GASTRIC MALT GASTRIC MALT LYMPHOMALYMPHOMA

IS IT CURABLE BY ERADICATION ??IS IT CURABLE BY ERADICATION ??

YASSINE.M YASSINE.M Mir Amin Mir Amin

01/10/200501/10/2005

HHelicobacter pylorielicobacter pylori• H pyloriH pylori is a spiral shaped bacterium that is a spiral shaped bacterium that

is found in the gastric mucus layer or is found in the gastric mucus layer or adherent to the epithelial lining of the adherent to the epithelial lining of the stomach. stomach. H pyloriH pylori causes more than 90% causes more than 90% of duodenal ulcers and more than 80% of of duodenal ulcers and more than 80% of gastric ulcersgastric ulcers

• 50% of world population is infected and is 50% of world population is infected and is the cause ofthe cause of::

• Duodenal/gastric ulcers and gastric Duodenal/gastric ulcers and gastric cancercancer

1.1. H. pyloriH. pylori burrows into mucus burrows into mucus layer of stomachlayer of stomach

2.2. Bacterium attaches to tight Bacterium attaches to tight junction of epithelial cellsjunction of epithelial cells

3.3. Specialized bacterial Specialized bacterial secretion system secretion system translocates bacterial translocates bacterial proteins to host, including proteins to host, including CagACagA

4.4. Change in cell morphology to Change in cell morphology to

“hummingbird” shape and“hummingbird” shape and generalized inflammationgeneralized inflammation

including CagAChange

How H. pylori survives in human stomach

Oncogenic Infectious AgentsOncogenic Infectious Agents

Agent Tumor Type Annual Cases WorldwideBacteriaHelicobacter pylori Stomach cancer, gastric lymphoma 505,000Campylobacter jejuni Alpha chain disease rareVirusesHuman papillomavirus Cervical, anal, vaginal, and other 447,000Hepatitis B virus Liver cancer 285,000Hepatitis C virus Liver cancer 113,000Human immunodeficiency virus Kaposis, NHL 52,000Human herpes type 8 Kaposis’s 44,000Epstein-Barr virus Lymphomas 30,000Human T-cell lymphotropic virus Adult T-cell leukemia 3000ParasitesSchistosomes Bladder cancer 10,000Liver flukes Cholangiocarcinoma 800

Mucosa - Associated Lymphoid Tissue Mucosa - Associated Lymphoid Tissue LymphomaLymphoma

Described by Isaacson and Wright in Described by Isaacson and Wright in 19831983

PseudolymphomaPseudolymphoma ????? ?????

MALTomaMALToma

Factors associated with acquired Factors associated with acquired MALTMALT

Helicobacter pylori Helicobacter pylori

Helicobacter HeilmaniiHelicobacter Heilmanii

Chronic infection / Chronic infection / inflammationinflammation

Borrelia BurgdorferiBorrelia Burgdorferi

Autoimmune conditions:Autoimmune conditions:

Sjögren’s SyndromeSjögren’s Syndrome

Hashimoto’s ThyroiditisHashimoto’s Thyroiditis

Predominant sites of MALT-lymphomaPredominant sites of MALT-lymphoma

Stomach Stomach

GI-TractGI-Tract

LungLung

Salivary GlandsSalivary Glands

Ocular AdnexaOcular Adnexa

SkinSkin

Standard stagingStandard staging

Ophthalmologic investigationOphthalmologic investigation Ear, nose and throat (incl Sono/MR)Ear, nose and throat (incl Sono/MR) Endosonography + Gastroscopy (multiple Endosonography + Gastroscopy (multiple biopsies)biopsies) Enteroklysma (-CT)Enteroklysma (-CT) ColonoscopyColonoscopy CT-Thorax + AbdomenCT-Thorax + Abdomen Bone marrow biopsy Bone marrow biopsy

Ann Arbor classification of extranodal Ann Arbor classification of extranodal Lymphoma(modified by Musshoff)Lymphoma(modified by Musshoff)

E1:E1:lymphoma restricted to GI tract on one side of diaphragmlymphoma restricted to GI tract on one side of diaphragm

EI1:EI1:infiltration limited to mucosa and submucosainfiltration limited to mucosa and submucosa

EI2:EI2:lymphoma extending beyong submucosa.lymphoma extending beyong submucosa.

EII:EII: lymphoma additionally infiltrating lymph nodes on same side of lymphoma additionally infiltrating lymph nodes on same side of diaphragmdiaphragm

EII1EII1:infiltration of regional lymph nodes:infiltration of regional lymph nodes

EII2:EII2: infiltration of lymph nodes beyond regional nodes infiltration of lymph nodes beyond regional nodes

EIII:EIII: lymphoma infiltrating GI tract and/or lymph nodes on both side of lymphoma infiltrating GI tract and/or lymph nodes on both side of diaphragmdiaphragm

EIV:EIV:localized infiltration of associated lymph nodes together with localized infiltration of associated lymph nodes together with diffuse or disseminated involvement of extra-GI organsdiffuse or disseminated involvement of extra-GI organs

The common karyotypic alterations The common karyotypic alterations

trisomies 3--30% and 18,trisomies 3--30% and 18, the translocations t(11;18)(q21;q21), 30%_40%the translocations t(11;18)(q21;q21), 30%_40%t(1;14)(p22;q32), t(1;14)(p22;q32), t(14;18)(q32;q21),t(14;18)(q32;q21), t(3;14)(q27;q32),t(3;14)(q27;q32), and the recently described t(3;14)(p14.1;q32). and the recently described t(3;14)(p14.1;q32).

Journal of Clinical OncologyJournal of Clinical Oncology, Vol 23, No 26 (September 10), 2005: pp. 6370-6378, Vol 23, No 26 (September 10), 2005: pp. 6370-6378

© 2005 © 2005 American Society of Clinical OncologyAmerican Society of Clinical Oncology

Resection or stomach Resection or stomach preservation ?preservation ?

Surgery,radiotherapy and chemotherapy has Surgery,radiotherapy and chemotherapy has been used alone or in various combinationbeen used alone or in various combination

Primary gastric lymphomas (PGL) have Primary gastric lymphomas (PGL) have traditionally been treated with surgery followed traditionally been treated with surgery followed by chemotherapy or radiotherapy by chemotherapy or radiotherapy

Surgery was thought to improve staging, Surgery was thought to improve staging, optimise local disease control and reduce risk of optimise local disease control and reduce risk of perforation or bleeding, but recent studies perforation or bleeding, but recent studies question its role question its role

GobbiGobbi PG PG, et al, et al

75 pt PGL , 22 LG, 27 IG , 27 HG75 pt PGL , 22 LG, 27 IG , 27 HG45 resected pt , 35 unresected45 resected pt , 35 unresectedTreatment modalities included surgery (S), Treatment modalities included surgery (S), chemotherapy (CT), radiotherapy (RT), chemotherapy (CT), radiotherapy (RT), and combinations thereof in the following and combinations thereof in the following proportions: only S in ten cases, S + CT in proportions: only S in ten cases, S + CT in 32 cases, S + RT in one case, S + CT + 32 cases, S + RT in one case, S + CT + RT in two cases, CT only in 25 cases, CT RT in two cases, CT only in 25 cases, CT + RT in five cases. + RT in five cases.

No substantial differences in response to No substantial differences in response to therapy and in survival were found in therapy and in survival were found in relation to the different treatments. relation to the different treatments.

No bleeding or perforations were observed No bleeding or perforations were observed in the 30 unresected patients in the 30 unresected patients

Cancer. 1990 Jun 1;65(11):2528-36.Cancer. 1990 Jun 1;65(11):2528-36.

PopescuPopescu RA RA, et al, et al

37 pt , 6 LG MALT, 9 HG MALT,20 DLBC37 pt , 6 LG MALT, 9 HG MALT,20 DLBC17 of whom had localised disease, were 17 of whom had localised disease, were treated with either surgery plus treated with either surgery plus chemotherapy or chemotherapy alone. chemotherapy or chemotherapy alone. 5-year overall survival for localised and 5-year overall survival for localised and advanced PGL was 94 and 50%, advanced PGL was 94 and 50%, respectively, with no differences between respectively, with no differences between the two treatments over a 53 months the two treatments over a 53 months median follow-up. median follow-up.

No perforations or serious bleeding No perforations or serious bleeding occurred. Surgery is associated with occurred. Surgery is associated with important morbidity and we detected no important morbidity and we detected no benefit of surgery prior to chemotherapy in benefit of surgery prior to chemotherapy in this limited series of patients.this limited series of patients.

Eur J Cancer. 1999 Jun;35(6):928-34 Eur J Cancer. 1999 Jun;35(6):928-34

M. Binn et alM. Binn et al

Between January 1988 and December 1996 Between January 1988 and December 1996

58 patients included in the trials promoted by the 58 patients included in the trials promoted by the Groupe d’Étude des Lymphomes de l’Adulte Groupe d’Étude des Lymphomes de l’Adulte (GELA) (LNH-87 and LNH-93) received (GELA) (LNH-87 and LNH-93) received chemotherapy and 48 included in the protocol of chemotherapy and 48 included in the protocol of the Groupe d’Étude des Lymphomes Digestifs the Groupe d’Étude des Lymphomes Digestifs (GELD) underwent surgical resection followed (GELD) underwent surgical resection followed by chemotherapy. by chemotherapy.

This study shows that in localized gastric DLBCL This study shows that in localized gastric DLBCL with IPI 0–1, a similar 5-year survival rate with IPI 0–1, a similar 5-year survival rate (>90%) is to be expected with either surgery plus (>90%) is to be expected with either surgery plus chemotherapy or chemotherapy alone. chemotherapy or chemotherapy alone.

Annals of OncologyAnnals of Oncology 14:1751-1757, 2003 14:1751-1757, 2003

© 2003 © 2003 European Society for Medical OncologyEuropean Society for Medical Oncology

KOCH et alKOCH et al

German Multicenter Study GIT NHL 01/92 German Multicenter Study GIT NHL 01/92 Only patients with PGL in stages IE and IIE Only patients with PGL in stages IE and IIE From October 1992 throughout November 1996, 277 From October 1992 throughout November 1996, 277 patients with PGL were accrued to the study and treated patients with PGL were accrued to the study and treated by medical, surgical, and/or radiotherapeutic by medical, surgical, and/or radiotherapeutic departments departments CONCLUSION: Although the study was not randomized, CONCLUSION: Although the study was not randomized, a stomach-conserving approach may be favored. a stomach-conserving approach may be favored.

Journal of Clinical OncologyJournal of Clinical Oncology, Vol 19, Issue 18 (September), 2001: 3874-3883, Vol 19, Issue 18 (September), 2001: 3874-3883© 2001 © 2001 American Society for Clinical OncologyAmerican Society for Clinical Oncology

KOCH et alKOCH et al

747 pt ,393 conservatif747 pt ,393 conservatif

In this nonrandomized study (02/96), we In this nonrandomized study (02/96), we reproduced the previous results of study 01/92 reproduced the previous results of study 01/92 showing no disadvantage for an organ-showing no disadvantage for an organ-preserving treatment. Therefore, primary preserving treatment. Therefore, primary stomach resection should be questioned.stomach resection should be questioned.

Journal of Clinical Oncology, Journal of Clinical Oncology, 10.1200/JCO.2005.04.031 10.1200/JCO.2005.04.031

Conservative management Conservative management plus surgery vs conservative aloneplus surgery vs conservative alone

KOCH AND AL JCO 2001

Eradication of H.pylori & MALTEradication of H.pylori & MALT

Despite abundant literature on histologic, Despite abundant literature on histologic, clinical, and biological features of MALT clinical, and biological features of MALT lymphoma, results of controlled trials to define lymphoma, results of controlled trials to define the optimal therapy have not yet been published, the optimal therapy have not yet been published, and only a few randomized studies are ongoing. and only a few randomized studies are ongoing. Literature data are confusing: insufficient staging Literature data are confusing: insufficient staging and outdated histologic classifications are a and outdated histologic classifications are a major problem of the older reports, and more major problem of the older reports, and more recent studies often refer to retrospective series recent studies often refer to retrospective series of patients not uniformly staged and treated of patients not uniformly staged and treated

Blood, Vol. 96 No. 2 (July 15), 2000: pp. 410-419 Blood, Vol. 96 No. 2 (July 15), 2000: pp. 410-419

The patients have been treated with a variety of The patients have been treated with a variety of combinations of surgery, radiotherapy, and combinations of surgery, radiotherapy, and chemotherapy, and the overall survival rates chemotherapy, and the overall survival rates range from 80% to 95% at 5 years. Therefore, range from 80% to 95% at 5 years. Therefore, while prognosis of patients with MALT while prognosis of patients with MALT lymphoma seems excellent regardless of lymphoma seems excellent regardless of treatment, optimal therapy remains to be treatment, optimal therapy remains to be determined determined

Blood, Vol. 96 No. 2 (July 15), 2000: pp. 410-419 Blood, Vol. 96 No. 2 (July 15), 2000: pp. 410-419

32 patients studied in 1992 showed that the MALT 32 patients studied in 1992 showed that the MALT lymphomas could also disappear: in six out of 10 lymphomas could also disappear: in six out of 10 patients with low grade MALT lymphomas follow up patients with low grade MALT lymphomas follow up

revealed regression of lymphomarevealed regression of lymphoma (neubauer etal) 1992(neubauer etal) 1992

In 1993 Wotherspoon and colleagues reported In 1993 Wotherspoon and colleagues reported regression of low grade gastric MALT lymphomas in five regression of low grade gastric MALT lymphomas in five out of six patientsout of six patients. . LancetLancet 1993; 1993;342342:575–7 :575–7

Lymphomas of MaLT type treated with helicobacter pylori: results of main series in the literatureLymphomas of MaLT type treated with helicobacter pylori: results of main series in the literature

AUTEUAUTEURR

YEARYEARSS

NN STAGESTAGE EVALUEVALUATIONATION

CR %CR % FOLLOFOLLOW_UP W_UP M +M +

RELAPSRELAPS

SAVIO SAVIO ETalETal

19961996 1212 IEIE TDMTDM 84(11)84(11) 24(14-24(14-36)36)

00

NeubauNeubauer et aler et al

19971997 5050 IEIE TDM+ETDM+EEE

80(40)80(40) 15(0-40)15(0-40) 55

PINATTI PINATTI et alet al

19971997 4545 IEIE TDMTDM 68(30)68(30) 23(2-66)23(2-66) 22

Nobre Nobre leitao et leitao et alal

19981998 1717 IEIE TDM+ETDM+EEE

100(17)100(17) 12(2-39)12(2-39) 11

STEINBSTEINBACH et ACH et alal

19991999 2828

2323IE+IIEIE+IIE

IEIETDM OR TDM OR EEEE

50(14)50(14)

56(13)56(13)(>18)(>18) 00

RuskonRuskone et ale et al

20012001 3434

2424IE+IIEIE+IIE

IEIETDM+ETDM+EEE

56(19)56(19)

79(19)79(19)23(8-44)23(8-44) 22

LEVY et LEVY et aa

ll

20022002 4848

3333IE+IIEIE+IIE

IEIETDM+ETDM+EEE

58(28)58(28)

76(25)76(25)34(6-60)34(6-60) 00

Alpen Alpen et alet al

1818 1818

00RR

NRNR00

--00

Liu et alLiu et al 2222 1010

1212RR

NRNR00

9900

7575

Liu et alLiu et al 111111 4848

6363RR

NRNR22

424244

6767

Grade Grade IEIE

9090 4646

3333RRNRNR

112626

22

7878

GradeIIGradeIIEE

2020 11

2020RR

NRNR11

1616 8080

n Reponse a l eradication t(11-18)n Reponse a l eradication t(11-18)

de H.pylori de H.pylori --------------------------

n n %%

t(11;18) (q21;q21)t(11;18) (q21;q21)

Characteristic translocation for MALT-lymphomasCharacteristic translocation for MALT-lymphomas⇒⇒ found in up to 50% of gastric MALT-lymphomasfound in up to 50% of gastric MALT-lymphomas

Not detected in other MZBL and extranodal DLBCLNot detected in other MZBL and extranodal DLBCL

Fusion of the apoptosis inhibitor gene API2 (11q21) and Fusion of the apoptosis inhibitor gene API2 (11q21) and the novel MALT1 gene (18q21)the novel MALT1 gene (18q21)

Fusion product inhibits apoptosis by caspase pathwaysFusion product inhibits apoptosis by caspase pathways

t(11;18) translocation t(11;18) translocation in gastric MALT-lymphomain gastric MALT-lymphoma

Number of patients:Number of patients: 111111

Response to eradication:Response to eradication: 4848

t(11;18) positive:t(11;18) positive: 2 / 48 responders2 / 48 responders 42 / 63 non-responders 42 / 63 non-responders

Liu et al, Gastroenterology 2002

Regression of MALToma after cure Regression of MALToma after cure of Helicobacter pylori infection (of Helicobacter pylori infection ( 三三 ))

Low -grade primary gastric MALToma can Low -grade primary gastric MALToma can complete regress after eradication of H pylori complete regress after eradication of H pylori infection.infection.Some high grade lymphomas of the stomach Some high grade lymphomas of the stomach may develop from low-grade MALToma.may develop from low-grade MALToma.H pylori infection associated with an early-H pylori infection associated with an early-stage tumor (EI) result in complete tumor stage tumor (EI) result in complete tumor regression in more than 80% of patients.regression in more than 80% of patients.Advanced tumor stage E or tumor with ⅡAdvanced tumor stage E or tumor with Ⅱtransition to high grade malignancy didn't transition to high grade malignancy didn't respond to cure of the H pylori infection.respond to cure of the H pylori infection.

Time to Remission Time to Remission after HP-Eradicationafter HP-Eradication

Isaacson et al.:Isaacson et al.: 4 weeks – 14 months 4 weeks – 14 months

Sackmann et al.:Sackmann et al.: 6 – 14 months6 – 14 months

Neubauer et al.:Neubauer et al.: 4 – 18 months4 – 18 months

Montalban et al.:Montalban et al.: 2 – 7 months 2 – 7 months

„The cases of late remission encourage us to wait for at least one year after eradication of H. pylori.“

A. Savio, Recent Results Cancer Res 2000.

Factors predicitive of responseFactors predicitive of response

Staging / Endosonographic assessment:Staging / Endosonographic assessment:Stage EI1 vs more advanced stagesStage EI1 vs more advanced stages

Probability of complete response stage EI1 Probability of complete response stage EI1 (n=22):(n=22):

6 mos6 mos 60%60%12 mos12 mos 79%79%14 mos14 mos 100%100%

gastric High –grade MALT lymphoma and gastric High –grade MALT lymphoma and H.pylori eradicationH.pylori eradication

High-grade mucosa-associated lymphoid tissue (MALT) lymphomas of the stomach High-grade mucosa-associated lymphoid tissue (MALT) lymphomas of the stomach are generally believed to be are generally believed to be Helicobacter pyloriHelicobacter pylori–independent–independent

Prospective Study of Prospective Study of Helicobacter pyloriHelicobacter pylori Eradication Therapy in Stage IE High-Grade Eradication Therapy in Stage IE High-Grade Mucosa-Associated Lymphoid Tissue Lymphoma of the Stomach Mucosa-Associated Lymphoid Tissue Lymphoma of the Stomach

From June 1995 through April 2000 16 pts 10 women 6 menFrom June 1995 through April 2000 16 pts 10 women 6 men

10 CR 62,5 %10 CR 62,5 %

These results suggest that high-grade transformation is not necessarily These results suggest that high-grade transformation is not necessarily associated with the loss of associated with the loss of H pyloriH pyloridependence in early-stage MALT dependence in early-stage MALT lymphomas of the stomach. lymphomas of the stomach.

Journal of Clinical OncologyJournal of Clinical Oncology, Vol 19, Issue 22 (November), 2001: 4245-4251, Vol 19, Issue 22 (November), 2001: 4245-4251© 2001 © 2001 American Society for Clinical OncologyAmerican Society for Clinical Oncology

BCL10 or NFkB in high grade BCL10 or NFkB in high grade MALTMALT

22pt stage IE HG MALT 1995_200222pt stage IE HG MALT 1995_2002BCL10 and Nuclear factor Kappa B evaluated by BCL10 and Nuclear factor Kappa B evaluated by immunohistochemistryimmunohistochemistryBCL10 found in 87,5 % OF 8 pts non responders and in BCL10 found in 87,5 % OF 8 pts non responders and in none of 14 pts HP dependent P<0,001none of 14 pts HP dependent P<0,0017pts with BCL10 expression had nuclear expression of 7pts with BCL10 expression had nuclear expression of NFKB NFKB BCL10 or NFkB is highly predictive of H.Pylori BCL10 or NFkB is highly predictive of H.Pylori independent statusindependent status

Journal of Clinical OncologyJournal of Clinical Oncology, Vol 22, No 17 (September 1), 2004: pp. 3491-3497, Vol 22, No 17 (September 1), 2004: pp. 3491-3497

© 2004 © 2004 American Society of Clinical OncologyAmerican Society of Clinical Oncology

conclusionconclusionHP is a major factor in the development of HP is a major factor in the development of MALT-lymphoma.MALT-lymphoma.

Eradication leads to durable remissions in Eradication leads to durable remissions in about 80% of selected patients.about 80% of selected patients.

t(11;18)+ patients seem to be unresponsive to t(11;18)+ patients seem to be unresponsive to HP eradication.HP eradication.

Relapse triggered by re-infection with HP Relapse triggered by re-infection with HP remains sensitive to eradicationremains sensitive to eradication