诊断与鉴别诊断与分层

多发性骨髓瘤诊断、鉴别诊断与分层MM诊断标准(WHOCriteriaBefore2008):1M+1mor3m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(WHOCriteriaAfter2008):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(renalinsufficiency)贫血(anemia)骨质破坏(bonelesions)其他：感染、淀粉样病变等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KyleRAandRajkumarSV.CecilTextbookofMedicine,22ndEdition,2004ImmunofixationtoDetermineTypeofMonoclonalProteinIgGkappaMprotein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kappalambdakappaImmunophenotyping骨髓瘤细胞•克隆性：轻链同种型限制性(kappa/lambda)•分化紊乱：CD138+以及CD38+/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SanMiguelBaillieresClinicalHaematol1995;4:735-59CD38+/CD45-ClonalLambdaPC’sonFlowDualFluorescentAnalysisonMyelomaPlasma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，Hb56g/L~78g/L,BM浆细胞4%~9%。M蛋白鉴定IgG,单克隆，IgG26g/L~31g/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，IgM12g/L~20g/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：β2M+血清白蛋白I期:β2M3.5mg/L，A≧3.5g/dLII期:介于I期和III期之间III期:β2M≧5.5mg/L细胞遗传学及分子学特性13号染色体或13q缺失(del13)t(4;14)p53缺失骨髓瘤预后因素t(11;14)(q13;q32)inMultipleMyeloma~25%ofMM(cf~100%ofmantlecelllymphoma)Breakpointsspreadover~300kbAssociatedwithectopicexpressionofcyclinD1at11q13Cellsmorelymphoplasmacytict(4;14)(p16;q32)inmultiplemyelomaoccursin~20%ofmyelomabreakpointsspreadover150kbassociatedwithectopicexpressionofFGFR3onder(4)andIgH-MMSEThybridmRNAtranscriptsonder(14)Chromosome14paintinorange4p16.3cosmidingreenFibroblastGrowthFactorReceptor3Ig-like,receptortyrosinekinaseexpressedinbrain,lung,kidney,chondrocytes(activating)mutationsarecommonestcauseofdwarfismnormalfunctionistolimitosteogenesisactivatingmutationsoccuronthetranslocatedalleleinMMandmaycausetumorprogressiont(14;16)(q32;q23)inmultiplemyelomaoccursin10-15%ofmyelomabreakpointsspreadover~500kbassociatedwithover-expressionofc-mafat16q23Chromosome14paintinorangec-mafprobeingreen126例遗传学异常患者自体干细胞移植(ASCT)总体生存率遗传学异常例数(%)中位OS(m)相对危险度(95%CI)p值p53del10(8)14.74.50.0025t(4:14)15(12)18.34.80.0005t(11:14)16(13)37.21.50.523113qdel39(31)34.42.30.0498无43(34)未获得1.0AnalysisschemaMedian=6%PCBonemarrowatdiagnosis(983patientsanalyzed)Ficoll+purificationCD138Del(13)=936ptst(11;14)=746ptst(4;14)=716ptsHyperdiploidy=657ptsDel(17p)=532pts1qgains=365ptsIncidencesDel(13)(965pts)=48%t(11;14)(760pts)=21%t(4;14)(727pts)=14%Ploidy(658pts)=40%c-myc(576pts)=13%Del(17p)(526pts)=11%1qgains(365pts)=35%Del(13)Del(13)=48%936ptsEFSOSNodel(13):487ptsDel(13):449ptsp=5.10-8Nodel(13):487ptsDel(13):449ptsp=9.10-7t(4;14)t(4;14)=14%716ptsEFSOSNot(4;14):616ptst(4;14)+:100ptsp=10-12Not(4;14):616ptst(4;14)+:100ptsp=2.10-8t(11;14)t(11;14)=21%746ptsEFSOSNot(11;14):592ptst(11;14)+:154ptsp=.20Not(11;14):592ptst(11;14)+:154ptsp=.28Del(17p)Del(17p)=11%532ptsEFSOSNodel(17p):474ptsDel(17p)+:58ptsp=1.10-7Nodel(17p):474ptsDel(17p)+:58ptsp=3.10-7Nodel(17p):494ptsDel(17p)60%:38ptsp=5.10-11Nodel(17p):494ptsDel(17p)60%:38ptsp=4.10-12Cytogeneticcorrelationst(4;14)anddel(13)84%del(13)=0or0p=2.10-13(C²)del(13)75%or75%p=2.10-11(C²)Tightassociationdel(17p)anddel(13)77%del(13)=0or0p=6.10-5(C²)del(13)75%or75%p=4.10-4(C²)Tightassociationdel(17p)andt(4;14)14%p=0.51IndependentparametersDel(13)ett(4;14)/del(17p)p=0.41p=0.12Del(13)0not(4;14),nodel(17p)EFSOSMultiparametricanalysisIndependentprognosticparametersEFS:del(17p)t(4;14)b2m3ou4Hb10g/dlOS:del(17p)t(4;14)b2m3ou4Prognosticparameters:del(13),t(4;14),del(17p),1qgains,b2m3/4Hb10,albumine30or35,platelets130mSMART2.0:ClassificationofActiveMMFISHDel17pt(14;16)t(14;20)GEPHighrisksignatureAllothersincluding:Hyperdiploidt(11;14)***t(6;14)FISHt(4;14)*CytogeneticDeletion13orhypodiploidyPCLI3%High-Risk20%Intermediate-Risk20%Standard-Risk60%***Prognosisisworsewhenassociatedwithhighbeta2Mandanemia**LDHULNandbeta2M5.5instandardriskmayindicateworseprognosis***t(11;14)isassociatedwithplasmacellleukemiamSMART2.0:ClassificationofActiveMMFISHDel17pt(14;16)t(14;20)GEPHighrisksignatureAllothersincluding:Hyperdiploidt(11;14)t(6;14)FISHt(4;14)*CytogeneticDeletion13orhypodiploidyPCLI3%3years5years7-10yearsmSMART2.0:TreatmentofActiveMMNovelapproachesNewdrugs“TT3like”approachforp53deletion?RegimenwhichprovidesahighORRandwhichminimizesearlytoxicityHDMcouldbedelayedinpatientsachievingCRLenalidomidemaintenanceBortezomibbasedcombinationHDM+/-consolidationLenalidomidemaintenanceTargetedtherapyHigh-RiskIntermediate-RiskStandard-RiskGEP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-PACE×1巩固:VDT-PACE×1维持：VRD1疗程剂量递增VDT-PACE采集PBSC(加大强度和密度的VDT-PAC