gastric malt lymphoma.ppt - the lebanese society of
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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