侯健MM-诊断与鉴别诊断与分层ppt课件.ppt

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,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,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,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,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：IgH、基因的克隆性重排,Kyle RA and Rajkumar SV. Cecil Textbook of Medicine, 22nd Edition, 2004,Immunofixation to Determine Type of Monoclonal Protein,IgG kappa M protein,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,Immunophenotyping,骨髓瘤细胞 克隆性：轻链同种型限制性(kappa/lambda) 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,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 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,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,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/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。,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,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,t(11;14)(q13;q32) in 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,t(4;14)(p16;q32) in multiple myeloma,occurs in 20% of myeloma breakpoints spread over 150kb associated with ectopic expression of FGFR3 on der(4) and IgH-MMSET hybrid mRNA transcripts on der(14),Chromosome 14 paint in orange 4p16.3 cosmid in green,Fibroblast Growth Factor Receptor 3,Ig-like, receptor tyrosine kinase expressed in brain, lung, kidney, chondrocytes (activating) mutations are commonest cause of dwarfism normal function is to limit osteogenesis activating mutations occur on the translocated allele in MM and may cause tumor progression,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,Chromosome 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,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 pts,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%,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): 449 pts,p=9.10-7,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,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,Del(17p),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,Cytogenetic correlations,t(4;14) and del(13),del(17p) and del(13),del(17p) and t(4;14),Del(13) et t(4;14)/del(17p),p=0.41,p=0.12,Del(13) 0 no t(4;14), no del(17p),EFS,OS,Multiparametric analysis,Independent prognostic parameters,Prognostic parameters: del(13), t(4;14), del(17p), 1q gains, b2m3/4 Hb10, albumine30 or 35, platelets130,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%,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 associated with plasma cell leukemia,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,mSMART 2.0: Treatment 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,GEP分层对TT3预后的影响,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) 4,