NKT细胞淋巴瘤课件

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,NK,细胞增殖性疾病,同济医院血液内科,周剑峰,2015,年,06,月,07,日,T,和,NK,细胞肿瘤的分类：,WHO 2008,WHO 2008: the mature T-cell and NK-cell neoplasms,T-cell prolymphocytic leukemia,T-cell large granular lymphocytic leukemia,Chronic lymphoproliferative disorder of NK-cells*,Aggressive NK cell leukemia,Systemic EBV+ T-cell lymphoproliferative disease of childhood,(associated with CAEBV),Hydroa vacciniforme-like lymphoma,Adult T-cell leukemia/lymphoma,Extranodal NK/T cell lymphoma, nasal type,Enteropathy-associated T-cell lymphoma,Hepatosplenic T-cell lymphoma,Subcutaneous panniculitis-like T-cell lymphoma,Mycosis fungoides,Szary syndrome,Primary cutaneous CD30+ T-cell lymphoproliferative disorder,Lymphomatoid papulosis,Primary cutaneous anaplastic large-cell lymphoma,Primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell,lymphoma*,Primary cutaneous gamma-delta T-cell lymphoma,Primary cutaneous small/medium CD4+ T-cell lymphoma*,Peripheral T-cell lymphoma, not otherwise specified,Angioimmunoblastic T-cell lymphoma,Anaplastic large cell lymphoma (ALCL), ALK+,Anaplastic large cell lymphoma (ALCL), ALK?*,2001 WHO,2008 WHO,Comments,Angioimmunoblastic Lymphoma,Angioimmunoblastic Lymphoma,Definition of origin cell,Anaplastic Large Cell Lymphoma,2 variants based on ALK (+/-) expression,Prognostic importance,Unspecified Peripheral T-cell Lymphoma,Peripheral T-cell Lymphomas not Otherwise,Specified,3 variants: lymphoepitelioid lymphoma, T zone,lymphoma (2001 WHO) and follicular lymphoma,(2008 WHO),T/NK-cell lymphoma, nasal type,T/NK-cell lymphoma, nasal type,No changes,Entheropathy-associated T-cell lymphoma,Entheropathy-associated T-cell lymphomas,Two variants: classical and monomorphic types,with genetic changes common to both,Hepatosplenic T-cell lymphoma,Hepatosplenic T-cell lymphoma,No changes,Subcutaneous panniculitis-like T-cell,lymphoma,Subcutaneous panniculitis-like T-cell lymphoma,Only ab and associated with autoimmune,disorder,Mycosis fungoides,Mycosis fungoides,New staging and new information about,pathogenesis,Szary syndrome,Szary syndrome,New markers,Primary cutaneous anaplastic large cell,lymphoma,Primary cutaneous anaplastic large cell lymphoma,Recognition of CD8+ cases,Lymphomatoid papulosis,Lymphomatoid papulosis,Three histological types,Primary cutaneous gamma-delta T-cell lymphoma,Three histopathologic patterns: epidermotropic,dermic, and subcutaneous subtypes,Primary cutaneous CD8+ aggressive,epidermotropic cytotoxic T-cell lymphoma,Provisional entity,Primary cutaneous CD4+ small/medium T-cell,lymphoma,Provisional entity,Blastic NK-cell lymphoma,Plasmocytoid dendritic cell neoplasm,Now it is one of the myeloid neoplasms,T-cell prolymphocytic leukemia,T-cell prolymphocytic leukemia,No changes,T-cell large granular lymphocytic,leukemia,T-cell large granular lymphocytic leukemia,New etiological features and new markers,Chronic lymphoproliferative disorder of,NK-cells,Provisional entity,Aggressive NK-cell leukemia,Aggressive NK-cell leukemia,No changes,Adult T-cell leukemia/lymphoma,Adult T-cell leukemia/lymphoma,Definition of the regulatory T-cell normal,counterpart,T,和,NK,细胞肿瘤分类的主要变化,EBV,相关淋巴增殖性疾病,J Korean Med Sci. 2008 Apr;23(2):185-92.,EBV,相关,T/NK,细胞增殖性疾病,J Dermatol. 2014;41(1):29-39.,潜伏性感染，不是裂解式感染，抗病毒治疗无效,NK/T,细胞淋巴瘤,NK/T,细胞淋巴瘤亚型分布,NK/T,细胞淋巴瘤占到所有,PTCL,的,10.4%,J Clin Oncol, 2008, 26(25):4124-30,NK/T,细胞淋巴瘤特征,?,分为鼻型,(,68%,),和非鼻型,(,26%,),其他为侵袭型（,6%,）,?,病理表现：形态多样，表现为血管中心性、大量坏死和,血管浸润,?,表型：大部分为,NK,细胞（,EBV+,，,CD56+,）,鼻型与非鼻型,NK/T,细胞淋巴瘤,鼻型,非鼻型,侵犯部位,上呼吸,皮肤、睾丸、胃肠道,疾病晚期,27%,68%,肿块,5cm,12%,68%,超过,2,个鼻外病灶,16%,55%,LDH,升高,45%,60%,B,症状,39%,54%,5,年,OS,率,42%,9%,中位,OS,19,月,4,月,鼻型与非鼻型,NK/T,细胞淋巴瘤,Nasal type:41%,Non-nasal:22%,Nasal type:34%,Non-nasal:13%,Ann Oncol 2008;19:1477-1484,放疗在,NK/T,细胞淋巴瘤中的地位,仅早期患者可作为根治手段，其余多数与化疗联用,什么样的,NK/T,细胞淋巴瘤可以单纯放疗,？,Nasal,versus,extra-nasal,the,stage,of the disease,Stage I,disease are further stratified based on risk factors,Age 60 years,B symptoms,ECOG performance status 2,Regional lymph node involvement Local tumor invasion,Elevated LDH,High Ki-67 staining,EBV DNA 6.1 x 10,7,copies/mL,更新了治疗方案后，化疗是,必不可少的治疗手段,?,局限期鼻型,NK/T,细胞淋巴瘤单纯放疗,RR,和,CR,分别达,78-94%,和,66-94%,，但,5y-OS,和中位,OS,仅分别为,35%-83%,和,50%,?,患者出现皮肤、骨髓、睾丸、内脏和淋巴结侵犯较常见,?,化疗仍然是必不可少的治疗手段,NK/T,细胞肿瘤具有不同寻常的表型特征,含门冬酰胺酶的方案,SMILE,方案,?,Smile,方案,S,teroid (DXM) 40 mg, iv, d2-4,M,TX,2,g/m2, iv, d1,I,FO 1.5g/m2, iv, d2-4,L,-ASP 6000U/m2, iv, d8,10,12,14, 16,18,20,E,topside 100mg/m2, iv ,d2-4,?,G-CSF,从第,6,天开始解救，,wbc 5000/ml,Yamaguchi M, et al. JCO, 2011; 29(33):4410-6,SMILE,方案疗效及毒性,?,CR,率,45%, CR+PR 79%,?,1y-OS 55%,?,毒性反应：,92%,患者出现,IV,度骨髓抑制，,61%,出现感染,?,8%,出现早期死亡,Yamaguchi M, et al. JCO, 2011; 29(33):4410-6,AspaMetDex,方案,?,S,teroid,（,DXM,）, 40mg, d1-4,po,?,M,TX 3.0g/m,2, d1, iv drip,?,I,FO 1.5g/m2, iv, d2-4,?,L,-Asp 6000U/m,2, d2,4,6,8, im,?,Etopside 100mg/m2, iv ,d2-4,Jaccard A, et al. Blood, 2011,117:1834-1839.,?,Smile,方案,S,teroid (DXM) 40 mg, iv, d2-,4,M,TX 2 g/m2, iv, d1,I,FO 1.5g/m2, iv, d2-4,L,-ASP 6000U/m2, iv,d8,10,12,14, 16,18,20,E,topside 100mg/m2, iv ,d2-4,近期疗效和毒性,?,近期疗效,18,例可评价，,14,例获得缓解（,78%,），,11,例完全缓解（,61%,）,3,例治疗中死亡,?,14,例有效患者，,6,例在治疗结束后,9,个月内复发,AspaMetDex,方案,远期生存,中位,OS12.2,个月,无效患者,4.2,个月,有效后进展患者,3.6,个月,PFS 12.2,个月,晚期结外,NK/T,细胞淋巴瘤治疗,GOLD,方案,Efficacy of gemcitabine combined with oxaliplatin,L-asparaginase and dexamethasone in patients with,newly-diagnosed extranodal NK/T-cell lymphoma,G,：,gemcitabine 1g/m2,，,d1,，,D8,O,：,Oxaliplatin 100mg/m2,，,d1,L,：,L-Asparaginase 10,000 U/m2,，,d1-5,D,：,dexamethasone 40mg,，,d1-4,14-day cycle,，,Ann Arbor I/II,期化疗后给予,IFRT,2008-2012,新诊断的,ENKTL,Guo HQ, Liu L, Wang XF, Lin TY, et al. Mol Clin Oncol. 2014 Nov;2(6):1172-1176,GOLD,方案,Guo HQ, Liu L, Wang XF, Lin TY,et al. Mol Clin Oncol. 2014 Nov;2(6):1172-1176,GOLD,方案,3Ys PFS 57%,3Ys OS 74%,1 Ys PFS 87% vs 66%,P 0.001,1 Ys OS 98% vs 75%,P 0.001,Guo HQ, Liu L, Wang XF, Lin TY,et al. Mol Clin Oncol. 2014 Nov;2(6):1172-1176,GOLD,方案,?,GOLD,的方案治疗,ENKL,获得很高的,ORR,（,91%,），,CR,率,62%,，,PR,率,29%,?,3,年,OS 74%,，,PFS 57%,?,Ann Arbor,分期是预后的重要影响因素，,III/IV,期患者的,OS/PFS,明显低于,I/II,期患者,Guo HQ, Liu L, Wang XF, Lin TY,et al. Mol Clin Oncol. 2014 Nov;2(6):1172-1176,同步,/,序贯化放疗（重点解决,I/II,期）,Concurrent,Sequential,Blood. 2013;121(25):4997-5005.,NCCN,指南,Blood. 2013;121(25):4997-5005.,NK/T,细胞淋巴瘤：现状点评,?,早期疾病解决比较好，强调放疗结合化疗,(,同步或序贯,);,?,化疗方案明显改进，许多过去的放化疗结论需要重新考虑,;,?,晚期,NK/T,疾病尚无标准方案，需要临床试验及持续改进,;,?,NK/T,细胞淋巴瘤晚期疾病将会成为关注的重点,血浆,EBV-DNA,定量,?,评估,EBV,相关肿瘤最精确的指标，与肿瘤负荷、分期、进展正相关,Bone Marrow Transplant. 2003;31(2):105-11; Blood. 2004;104(1):243-9,SMILE,方案治疗后血浆,EBV-DNA,定量与预后的关系,?,预测,DFS,和,OS,最有价值的独立预后参数,Leukemia. 2014;28(4):865-70,Persistently undetectable,Persistently detectablepresentation,ANKL,Gene Name,Chrom:Position,Mution Type,Prediction from SIFT,Prediction from Polyphen-2,Substitution,Gene description,The candidate somatic variants in FHL2 patient,FASTKD3,chr5: 7868314,SpliceSite,-,-,-,FAST kinase domains 3,HOXA10,chr7:27213757,cds-Indel,-,-,-,-,SVEP1,chr9:113137745,SpliceSite,-,-,-,von Willebrand factor type A, EGF and,pentraxin domain containing 1,The candidate variants related with the family under an autosomal recessive model,PCDH18,chr4:138442574,missence,TOLERATED,probably damaging,S1006L,protocadherin 18,CDK11B,chr1:1654067,missence,-,-,-,-,MAGEC1,chrX:140993945,missence,TOLERATED,benign,F252S,melanoma antigen family C, 1,NOS1,chr12: 117691485,missence,TOLERATED,benign,L869P,nitric oxide synthase 1 (neuronal),PPP1R14BP3,chr4:140036422,missence,-,-,-,protein phosphatase 1, regulatory,(inhibitor) subunit 14B pseudogene 3,The candidate variants related with the family under an autosomal dominant model,MLL3,chr7: 151970859,missense,DAMAGING,probably damaging,G315S,myeloid/lymphoid,or,mixed-lineage,leukemia 3,PCDH18,chr4: 138442574,missence,TOLERATED,probably damaging,S1006L,protocadherin 18,ANKRD36,chr2: 97830177,missence,TOLERATED,-,G501V,-,EBV,持续感染与基因组不稳定,ANKL,的体细胞高频突变,The,most,common,abnormalities,unbalanced,chromosomal,abnormalities.,No,specific chromosomal abnormalities associated with ANKL had been identified,ANKL,的诊断要点,ANKL,是一种罕见但具有高度侵袭性的,NK,细胞肿瘤,?,急骤起病，病情凶险，生存期仅,2,周,2,个月,?,高度侵袭性经过：不明原因高热、血象三少、,肝脾淋巴结肿大、凝血功能异常、噬血细胞综,合征、多器官功能衰竭,?,异常,NK,细胞免疫表型,?,EB,病毒,DNA,阳性,?,IgH/TCR,受体基因重排阴性,?,外周血,/,骨髓找到形态幼稚的大颗粒淋巴细胞,ANKL,的,PET-CT,：,25%,（,阴性,）,37.5%,（,特异性,）, 37.5%,（,非特异性,）,ANKL,流式诊断要点,CD45,异常表达,NK,细胞表面抗原异常表达,NK,细胞克隆性异常,Ki,指数多高于,40%,Transl Res,. 2014;163(6):565-77,治疗策略,1,?,控制,HLH,?,VP16 + DEX,2,?,减瘤,?,门冬为基础方案,AspaMetDex,3,?,纠正遗传缺陷,?,SCT,诊疗策略,?,识别免疫表型异常的,NK,细胞是诊断的关键,?,及时诊断，纠正初诊时合并的噬血细胞综合征非常重要,?,早期使用含,L-ASP,的化疗方案、序贯,allo-SCT,是目前最,可能有效的治疗策略。未来的治疗策略更新中,?,血浆,EBV-DNA,是监测肿瘤负荷、评价预后的独立参数,慢性活动性,EBV,感染（,CAEBV,）,CAEBV,Postepy Hig Med Dosw, 2013; 67: 481-490,CAEBV,的发病进程,Pathol Int. 2008;58(4):209-17.,CAEBV,ENK/TL & ANKL,Polymorphic,LPD,(Category,A1),Polymorphic,LPD with clonal,proliferation,(Category A2),Monomorphic,LPD (Category,A3),Monomorphic,LPD with,clonal,proliferation,(Category B),Polymorphic,LPD,Polymorphic,LPD with clonal,proliferation,Monomorphic,LPD,ENK/TL & ANKL,Marrow Failure,RA/RAS/RCMD,RAEB,AML,CAEBV,的发病进程,诊断标准,(CAEBV Study Group),Pathol Int. 2008;58(4):209-17.,治疗策略,Bone Marrow Transplant. 2011;46(1):77-83.,异基因造血干细胞移植的疗效,EFS and OS for allo-HSCT,MAC=myeloablative conditioning; RIC=reduced-intensity conditioning.,Bone Marrow Transplant. 2011;46(1):77-83.,发病机制,Highly activated yet ineffective,multisystem inflammatory response/,Immunopathology,噬血细胞性淋巴组织增生症（,HLH,）发病机制,IL-1, IL-6, TNF-,etc.,Tissue Infiltration,（组织浸润）,Cytokine Storm,MSOF,多系统,和器官,衰竭,IFN-,诊断,(HLH-2004),鉴别诊断,?,原发性和继发性的鉴别：,分子诊断,?,继发性,HLH,的,病因诊断,：感染（,EB,病毒感染最常见）、肿瘤、结缔组织病、,移植、药物等,治疗,(HLH-2004),NK,细胞肿瘤：关键要点,?,多数起源于,EBV,慢性感染后转化,?,疾病累及巨大的人群,?,诊断治疗存在盲区,?,具特征性改变，与,B -NHL,是完全不同的疾病,?,基于疾病机制的新认识，诊断治疗模式正在转化,