1、NK 细胞增殖性疾病细胞增殖性疾病 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 lymphoprolif
2、erative 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 syn
3、drome 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 l
4、ymphoma*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 Lar
5、ge 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-c
6、ell 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
7、-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 cuta
8、neous 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 epidermot
9、ropic 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-cel
10、l 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
11、 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 细胞淋巴瘤细胞淋巴瘤 NK/T 细胞淋巴瘤亚型分布细胞淋巴瘤亚型分布 NK/T 细胞淋巴瘤占到所有 PTCL 的10
12、.4%J Clin Oncol,2008,26(25):4124-30 NK/T 细胞淋巴瘤特征细胞淋巴瘤特征?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+）鼻型与非鼻型鼻型与非鼻型 NK/T 细胞淋巴瘤细胞淋巴瘤 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
13、 type:41%Non-nasal:22%Nasal type:34%Non-nasal:13%Ann Oncol 2008;19:1477-1484 放疗在放疗在 NK/T 细胞淋巴瘤中的地位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
14、 symptoms,ECOG performance status 2 Regional lymph node involvement Local tumor invasion Elevated LDH High Ki-67 staining EBV DNA 6.1 x 107 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
15、表型特征细胞肿瘤具有不同寻常的表型特征 含门冬酰胺酶的方案含门冬酰胺酶的方案 SMILE 方案方案?Smile方案 Steroid(DXM)40 mg,iv,d2-4 MTX 2 g/m2,iv,d1 IFO 1.5g/m2,iv,d2-4 L-ASP 6000U/m2,iv,d8,10,12,14,16,18,20 Etopside 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 方案疗效及毒性方案疗效及毒性?CR率45%,CR+PR 79%?1y-OS
16、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?Steroid（DXM）,40mg,d1-4,po?MTX 3.0g/m2,d1,iv drip?IFO 1.5g/m2,iv,d2-4?L-Asp 6000U/m2,d2,4,6,8,im?Etopside 100mg/m2,iv,d2-4 Jaccard A,et al.Blood,2011,117:1834-1839.?Smile方案 Steroid(DXM)40 mg,iv,d2-4 MTX 2
17、g/m2,iv,d1 IFO 1.5g/m2,iv,d2-4 L-ASP 6000U/m2,iv,d8,10,12,14,16,18,20 Etopside 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
18、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
19、 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
20、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
21、点评细胞淋巴瘤：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方案治疗后血浆方案治疗后血浆EBV-DNA 定量与预后的关系定量与预后的关系?预测DFS和OS最有价值的独立预后参数 Leuke
22、mia.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 domai
23、ns 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
24、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
25、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 missenc
26、e TOLERATED-G501V-EBV 持续感染与基因组不稳定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
27、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，
28、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(C
29、ategory 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 Trans
30、plant.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）（组织浸润）Cytokine Storm MSOF多系统和器官衰竭 IFN-诊断诊断(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、药物等移植、药物等 治疗治疗(HLH-2004)NK 细胞肿瘤：关键要点细胞肿瘤：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
