侯健MM-诊断与鉴别诊断与分层ppt课件

1、.,1,多发性骨髓瘤诊断、鉴别诊断与分层,第二军医大学长征医院 侯健,.,2,.,3,MM诊断标准(WHO Criteria Before 2008):1M+1m or 3m,主要诊断标准 活检发现有浆细胞瘤 骨穿分类浆细胞30% 血清M蛋白IgG35g/L或IgA20g/L或24h尿单克隆轻链 1g/L 次要诊断标准 骨穿分类浆细胞10%30% M蛋白量低于主要标准 溶骨性损害 正常IgG6g/L,IgA1g/L, IgM0.5g/L,.,4,诊断MM应注意的问题,具体数值的界定是人为的，且骨髓瘤细胞分布常常是不均匀的 把握瘤细胞的生物学特性和疾病本质 生物学上，骨髓瘤细胞表现为单克隆性 临

2、床上，MM具有危害性，造成器官损害-(CRAB)特征 重视形态学在MM诊断中的重要性 注意与相关疾病的鉴别，尤其采用3条次要标准时更应谨慎,.,5,MM诊断标准(WHO Criteria After 2008): 克隆性浆细胞增生造成器官与组织损伤,高血钙(hypercalcemia) 肾功能不全(renal insufficiency) 贫血(anemia) 骨质破坏(bone lesions) 其他：感染、淀粉样病变等,CRAB,.,6,浆细胞克隆性的鉴定,蛋白水平: 膜电泳、免疫电泳、免疫固定电泳、sFLC及其比值的改变 细胞水平: 轻链同种型限制性(免疫组化或免疫荧光) 基因水平：Ig

3、H、基因的克隆性重排,.,7,.,8,.,9,.,10,Kyle RA and Rajkumar SV. Cecil Textbook of Medicine, 22nd Edition, 2004,Immunofixation to Determine Type of Monoclonal Protein,IgG kappa M protein,.,11,.,12,在细胞水平上，运用FACS检测外周血和骨髓中和 阳性细胞, 监测 LCIS现象,kappa lambda kappa,.,13,Immunophenotyping,骨髓瘤细胞 克隆性：轻链同种型限制性(kappa/lambda)

4、分化紊乱：CD 138+ 以及CD 38+/CD45- 克隆性浆细胞 CD19-/CD56+ ，正常浆细胞CD19+/CD56-，大约15-20% MM患者浆细胞表达CD20 抗原,San Miguel Baillieres Clinical Haematol 1995;4:735-59,.,14,CD38+/CD45- Clonal Lambda PCs on Flow,Dual Fluorescent Analysis on Myeloma Plasma,鉴别诊断,反应性浆细胞增多（RP） 骨转移性癌、骨结核的溶骨性病变 其他可以出现M蛋白的疾病,其他可以出现M蛋白的疾病 WM MGUS

5、淀粉样变性 孤立性浆细胞瘤（骨或髓外） 非霍奇金淋巴瘤（B细胞性） Castleman病 CLL POEMS 重链病 浆细胞白血病,.,16,MM与骨转移性癌、骨结核的溶骨性病变,病例1 女性，56岁，胸痛8年，贫血，Hb 56g/L78g/L, BM浆细胞4%9%。M蛋白鉴定IgG,单克隆， IgG 26g/L31g/L。多处肋骨破坏，大量胸水，但从未找到癌细胞。在外院诊断MM，经过8次化疗症状无改善。 入我科后体检发现左乳皮肤呈桔皮样改变，活检证实为乳腺癌,.,17,MM与骨转移性癌、骨结核的溶骨性病变,病例2 男性，82岁，体检时发现球蛋白升高。M蛋白鉴定IgM,单克隆， IgM 12g

6、/L20g/L。BM浆细胞6%8%。X线摄片示头颅有3处直径约1cm 的缺损。血常规正常。 追问病史，患者3年前曾因硬脑膜下血肿行钻孔减压术。,.,18,IgM-MM与巨球蛋白血症的鉴别,溶骨改变 高黏滞综合征 淋巴样浆细胞 肝脾肿大 CD20表达,.,19,游离轻链及其比值 ISS：2 M + 血清白蛋白 I 期: 2 M 3.5 mg/L，A 3.5 g/dL II期: 介于I期和III期之间 III期:2 M 5.5 mg/L 细胞遗传学及分子学特性 13号染色体或13q 缺失(del 13) t(4;14) p53缺失,骨髓瘤预后因素,.,21,t(11;14)(q13;q32) in

7、 Multiple Myeloma,25% of MM (cf 100% of mantle cell lymphoma) Breakpoints spread over 300kb Associated with ectopic expression of cyclin D1 at 11q13 Cells more lymphoplasmacytic,.,22,t(4;14)(p16;q32) in multiple myeloma,occurs in 20% of myeloma breakpoints spread over 150kb associated with ectopic e

8、xpression of FGFR3 on der(4) and IgH-MMSET hybrid mRNA transcripts on der(14),Chromosome 14 paint in orange 4p16.3 cosmid in green,.,23,Fibroblast Growth Factor Receptor 3,Ig-like, receptor tyrosine kinase expressed in brain, lung, kidney, chondrocytes (activating) mutations are commonest cause of d

9、warfism normal function is to limit osteogenesis activating mutations occur on the translocated allele in MM and may cause tumor progression,.,24,t(14;16)(q32;q23) in multiple myeloma,occurs in 10-15% of myeloma breakpoints spread over 500kb associated with over-expression of c-maf at 16q23,Chromoso

10、me 14 paint in orange c-maf probe in green,126例遗传学异常患者自体干细胞移植(ASCT)总体生存率,.,26,Analysis schema,Median = 6% PC,Bone marrow at diagnosis (983 patients analyzed) Ficoll + purification CD138 Del(13) = 936 pts t(11;14) = 746 pts t(4;14) = 716 pts Hyperdiploidy = 657 pts Del(17p) = 532 pts 1q gains = 365 p

11、ts,.,27,Incidences,Del(13) (965 pts) = 48% t(11;14) (760 pts) = 21% t(4;14) (727 pts) = 14% Ploidy (658 pts) = 40% c-myc (576 pts) = 13% Del(17p) (526 pts) = 11% 1q gains (365 pts) = 35%,.,28,Del(13),Del(13)=48% 936 pts,EFS,OS,No del(13): 487 pts,Del(13): 449 pts,p=5.10-8,No del(13): 487 pts,Del(13)

12、: 449 pts,p=9.10-7,.,29,t(4;14),t(4;14)=14% 716 pts,EFS,OS,No t(4;14): 616 pts,t(4;14)+: 100 pts,p=10-12,No t(4;14): 616 pts,t(4;14)+: 100 pts,p=2.10-8,.,30,t(11;14),t(11;14)=21% 746 pts,EFS,OS,No t(11;14): 592 pts,t(11;14)+: 154 pts,p=.20,No t(11;14): 592 pts,t(11;14)+: 154 pts,p=.28,.,31,Del(17p),

13、Del(17p)=11% 532 pts,EFS,OS,No del(17p): 474 pts,Del(17p) +: 58 pts,p=1.10-7,No del(17p): 474 pts,Del(17p) +: 58 pts,p=3.10-7,.,32,Cytogenetic correlations,t(4;14) and del(13),del(17p) and del(13),del(17p) and t(4;14),.,33,Del(13) et t(4;14)/del(17p),p=0.41,p=0.12,Del(13) 0 no t(4;14), no del(17p),E

14、FS,OS,.,34,Multiparametric analysis,Independent prognostic parameters,Prognostic parameters: del(13), t(4;14), del(17p), 1q gains, b2m3/4 Hb10, albumine30 or 35, platelets130,.,35,mSMART 2.0: Classification of Active MM,FISH Del 17p t(14;16) t(14;20) GEP High risk signature,All others including: Hyp

15、erdiploid t(11;14)* t(6;14),FISH t(4;14)* Cytogenetic Deletion 13 or hypodiploidy PCLI 3%,High-Risk 20%,Intermediate-Risk 20%,Standard-Risk 60% *,* Prognosis is worse when associated with high beta 2 M and anemia * LDH ULN and beta 2 M 5.5 in standard risk may indicate worse prognosis * t(11;14) is

16、associated with plasma cell leukemia,.,36,mSMART 2.0: Classification of Active MM,FISH Del 17p t(14;16) t(14;20) GEP High risk signature,All others including: Hyperdiploid t(11;14) t(6;14),FISH t(4;14)* Cytogenetic Deletion 13 or hypodiploidy PCLI 3%,3 years,5 years,7-10 years,.,37,mSMART 2.0: Treat

17、ment of Active MM,Novel approaches New drugs “TT3 like” approach for p53 deletion ?,Regimen which provides a high ORR and which minimizes early toxicity HDM could be delayed in patients achieving CR Lenalidomide maintenance,Bortezomib based combination HDM +/- consolidation Lenalidomide maintenance Targeted therapy,High-Risk,Intermediate-Risk,Standard-Risk,.,38,GEP分层对TT3预后的影响,.,39,TT4方案：更强调分层治疗和强化治疗,低危组,高危组,TT3组,TT3-LITE组,同前,诱导:VDT-PACE1,巩固:VDT-PACE1,维持：VRD,1疗程剂量递增VDT-PACE,采集 PBSC,(加大强度和密度的 VDT-PACE+PBSC