1、胃肠结外淋巴瘤（优选）胃肠结外淋巴瘤定义定义 来源于淋巴结外的淋巴组织来源于淋巴结外的淋巴组织 甚至来源于正常情况下不含淋巴组织的部位甚至来源于正常情况下不含淋巴组织的部位 当结内和结外病变同时存在时，定义较困难当结内和结外病变同时存在时，定义较困难发病率发病率 占非霍奇金淋巴瘤的占非霍奇金淋巴瘤的25%淋巴瘤淋巴瘤淋巴结淋巴结淋巴结外淋巴结外胃肠道胃肠道非胃肠道非胃肠道胃胃:B-cell MALT DLBCL H.Pylori肠道肠道:T-cell Celiac disease睾丸睾丸脑脑T/NK 鼻型鼻型INTERNATIONAL EXTRANODAL LYMPHOMA STUDY GRO
2、UP Extranodal Lymphoma Survival by histology and site in the IELSG series 少见少见 :所有胃肠道肿瘤的所有胃肠道肿瘤的3%绝大多数胃肠道淋巴瘤来源于胃绝大多数胃肠道淋巴瘤来源于胃原发胃肠道淋巴瘤原发胃肠道淋巴瘤P Koch J Clin Oncol 200115%3%75%Non Hodgkins Lymphoma Classification Project.Blood 1997;89:3909-18Frequency%G Gastric I IntestinNodal site1.4%G-4%I0%G-25%I0%G
3、-20%I胃肠道淋巴瘤分类胃肠道淋巴瘤分类Mantle cell L.Diffuse large B cell lymphomaT-cell lymphomaBurkitt.LMALT Lymphoma 1%G -20%(colon)Follicular L.38%G-10%I 60%系统检查分期系统检查分期MALT lymphoma:ESMO GUIDELINES Dreyling M,Thieblemont C.et al.Ann Oncol 2012LymphomaGI lymphomaMandatory physical exam complete blood counts basic
4、 biochemical studies(renal and liver function,LDH and 2MG,serum protein immunofixation)HIV,HCV and HBV serology CT of the chest,abdomen and pelvis-GASTRIC:Gastroduodenal endoscopy with multiple biopsies taken from each region of the stomach,duodenum,gastro-esophageal junction and from any abnormal-a
5、ppearing site;H.pylori status must be evaluated in gastric L.-SMALL INSTESTINE (IPSID Immuno-Proliferative Small Intestinal Disease):Campylobacter Jejuni search in the tumor biopsy by PCR,immunohistochemistry or in situ hybridization may be performed.-LARGE INTESTINE:colonoscopyRecommended bone marr
6、ow aspirate and biopsy If clinically indicated,head&neck MRI studies and other imaging are to be realizedAuto-antigens-Thyroid Hashimoto thyroiditis-Salivary gland Myoepithelial sialoadenitis+/-Sjgren S.-Lung Lymphoid interstitial pneumopathy MZL（边缘区淋巴瘤）（边缘区淋巴瘤）:与慢性抗原刺激相关与慢性抗原刺激相关MALT LymphomasSite
7、Infectious agents-Stomach Helicobacter pylori-Intestin Campylobacter jejuni-Ocular adnexa Chlamydia psittaci-skin Borrelia burgdorferi Hepatitis C VirusMicrobial pathogens1.2.+Splenic MZLIsaacson P,Wright DH.Cancer 1983HELICOBACTER PYLORI in STOMACHMZL:associated with a chronic antigenic stimulation
8、chronic Ag stimulation chronic inflammationINFECTIONAUTOANTIGENAcquisition of MALTAg-dependantMALT lymphomaAg-independantMALT lymphomaEpithelium of extranodal sitesMALT CONCEPTMALT淋巴瘤常见的遗传损伤淋巴瘤常见的遗传损伤NF-KB activationBertoni F.et al.Oncology 2011 Normal stomachChronic gastritis MALT Lymphoma+addition
9、al factors:host,environment,geneticHPNFKBt(11;18)API2-MALT1 t(1,14)BCL10t(14;18)Ig-MALT1E.De Kerviler Saint-Louis Hospital,Paris胃胃MALT 淋巴瘤内镜淋巴瘤内镜Pseudogastritis30%Nodular infiltration 25%Ulcers45%JC Delchier Henri Mondor Hospital,Crteilt(11;18)API2-MALT1LY03 interim analysis,2000 190CT 62 3-2415Auto
10、-antigensMALT LymphomasTestisBrainT/NK nasal TypeHitchcock,2002 934 median78%(100%local)t(1,14)BCL10Extranodal Lymphoma Survival by histology and site in the IELSG seriesNormal stomachphysical exam-Thyroid Hashimoto thyroiditisNormal stomachMALT Lymphoman=120 patients-Ocular adnexa Chlamydia psittac
11、iAcquisition of MALTSteinbach,199923CTEUS 56 3-450MZL（边缘区淋巴瘤）:与慢性抗原刺激相关Extranodal Lymphoma Survival by histology and site in the IELSG seriest(11;18)API2-MALT1Normal stomachChronic gastric MALT Lymphoma+additional factors:host,environment,geneticHPNFKBt(11;18)API2-MALT1 t(1,14)BCL10t(14;18)Ig-MALT1A
12、TBHussel,Lancet 1993;Wootherspoon,Lancet 1993;Wndisch,JCO 2005依赖依赖H.PyloriH.Pylori的的胃胃MALT MALT 淋巴瘤的治疗淋巴瘤的治疗Hp.eradicationComplete response:60%-100%Response:3 to 28 months!Resistance associated to t(11;18)Hussel,Lancet 1993;Wootherspoon,Lancet 1993;Wndisch,JCO 2005LymphomaReference n stagingCR ratet
13、ime to CR relapses procedure (%)(mos.)(n)Savio,199612 CT 84 2-40Pinotti,199745CT 67 3-182Neubauer,1997 50CTEUS 80 1-95Nobre Leitao,199817 CT+EUS 100 1-121Steinbach,199923CTEUS 56 3-450Montalban,200119CTEUS 95 2-19 0Ruskone-Formestraux,200124CT+EUS 79 2-18 2LY03 interim analysis,2000 190CT 62 3-2415抗
14、生素和质子泵治疗抗生素和质子泵治疗stage Istage I 胃胃 MALT MALT 淋巴瘤淋巴瘤After 5 years=71%Median follow-up=7 yearsFischbach et al,Gut 56:1685-7,2007Pinotti et al,10-ICML Abstract#361Stathis A et al,Ann Oncol 2009n=120 patients抗生素治疗后的缓解期抗生素治疗后的缓解期Normal stomachChronic gastric MALT LymphomaHPt(11;18)API2-MALT1 t(1,14)BCL10
15、t(14;18)Ig-MALT1DLBCLp53 deletion,p16 deletionGastric DLBCL Dependant to Hp.?10 pts with Gastric DLBCL-Stage IE or IIE PPI-amoxicillin-clarithromycin for 7 daysCase NAge/sexTumor LocationStageHp.TreatmentNber of eradicationResponseTo lymphomaTime to CR(mo)1234567891067/M65/F60/M56/F44/M74/F35/M34/F7
16、5/M73/FAntrumAntrumCorpusAntrumAntrumCorpusAntrumCorpusAntrumCorpusIEIIE2IEIEIEIIE1IEIIE2IIE1IIE12111112211CRCRCRCRCRResidual MALTCRCRCRCR1222221432JC Delchier et al.IELSG 2011 Biomarkers associated with antigen dependanceRT in localized gastric MALT lymphomaAuthor n RT dose(Gy)FFPSchechter,19981728
17、43100%at 2 yrTsang,2001 92030100%at 5 yrYahalom,20025130 median89%at 4 yr Hitchcock,2002 934 median78%(100%local)Goda JS,2010 25 2530 79%at 5 yr 烷化剂单药治疗烷化剂单药治疗24 例患者,17 例stage I，7 例stage IVCyclophosphamide or Chlorambucil for 824 mos.100%ORR(75%CR)5year EFS:50%5year OS:75%5 relapses at initial sites
18、(1 with transformation)Hammel et al,JCO 1995(cyclophosphamide or chlorambucil)LymphomaNodalExtranodalGastro-intestinalNon Gastro-intestinalGastric:B-cell MALT DLBCL H.PyloriIntestinal:T-cell Celiac diseaseTestisBrainT/NK nasal Type胃肠道弥漫大胃肠道弥漫大B B细胞淋巴瘤细胞淋巴瘤 60%of primary GI lymphomaGI DLBCL临床表现临床表现 侵
19、袭性侵袭性 B 症状症状 大肿块大肿块 坏死坏死 穿孔风险穿孔风险:10%!P Koch J Clin Oncol 2001:19:3861GI DLBCL治疗目的治疗目的One GoalTo cure the patient with the first line of treatmentGI DLBCLTREATMENTNo surgeryBiomarkers are needed to detect the Hp.dependant gastric DLBCLStandard RCHOPGI DLBCLAnn Oncol 2012Normal stomachChronic gastric
20、Residual MALTLymphomaIf clinically indicated,head&neck MRI studies and other imaging are to be realizedLARGE INTESTINE:colonoscopyMALT LymphomasResistance associated to t(11;18)Gastro-intestinal-skin Borrelia burgdorferiGastric DLBCL Dependant to Hp.-Intestin Campylobacter jejuniAuto-antigensDiffuse
21、 large B cell lymphomaRT in localized gastric MALT lymphomaNodular infiltrationMALT lymphoma胃肠道弥漫大B细胞淋巴瘤t(1,14)BCL10t(1,14)BCL10De Kerviler Saint-Louis Hospital,ParisHussel,Lancet 1993;Wootherspoon,Lancet 1993;Wndisch,JCO 2005physical examTestisBrainT/NK nasal TypeStandard RCHOPJC Delchier Henri Mon
22、dor Hospital,CrteilTumor LocationRT in localized gastric MALT lymphomapylori status must be evaluated in gastric L.MALT LymphomasChronic gastritis-skin Borrelia burgdorferiMALT淋巴瘤常见的遗传损伤24 例患者,17 例stage I，7 例stage IV+additional factors:100%ORR(75%CR)Resistance associated to t(11;18)Ann Oncol 2012 LymphomaNodalExtranodalGastro-intestinalNon Gastro-intestinalGastric:B-cellMALTDLBCLH.PyloriIntestinal:T-cell Celiac diseaseTestisBrainT/NK nasal TypeEATL
