Helicobacter pylori

&

Gastric MALT Lymphoma

Zine - Charaf AMIR–TIDADINI , Fatima ASSELAH Department of Histopathology CHU Mustapha

Algiers, ALGERIA

IAP AD, Algiers 2008IAP AD, Algiers 2008

Helicobacter pylori and Gastric MALT Lymphoma

Background

Most extra nodal lymphomas arise in Stomach Most extra nodal lymphomas arise in Stomach

GG’’MM’’L L

Isaacson 1983: Marginal zone B L ; Indolent Isaacson 1983: Marginal zone B L ; Indolent localized at diagnosis localized at diagnosis

H pylori : the leading cause (Development, (Development, progression); progression); 60-90% regression after Hperadication (Fischbach, 2004)

Increasing GL incidence Increasing GL incidence in Algerians

-- 67 % 67 % of GI lymphomas

-- 37 % 37 % of gastric cancers Vs 10 % *

Average mean age at 44 years in Algerian population / Average mean age at 44 years in Algerian population / 22 decades younger than in occident (61 y)decades younger than in occident (61 y)**25% < 30 years old (serum immunoelectrophoresis 25% < 30 years old (serum immunoelectrophoresis careful endoscopy + duodenocareful endoscopy + duodeno--jejunal biopsies to jejunal biopsies to exclude the extension to the stomach of an IPSID)exclude the extension to the stomach of an IPSID)

No difference according to gender No difference according to gender (M/F ratio : 1/1.2)(M/F ratio : 1/1.2)**

** OMS, 2008*Anon, Blood 1997*Anon, Blood 1997

Gastric MALT Lymphoma : G’M’L

Epidemiology

GG’’MM’’L : PRECURSOR LESIONS L : PRECURSOR LESIONS

H pylori H pylori Chronic Gastritis Chronic Gastritis In Malt lymphoma the prevalence of In Malt lymphoma the prevalence of H. pylori H. pylori infection is 90% Vs 96% in our seriesinfection is 90% Vs 96% in our series

Giemsa

Helicobacter pylori Helicobacter pylori

–– gramgram--negative spiral negative spiral microaerophilicmicroaerophilic bacterium bacterium –– campylobacteralescampylobacterales order, order, HelicobacteraceaHelicobacteracea familyfamily–– capable to colonize the hostile environment of the human capable to colonize the hostile environment of the human

stomachstomach–– Secreting Secreting ureaseurease to neutralize the local acid pH.to neutralize the local acid pH.–– Since its successful isolation in 1983 by Warren and Since its successful isolation in 1983 by Warren and

Marshall, Marshall, H. pylori H. pylori has been linked to various pathologies has been linked to various pathologies and a strong association with gastric carcinoma and GLand a strong association with gastric carcinoma and GL’’MM’’(carcinogen class I : OMS 1994)(carcinogen class I : OMS 1994)

–– Over 50% of the worldOver 50% of the world’’s population carries this infection, in s population carries this infection, in Algeria more than 90% of general population are Algeria more than 90% of general population are HpHpinfected (infected (MegraudMegraud, 1989) , 1989)

NOBEL Price of Medecine 2005NOBEL Price of Medecine 2005

Warren & Marshall Warren & Marshall

Infection rates vary among the developed and developing Infection rates vary among the developed and developing countries of the worldcountries of the world

–– decline in most of the western countries mainly due to the succedecline in most of the western countries mainly due to the success ss of combination therapies and improved personal hygiene and of combination therapies and improved personal hygiene and community sanitation to prevent recommunity sanitation to prevent re--infectioninfection

–– However, the situation is not improving in many of the developinHowever, the situation is not improving in many of the developing g countries like in Algeriacountries like in Algeria

HELICOBACTER Pylori

Hp Hp infection infection --> acquired during childhood> acquired during childhood

Transmission occurs predominantly within familiesTransmission occurs predominantly within families

Hp Hp causes chronic active gastritis, only a small minority causes chronic active gastritis, only a small minority (1 (1 –– 2%) develop a malignant disease (gastric carcinoma 2%) develop a malignant disease (gastric carcinoma and GLand GL’’MM’’))

Distinct genotypes have been found to be associated Distinct genotypes have been found to be associated with particular geographic regionswith particular geographic regions

The The cagcag pathogenicitypathogenicity island (island (cagcag PAI) and the PAI) and the cagAcagAgene are principle virulence factors within the gene are principle virulence factors within the HpHp strains.strains.

HELICOBACTER Pylori

Non specific symptoms Non specific symptoms –– Abdominal pain : most common presenting symptomAbdominal pain : most common presenting symptom–– Dyspepsia, nausea, vomitingDyspepsia, nausea, vomiting……–– Palpable Palpable epigastricepigastric mass, Weight Lossmass, Weight Loss……

At endoscopy :At endoscopy :–– Enlarged gastric folds, gastritisEnlarged gastric folds, gastritis–– Superficial erosionsSuperficial erosions–– Suspect Suspect antralantral ulceration (> 80% of cases) ulceration (> 80% of cases)

G ‘M’ L

Clinical features

G’M’L : Macroscopy apearance

Gastric LymphomaGastric Lymphoma

HistologicalHistological Classification Classification (OMS 2008)(OMS 2008)

MALT L (G ‘M’ L)

Diffuse large B cell L

– Diffuse large B cell L + MALT L component

Others : rares / Mantle cell L (cycline D1) , FL (CD10, Bcl2),

CLL (CD5), Burkitt L, T L (HTLV1), HDK …

Histological features Histological features GG’’MM’’L L (1)(1)

Stereotypy Stereotypy –– NeoplasticNeoplastic cells infiltrate cells infiltrate

around reactive B around reactive B --cell follicles cell follicles

–– Marginal zone cell distribution Marginal zone cell distribution and spreading outwards and spreading outwards diffuse to lamina diffuse to lamina propriapropria

Reactive non Reactive non neoplasticneoplastic follicles follicles Important component of MALT L. Important component of MALT L. Often colonizedOften colonized

• Closely simulate those of a Peyer’s plaque

Histological features : GHistological features : G’’MM’’L L (2)(2)

Exhibit a variety of cytological appearances with Exhibit a variety of cytological appearances with –– Lymphocytic cells Lymphocytic cells : small to medium sized, small : small to medium sized, small

irregular nuclei characteristic of irregular nuclei characteristic of centrocytecentrocyte-- like like cells (cells (CLCCLC))

–– monocytoidmonocytoid BB--cells cells with abundant pale cytoplasm with abundant pale cytoplasm and well defined cell bordersand well defined cell borders

–– Scattered large transformed Scattered large transformed centroblastcentroblast or or immunoblastimmunoblast--like cellslike cells usually dispersed usually dispersed

–– Variable numbers of Variable numbers of plasma reactive cells plasma reactive cells are are frequently present beneath the surface epithelium, frequently present beneath the surface epithelium, a few of them may be proliferative monoclonal a few of them may be proliferative monoclonal cellscells

Histological features : GHistological features : G’’MM’’L L (3)(3)

LymphoepithelialLymphoepithelial lesions (LEL) :lesions (LEL) : Characteristic feature Characteristic feature Invasion of individual crypts by aggregates (Invasion of individual crypts by aggregates (≥≥ 3) of 3) of CentrocytCentrocyt Like Cell (CLC) Like Cell (CLC)

DDegenerative changes + disintegration of the crypt egenerative changes + disintegration of the crypt epithelium (epithelium (oncocyteoncocyte-- like)like)

L E L

EMA

Histological features : GHistological features : G’’MM’’L L (4)(4)

Foci of DLBCL Foci of DLBCL may be seen suggesting that there may be seen suggesting that there has been transformation from one to the other has been transformation from one to the other (Isaacson:1 (Isaacson:1 --10% of 10% of blasticblastic cells in cluster of 20 cells in cluster of 20 cells or diffuse infiltrate of cells or diffuse infiltrate of blasticblastic cells = high grade cells = high grade component)component)

Giemsa

Progression to DLBCL

Islands or clusters of 20 blastic cellsDiffuse infiltrate of large cells

Histological features : GHistological features : G’’MM’’L L (4)(4)

In our In our serieserie, 2/3 (157/ 244: 65%) of gastric , 2/3 (157/ 244: 65%) of gastric lymphoma are of MALT type lymphoma are of MALT type HpHp associated. associated. The others (87/ 244 : 1/3) are DLBCL with GThe others (87/ 244 : 1/3) are DLBCL with G’’MM’’ L L componentcomponent

96% of GL are associated to 96% of GL are associated to HpHp gastritisgastritis

GG‘‘MM’’L Histopathology : SummaryL Histopathology : Summary

Two componentsTwo components1.1. Malignant Malignant

LymphocytLymphocyt cells cells centrocyticcentrocytic -- likelikeMonocytoidMonocytoid cellscellsPlasmacytoidPlasmacytoid cells cells ExpandedExpanded\\confluent marginal zonesconfluent marginal zonesScattered large transformed Scattered large transformed centroblastcentroblast or or immunoblastimmunoblast--like cells like cells LymphoepithelialLymphoepithelial lesionslesions

2. Reactive2. ReactiveReactive germinal centers may be colonized Reactive germinal centers may be colonized by marginal zone cellsby marginal zone cells

G G ’’MM’’ LLImmunophenotypeImmunophenotype

No specific phenotypeNo specific phenotype

They are typically CD20+ They are typically CD20+ –– and B marker like CD19, CD79aand B marker like CD19, CD79a……

–– CD43+ sometimes, CD43+ sometimes, –– BCLBCL--2+2+–– CD5 and CD10 negativeCD5 and CD10 negative–– express surface and cytoplasm immunoglobulin (express surface and cytoplasm immunoglobulin (IgMIgM, ,

few few IgAIgA or or IgGIgG))–– Light chain restriction sometimesLight chain restriction sometimes

G‘M’L : Immunophenotype

CD 20

GG’’MM’’L : L : ImmunophenotypeImmunophenotype

–– CD21, CD23 or CD35 can be used to highlight CD21, CD23 or CD35 can be used to highlight colonized folliclescolonized follicles

–– EMA can be used to highlight EMA can be used to highlight lymphoepitheliallymphoepitheliallesionslesions

–– BclBcl--10 over expression confers 10 over expression confers an increasing capacity of an an increasing capacity of an autonomous development of GL, autonomous development of GL, so no responding to so no responding to tritherapytritherapy

Differential diagnosisDifferential diagnosis

Difficulties of diagnosis specific to the G Difficulties of diagnosis specific to the G ‘‘MM’’ LL

Diagnosis relatively easy on Diagnosis relatively easy on gastrectomygastrectomyspecimen, can be difficult on biopsies specimen, can be difficult on biopsies –– especially if they are very few, of small size especially if they are very few, of small size

and crushed and crushed research of histological criteria research of histological criteria of GLof GL’’MM’’

–– LEL LEL ≠≠ lymphoepitheliallymphoepithelial images images (chronic (chronic gastritis with severe intensity) gastritis with severe intensity) histological histological scoring of lymphoid infiltrations in the scoring of lymphoid infiltrations in the stomach according to stomach according to WotherspoonWotherspoon and and colleagues (Gut, 2006) may be helpfulcolleagues (Gut, 2006) may be helpful

Histological scoring of lymphoid infiltrations in the Histological scoring of lymphoid infiltrations in the stomach according to stomach according to WotherspoonWotherspoon (Gut, 2006)(Gut, 2006)

Score Diagnosis Histological features

0 NormalScattered plasma cells in lamina propria (LP). No lymphoid follicles

1 Chronic active gastritisSmall clusters of lymphocytes in LP. No lymphoid follicles. No LEL

2Chronic active gastritisWith florid lymphoid follicle formation

Prominent lymphoid follicle with surrounding mantle zone and plasma cells. No LEL (lymphoepithelial lesions)

3Suspicious lymphoid infiltrate, probably reactive

lymphoid follicles surrounded by small lymphocytes that infiltrate diffusely in LP +/- into epithelium

4Suspicious lymphoid infiltrate, probably lymphoma

lymphoid follicles surrounded by marginal zone cells that infiltrate diffusely in LP and into epithelium in small groups

5 MALT lymphomaDense infiltrate of marginal zone cells in LP with proeminent LEL

G‘M’LDifferential diagnosis on Bx

Floride acquired MALT G ‘M’ L

Malt type L Vs florid acquired Malt in CG

- sometimes difficult multiples specimen, better directed

morphological arguments / IHC

Kappa Lambda

IHC : monoclonality

Difficulties of diagnosis specific to the GDifficulties of diagnosis specific to the G‘‘MM’’LL

G G ‘‘MM’’ L Vs another type of small BL Vs another type of small B--cell lymphomacell lymphoma–– Follicular lymphoma : CD 10, Bcl2, Bcl6Follicular lymphoma : CD 10, Bcl2, Bcl6–– Lymphocytic lymphoma : clinique, CD5, CD43, CD23Lymphocytic lymphoma : clinique, CD5, CD43, CD23–– Mantle cells lymphoma (lymphomatose polyposis) Mantle cells lymphoma (lymphomatose polyposis)

cells with same cleaved feature (centrocyte cells with same cleaved feature (centrocyte -- like) :like) :Activated cells + respected Activated cells + respected ggerminatives centers erminatives centers + LEL exceptional+ LEL exceptionalGastric localization is rare, characteristic Gastric localization is rare, characteristic

endoscopic aspect, fast dissemination and fatal endoscopic aspect, fast dissemination and fatal evolution may help for diagnosisevolution may help for diagnosisIHC (cycline D1) IHC (cycline D1)

Difficulties of diagnosisDifficulties of diagnosis

–– DLBCL with MALT type component Vs MALT DLBCL with MALT type component Vs MALT lymphoma lymphoma (on superficial specimen): 1 to 10% of (on superficial specimen): 1 to 10% of blastic cells in cluster of 20 cells are in favor of blastic cells in cluster of 20 cells are in favor of high grade componenthigh grade component (Isaacson) (Isaacson)

–– DLBCL with cluster of 20 blastic cells Vs colonized DLBCL with cluster of 20 blastic cells Vs colonized residual follicle center residual follicle center : IHC using CD21 or CD23 : IHC using CD21 or CD23 may be help to differential diagnosis between may be help to differential diagnosis between cluster of blastic cells and colonized folliclecluster of blastic cells and colonized follicle

–– On undifferentiated zonesOn undifferentiated zones :Alcian Blue highlighting :Alcian Blue highlighting mucins, a poor differentiated carcinoma with mucins, a poor differentiated carcinoma with mucipares cells can be diagnosed ; IHC : EMA, CKmucipares cells can be diagnosed ; IHC : EMA, CK

CD23 germinal center CD23 Malt L

Islands or clusters of 20 blastic cellsDc # : colonized germinatif résiduel center (cfd CD23+)

DLBCL Vs germinatif résiduel center

Organoid net work of Fol. dentr. cell

Disorganized net- work

Differential diagnosis on Bx

Dc # : morphologic features / nucleihistochemestry stains / Giemsa, AB

IHC / EMA, CD 20

DLBCL Vs indifferenciated carcinoma

CD 20DLBCL

Differential diagnosis on Bx

Histological evaluation Histological evaluation after early Gafter early G’’MM’’L L Hp Hp eradicationeradication

Wundisch Histological grading Wundisch Histological grading (J. Clin. Oncol, 2005)(J. Clin. Oncol, 2005)

Triple therapy for one week (OAM / OAC)- Omeprazole 20mg 2x/d- Amoxycillin 1000mg- Metronidazole 500mg or Clarythromycin 500mg Few cases required 3 to 4 cures for Hp eradication (45 d interval)

Follow up examination including endoscopy and histology

3 m intervals / two y, every 6 m then after

Histological grading for evaluation

H pylori and early Gastric MALT Lymphomas

Evaluation of histological response of early GEvaluation of histological response of early G’’MM’’L L after after Hp Hp eradication : eradication : Wundisch Histological grading Wundisch Histological grading

(J. Clin. Oncol, 2005)(J. Clin. Oncol, 2005)

Best method of post treatment follow up Best method of post treatment follow up –– Serial endoscopy with histological assessment of Serial endoscopy with histological assessment of

multiples biopsies (and ultrasound endoscopy) multiples biopsies (and ultrasound endoscopy)

Grading describeGrading describess 5 levels of response using 3 factors : 5 levels of response using 3 factors : –– lymphoid infiltratelymphoid infiltrate–– LEL LEL –– and stromal changesand stromal changes

Results may be complete remission Results may be complete remission CRCR, histological , histological residual disease residual disease hRDhRD, partial remission , partial remission PRPR and no change and no change NONO or progression of the disease or progression of the disease PDPD

Evaluation of histological response of early GEvaluation of histological response of early G’’MM’’L, after L, after Hp Hp eradicationeradicationWundisch Histological grading Wundisch Histological grading (J. Clin. Oncol, 2005)(J. Clin. Oncol, 2005)

In our serie 61 of 157 patients (39%) with early MALT In our serie 61 of 157 patients (39%) with early MALT lymphoma, had lymphoma, had HpHp eradication :eradication :–– 57% CR (Vs 60 57% CR (Vs 60 àà 90 % : 90 % : Fischbach study, 2004Fischbach study, 2004) ) thatthat

needs : 2 successives negatives biopsies with multiple needs : 2 successives negatives biopsies with multiple specimens and a mapping to confirm the CR specimens and a mapping to confirm the CR

–– 21% hRD (vs 18%, 21% hRD (vs 18%, FischbachFischbach) : No therapeutic nor ) : No therapeutic nor prognostic signification, so a watch and wait strategy prognostic signification, so a watch and wait strategy must appliedmust applied

–– PR and NC Vs PD : 20% (vs 16%) show after PR and NC Vs PD : 20% (vs 16%) show after sequential biopsies a blastic component; low and high sequential biopsies a blastic component; low and high grade component may be synchronous in GL so that grade component may be synchronous in GL so that needs a gastric mapping which minimizes sampling needs a gastric mapping which minimizes sampling errorserrors

CR

hRD

PR

N C vs PD

G G ‘‘MM’’ LL

Histological eradication therapy response Histological eradication therapy response depends ofdepends of

–– Histological lymphoma Histological lymphoma gradegrade–– StageStage (nodes infiltration and depth infiltration (nodes infiltration and depth infiltration

assessed by endoscopic ultrasonography)assessed by endoscopic ultrasonography)–– Associated Associated genetics abnormalities genetics abnormalities

/ t(11,18); t(1,14) / t(11,18); t(1,14) IHC study using BclIHC study using Bcl--1010 : Nuclear +ve

GG‘‘MM’’LL

Eradication therapy : simple, efficient

regression --> 56 à 100%Wotherspoon,1993 : 5/6 cases

Bayerdorffler ; 1997

Isaacson,1999 : 6/6 cases

Fischbach, 2002-2004 : 56/90 cases

Wundisch, 2005 : 96/120 cases

Amir et al., 2007 : 35/61 cases

Shiho, 2008 : 66/74 cases

SHIHO et al. Tohoku J. Exp. Med., 2008, 214, 79SHIHO et al. Tohoku J. Exp. Med., 2008, 214, 79-- 8787

GG‘‘MM’’LL

CR : 2 series successive Bx (-) / multiples specimensgeneraly obtained between 6 -18 months after Therapy

No response ---> Foci of large cells !

t (11;18) / t(1,14)

hRD monoclonal persistance : no signification

Molecular pathology Molecular pathology

GG‘‘MM’’L : Molecular pathology L : Molecular pathology

A number of genetic and epigenetic abnormality have been described (Isaacson, 2005):

• t(11,18)(q21;q21), t(1;14)(p22;q32), t(14;18)(q32;q21) 3 chromosomal translocations are specifically associated with Malt Lymphoma Role in diagnosis, prognosis

• Trisomies 3 (60%) , 12 and 18 less frequent

• p53 LOH/mutation, p15, p16 promoter methylation ...

•PAX5/IGH

T(11;18) T(11;18) MLT MLT and and API2API2 genesgenes

–– t (11;18) (q21; q21) in 30t (11;18) (q21; q21) in 30--40% MALT L40% MALT L

caused reciprocal fusion of the API2 and MALT1 genescaused reciprocal fusion of the API2 and MALT1 genes

not been detected in MALT with DLBCLnot been detected in MALT with DLBCL

This kind of lymphoma gain autonomous growth ability This kind of lymphoma gain autonomous growth ability

and resistant to and resistant to HpHp eradicationeradication

Other mutationsOther mutations

–– t(14;18) (genes t(14;18) (genes IGHIGH and and MLTMLT) ) cytogenetically similar but molecularly cytogenetically similar but molecularly distinct from follicular lymphomadistinct from follicular lymphoma

–– t(1;14)(p22;q32) and t(1;2)(p22;p12) < 5% : t(1;14)(p22;q32) and t(1;2)(p22;p12) < 5% : exclusive exclusive HpHp independent independent -- GL GL ‘‘MM’’ and those and those may undergo high grade transformation; this may undergo high grade transformation; this translocation juxtaposes BCLtranslocation juxtaposes BCL--10 to an 10 to an immunoglobulin gene locus thus deregulating immunoglobulin gene locus thus deregulating its expressionits expression

BclBcl--1010

t (1;14) and t (1;2) involve t (1;14) and t (1;2) involve the bclthe bcl--10 gene10 gene

= Advance stage of lymphoma= Advance stage of lymphomat(11;18) does not involve the t(11;18) does not involve the bclbcl--10 gene10 gene

NuclearNuclear bclbcl--10 10 immunohistochemistry immunohistochemistry detects both t(11;18) and detects both t(11;18) and t(1;14)t(1;14)

Pathogenesis Pathogenesis of gastric MALT lymphomaof gastric MALT lymphoma

Pathogenesis of GPathogenesis of G’’MM’’LL

Normal gastric mucosa is devoid of lymphoid tissueNormal gastric mucosa is devoid of lymphoid tissue

Multistage process starting with Multistage process starting with HpHp infection infection stimulating Hpstimulating Hp--specific Tspecific T--cell clones cell clones B cell follicles B cell follicles ppromotes malignant transformation of reactive romotes malignant transformation of reactive BB--cells due to acquisition of genetics abnormalitiescells due to acquisition of genetics abnormalitiesinduces and sustains an active proliferating Binduces and sustains an active proliferating B--cell cell population that may develop genetic abnormalitiespopulation that may develop genetic abnormalitiesattracting and activating neutrophils, which release attracting and activating neutrophils, which release

oxygen reactive species = genotoxic and causes genetic oxygen reactive species = genotoxic and causes genetic abnormalitiesabnormalities

Chronic Hp infection

Acquired MALT

Hp specific T cells

B cells proliferation

T(1;14) (p:22;p:32)

MALT Lymphoma

MALT Lymphoma

t (11;18) (q:21; q21)MALT Lymphoma

Trisomies 3, 12, 18

EarlyMALT Lymphoma

MALT Lymphomaadvanced

inactivation p53, p16

c. myc ; BCL-6

directe Ag stimulation

Hpdependant

Hpindependant

5%

65% 30%

Conclusion Conclusion (1)(1)

Helicobacter pylori play a crucial role in the Helicobacter pylori play a crucial role in the development and progression of gastric lymphomadevelopment and progression of gastric lymphoma

GL is a relatively prevalent gastric malignant tumor; GL is a relatively prevalent gastric malignant tumor; GLGL’’MM’’ is an indolent disease but may become locally is an indolent disease but may become locally aggressive, spread, or undergo high grade aggressive, spread, or undergo high grade transformationtransformation

True prolonged remissions are possible right by Hp True prolonged remissions are possible right by Hp eradication treatment eradication treatment

Conclusion Conclusion (2)(2)

Eradication therapy is efficient and simple; it Eradication therapy is efficient and simple; it

permitted the regression of more than a half of permitted the regression of more than a half of

early gastric MALT lymphomas in our Hp early gastric MALT lymphomas in our Hp

positive patients.positive patients. Careful endoscopic evaluation Careful endoscopic evaluation

with multiple biopsy and endoscopic with multiple biopsy and endoscopic

ultrasonography would help in staging and ultrasonography would help in staging and

monitoring patientsmonitoring patients

Conclusion Conclusion (3)(3)

Histological diagnosis depends onHistological diagnosis depends on–– clinical data information, clinical data information, –– MALT sites exploration with multiple directed and MALT sites exploration with multiple directed and

performed biopsy specimens (gastric mapping with performed biopsy specimens (gastric mapping with more than 20 specimens in order to identify a high more than 20 specimens in order to identify a high grade component)grade component)

–– best histological techniques with good HE and CD20 best histological techniques with good HE and CD20 (IHC)(IHC)

Immunohistochemistry, molecular biology would allow a Immunohistochemistry, molecular biology would allow a better comprehension of these GL for better treating and better comprehension of these GL for better treating and why not preventing them by vaccination.why not preventing them by vaccination.

XXVII International Congress of the IAPAthens, Greece 2008

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