased risik for

gastric cancer(Machado, Gastroenterology 2003)

• Proinflammatory IL-1 polymorphisms are associated withmore severe inflammation and increased prevalence of IM andatrophic gastritis. ATA haplotype carriers of IL-10 werecolonized by more virulent Hp strains(Rad et al., Gut 2004)

• Genetic polymorphisms in IL-8, IL-10, and TNF-alphaplay a role in gastric carcinogenesis in the Chinese population(Lu et al., Carcinogenesis 2005)

• IL-1B polymorphisms may predispose to gastric cancer in theChinese pand Korean population(Yang et al., Cancer Lett 2004; Chang et al., Int J Cancer 2005)

Host genetics Hp strains

risk gastritis phenotype

gastric cancer

Environmental and dietary factors

Hp and risk of gastric cancer

Helicobacter pylori and gastric cancerEvidence for an association

• Epidemiology• Induction of gastritis, atrophy, IM• Ascorbin acid• Hyperproliferation• O2-radicals, NO• Hypochlorhydria, hypergastrinemia• Animal studies• Observational studies• Interventional studies

Hp and gastric cancerUemura et al., N Engl J Med 2001

patients with gastric/duodenal ulcer, gastral hyperplasia, NUDn = 1526

endoscopc-bioptic survey over 7.8 years (1-10,6)

Hp +n=1246

Hp -n=280

cancer in 2,9% cancer in 0%Hp -Hp +

p < 0,001

Hp and gastric cancerUemura et al., N Engl J Med 2001

Cancer risk was associated with:

severe atrophyCorpus dominant gastritis

intestinal metaplasia

Hp positive patients

2,9 %NUD4,7%

Hplasia2,2%

Uv3,4%

Ud0 %

cancer risk

Hp and gastric cancerChemopreventive study

Correa et al., J Natl Cancer Inst 2000

Columbia: high prevalence of cancer and of multifocal atrophy/IM

randomisation

Hp eradication Beta-Caroten Ascorbin acid

Comparison of histologies before and after 6 years:significant reduction of atrophy/IM

combination not superior to monotherapy

Hp eradication for prevention ofgastric cancer in a high risk area

Wong BCY et al., JAMA 2004

GASTRO UPDATE 2005 Oberer GI-Trakt 145/1

prospective randomised placebo controlledpopulation-based interventional study in

1630 healthy Hp infected individuals from aChinese region with high cancer incidence

n = 988initially no precancerous lesions

(atrophy, IM, dysplasia)

Hp eradication for prevention ofgastric cancer in a high risk area

Wong BCY et al., JAMA 2004

GASTRO UPDATE 2005 Oberer GI-Trakt 145/2

primary study aim:Is there a difference in the incidence of

gastric cancer between eradication and placeboduring a 7.5-years follow-up ?

Gastric carcinomaeradication n = 7placebo n = 11p 0,33

Hp eradication for prevention ofgastric cancer in a high risk area

Wong BCY et al., JAMA 2004

GASTRO UPDATE 2005 Oberer GI-Trakt 145/3

secondary study aim:Is there a difference between individuals

with / without precancerous lesionsin the eradication and control group ?

Gastric carcinoma

eradication n = 0placebo n = 6p 0,02

no precancerous lesions

Gastric carcinogenesisnormal gastric mucosa

chronic-active gastritis

atrophic gastritis

intestinal metaplasia

dysplasia

carcinoma

Hp Hp

? point of no return

?

Prevalence of Hp and gastric cancerin long-living elderly in JapanMasaya Kawade et al., J Gastroenterol Hepatol 2004

0

10

20

30

40

50

60

%

65-74 75-84 > 85

Hp seropositivity

02468

1012

%

65-74 75-84 > 85

Prevalence

gastric cancer colon cancer

* **

The lower prevalence of gastric cancer in the elderlymay be due to disappearance of Hp colonization

Host genetics Hp strains

risk gastritis phenotype

gastric cancer

Environmental and dietary factors

Hp and risk of gastric cancer

Hp genotypinghost genotyping

selective early prophylactic Hp eradication

Gastric cancer originating frombone marrow-derived cells and Hp

Houghton J, et al., Science 2004

• Bone marrow-derived cells (BMDCs) are frequentlyrecruited to sites of inflammation

• Hp infection of mice induced population of the stomachwith BMDCs.

• Subsequently, these cells progressed through metaplasiaand dysplasia to cancer

• Epithelial cancers can originate from BMDCs after Hpinduced gastritis.New aspects of host and exogene factors interactions withpotential implications on carcinogenesis

Helicobacter pylori

Peptic ulcer

MALT lymphoma gastric cancer

dyspepsiaExtragastricdiseases

Hp eradication forgastric cancer prophylaxis ?

Hp eradication should be performedin cases of• EMR or subtotal surgical resection ofhigh grade dysplasia or gastric cancer

• familial clustering of gastric cancer• risk gastritis

(predominant corpus gastritis, atrophy, IM)• young patient (< 40 years ?)

• patient´s desire

Helicobacter pylori

Peptic ulcer

MALT lymphoma gastric cancer

dyspepsiaExtragastricdiseases

Helicobacter pylori and MALT-lymphoma

aetiopathogenetic roleof Hp for MALT-lymphoma

molecularbiologicalfindings

epidemiologicaldata

animalstudies

morphologicaldata

Helicobacter pylori and gastric MALT lymphoma

Morphological data

Lymphoid follicles in gastric mucosa represent animmune response to Campylobacter pylori. Thisacquired lymphoid tissue has characteristics of MALT.(Wyatt 1988; Stolte 1989)

Successful treatment of Hp is followed by regressionof MALT(Stolte 1992)

Hp infection is present in 92% of 110 patients withgastric MALT lymphoma(Wotherspoon 1991)

Helicobacter pylori and gastric MALT lymphoma

Epidemiological data

The incidence of gastric MALT lymphoma depends onthe rate of Hp infection(Doglioni, Lancet 1992)

Case-control-study:Hp leads to a 6-fold risk for gastric MALT lymphoma.Hp infection preceeds the development for gastriclymphoma.(Parsonnet, NEJM 1994)

Helicobacter pylori and gastric MALT lymphoma

Molecularbiological data

The growth of tumor cells from low grade gastricMALT lymphoma can be stimulated by Hp

The neoplastic B cells are not immuneresponsive to Hpbut lymphoma proliferation is mediated bycontact-dependent Hp specific T cells

Hp dependent T cell activation B cell proliferationmonoclonal selection

(Hussel, Lancet 1993, J Pathol 1996)

Helicobacter pylori and gastric MALT lymphoma

Hp induces acquisition of lymphoid tisuein the gastric mucosa:Condition for the developmentof gastric MALT lymphoma

Hp represents an antigenic stimulus forthe lymphoma growth:Progression of gastric MALT lymphoma

HELICOBACTER PYLORI ERADICATION INLOW GRADE GASTRIC MALT - LYMPHOMA

Wotherspoon et al., Lancet 1993

“Hp eradicationshould be the first choice of treatment “

6 patients with low grade gastric B-cell-lymphomaof MALT-type

Hp eradication

regression of lymphoma: 5/6 cases

Helicobacter pylori eradicationin low grade gastric MALT-lymphoma

of stage I

lymphoma regression in 70 - 80%

(literature)

What is the long-term outcome afterexclusive Hp eradication therapy ?

Are lymphoma regressions long lasting ?

Does it offer a real chance of cure ?

How often do relapse, progressionor high grade transformation occur ?

CR62 (65%)

MRD15 (16%)

PR9 (10%)

NC7 (7%)

PD1 (1%)

?1 (1%)

Hp eradication

n = 95

Follow-up49,5 (12-89 mo)

Fischbach et al., Gut 2004;53:34-37

Long-term outcomeafter Helicobacter pylori eradication therapy

Conclusions

The majority of patients havea favourable long-term outcome.

Hp eradication offers a real chance of cure

Are there any predictors forlymphoma regression

after successful eradication of Hp ?

Hp associated gastritisreactive benign disease

malignancy

Hp

dependent

geneticchanges

Marginal zone B celllymphoma of MALTt(1;14) < 5% Apoptose regulierendes BCL10

t(11;18) -t(11;18) +

DLBCLt(11;18) -

numerous genetic changes

high gradetransformation

de novo

mostly singleclonal abnormality

Hp eradicationfailure

(definition?)

Hp eradicationresponsive

Hp induces andSustains an acttive

ProliferatingB-cell population

Hp attracts andactivates neutrophils

Release

Translocation t(11;18) and regression ofgastric MALT-lymphoma after Hp eradication

Liu et al., Gastroenterology 2002

46

1 0 1

17

26

4

16

05

101520253035404550

I >II I >II

t(11;18) -t(11;18) +

completeregression

noregression

t(11;18) positive MALT-lymphoma do not/rarelyrespond to Hp eradication therapy:

predictor of treatment failure ?

Minimal residual low-gradegastric MALT-type lymphoma aftereradication of Helicobacter pylori

Fischbach W, Goebeler-Kolve ME, Starostik P,Greiner A, Müller-Hermelink HK

Lancet 2002; 360:547-548

Fischbach et al., Lancet 2002

No relapseNo lymphoma dissemination

No high grade transformation

MRD after successful eradication of H. pyloriExperience from a clinical series

of the EGILS group (Fischbach W, DDW 2005, submiited)

Follow-up42,2 (2–144 months)

PD n = 6 (6%)

MRD n = 67 (62%)

Hp eradicationafter 12 months:

MRD

Low grade gastricMALT lymphoma

stage In = 108

CR n = 35 (32%)

local progression: n=5high grade lymphoma n=1

Favourable naturalcourse of disease

in 95%

It is justifiable topostpone oncological treatment

in patients with MRDafter successful eradication of Hp

A watch-and-wait strategy isa valid approach to manage MRD

Therapy of early gastric lymphoma

MALT

Hp eradicationif Hp-, progression

or relapse:RTx (surgery)

MRD:watch-and-wait

RTx (surgery)

CTx

large B-cell-ly

CTx + RTx( surgery + CTx)

((Hp eradication))

CTx + RTx(surgery + CTx)

CTx + RTx

stage

I 1/2

II 1/2

III / IV