[教育]診斷與鑒別診斷與分層

1、多發(fā)性骨髓瘤診斷、鑒別診斷與分層,,MM診斷標(biāo)準(zhǔn)(WHO Criteria Before 2008):1M+1m or 3m,主要診斷標(biāo)準(zhǔn)活檢發(fā)現(xiàn)有漿細(xì)胞瘤骨穿分類漿細(xì)胞>30%血清M蛋白IgG>35g/L或IgA>20g/L或24h尿單克隆輕鏈> 1g/L次要診斷標(biāo)準(zhǔn)骨穿分類漿細(xì)胞10%~30%M蛋白量低于主要標(biāo)準(zhǔn)溶骨性損害正常IgG<6g/L,IgA<1g/L, IgM<0

2、.5g/L,診斷MM應(yīng)注意的問題,具體數(shù)值的界定是人為的，且骨髓瘤細(xì)胞分布常常是不均勻的把握瘤細(xì)胞的生物學(xué)特性和疾病本質(zhì)生物學(xué)上，骨髓瘤細(xì)胞表現(xiàn)為單克隆性臨床上，MM具有危害性，造成器官損害--(CRAB)特征重視形態(tài)學(xué)在MM診斷中的重要性注意與相關(guān)疾病的鑒別，尤其采用3條次要標(biāo)準(zhǔn)時更應(yīng)謹(jǐn)慎,MM診斷標(biāo)準(zhǔn)(WHO Criteria After 2008): 克隆性漿細(xì)胞增生造成器官與組織損傷,高血鈣(hypercalcemi

3、a)腎功能不全(renal insufficiency)貧血(anemia)骨質(zhì)破壞(bone lesions)其他：感染、淀粉樣病變等,CRAB,漿細(xì)胞克隆性的鑒定,蛋白水平: 膜電泳、免疫電泳、免疫固定電泳、sFLC及其比值的改變細(xì)胞水平: 輕鏈同種型限制性(免疫組化或免疫熒光)基因水平：IgH、?、?基因的克隆性重排,Kyle RA and Rajkumar SV. Cecil Textbook of Medicine

4、, 22nd Edition, 2004,Immunofixation to Determine Type of Monoclonal Protein,IgG kappa M protein,在細(xì)胞水平上，運用FACS檢測外周血和骨髓中?和 ? 陽性細(xì)胞, 監(jiān)測 LCIS現(xiàn)象,kappa lambda kappa,,,,,,,,,,,,,,,,,,,,,,,Immunophenotyping,骨髓瘤

5、細(xì)胞克隆性：輕鏈同種型限制性(kappa/lambda)分化紊亂：CD 138+ 以及CD 38+/CD45-克隆性漿細(xì)胞 CD19-/CD56+ ，正常漿細(xì)胞CD19+/CD56-，大約15-20% MM患者漿細(xì)胞表達(dá)CD20 抗原,San Miguel Baillieres Clinical Haematol 1995;4:735-59,CD38+/CD45- Clonal Lambda PC’s on Flow,Dual F

6、luorescent Analysis on Myeloma Plasma,鑒別診斷,反應(yīng)性漿細(xì)胞增多（RP）骨轉(zhuǎn)移性癌、骨結(jié)核的溶骨性病變其他可以出現(xiàn)M蛋白的疾病,其他可以出現(xiàn)M蛋白的疾病WMMGUS淀粉樣變性孤立性漿細(xì)胞瘤（骨或髓外）非霍奇金淋巴瘤（B細(xì)胞性）Castleman病CLLPOEMS重鏈病漿細(xì)胞白血病,MM與骨轉(zhuǎn)移性癌、骨結(jié)核的溶骨性病變,病例1 女性，56歲，胸痛8年，貧血，Hb 56g/L

7、~78g/L, BM漿細(xì)胞4%~9%。M蛋白鑒定IgG,?單克隆， IgG 26g/L~31g/L。多處肋骨破壞，大量胸水，但從未找到癌細(xì)胞。在外院診斷MM，經(jīng)過8次化療癥狀無改善。入我科后體檢發(fā)現(xiàn)左乳皮膚呈桔皮樣改變，活檢證實為乳腺癌,,MM與骨轉(zhuǎn)移性癌、骨結(jié)核的溶骨性病變,病例2 男性，82歲，體檢時發(fā)現(xiàn)球蛋白升高。M蛋白鑒定IgM,?單克隆， IgM 12g/L~20g/L。BM漿細(xì)胞6%~8%。X線攝片示頭顱有3處直徑約1c

8、m 的缺損。血常規(guī)正常。追問病史，患者3年前曾因硬腦膜下血腫行鉆孔減壓術(shù)。,IgM-MM與巨球蛋白血癥的鑒別,溶骨改變高黏滯綜合征淋巴樣漿細(xì)胞肝脾腫大CD20表達(dá),游離輕鏈及其比值ISS：β2 M + 血清白蛋白 I 期: β2 M < 3.5 mg/L，A ≧ 3.5 g/dL II期: 介于I期和III期之間 III期:β2 M≧

9、 5.5 mg/L 細(xì)胞遺傳學(xué)及分子學(xué)特性 13號染色體或13q 缺失(del 13) t(4;14) p53缺失,骨髓瘤預(yù)后因素,t(11;14)(q13;q32) in Multiple Myeloma,~25% of MM (cf ~100% of mantle cell lymphoma)Breakpoints spread ove

10、r ~300kbAssociated with ectopic expression of cyclin D1 at 11q13Cells more lymphoplasmacytic,t(4;14)(p16;q32) in multiple myeloma,occurs in ~20% of myelomabreakpoints spread over 150kbassociated with ectopic expressi

11、on of FGFR3 on der(4) and IgH-MMSET hybrid mRNA transcripts on der(14),Chromosome 14 paint in orange4p16.3 cosmid in green,Fibroblast Growth Factor Receptor 3,Ig-like, receptor tyrosine kinaseexpressed in brain, lung,

12、 kidney, chondrocytes(activating) mutations are commonest cause of dwarfismnormal function is to limit osteogenesisactivating mutations occur on the translocated allele in MM and may cause tumor progression,,t(14;16)(

13、q32;q23) in multiple myeloma,occurs in 10-15% of myelomabreakpoints spread over ~500kbassociated with over-expression of c-maf at 16q23,Chromosome 14 paint in orangec-maf probe in green,126例遺傳學(xué)異常患者自體干細(xì)胞移植(ASCT)總體生存率,

14、Analysis schema,,,Median = 6% PC,,Bone marrow at diagnosis(983 patients analyzed)Ficoll + purification CD138Del(13) = 936 ptst(11;14) = 746 ptst(4;14) = 716 ptsHyperdiploidy = 657 ptsDel(17p) = 532 pts1q

15、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(

16、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

17、(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 pt

18、s,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)

19、> 0no t(4;14), no del(17p),EFS,OS,Multiparametric analysis,,,,Independent prognostic parameters,Prognostic parameters: del(13), t(4;14), del(17p), 1q gains, b2m>3/4Hb<10, albumine<30 or 35, platelets<130

20、,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 hypodiplo

21、idyPCLI >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 progn

22、osis*** 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),

23、FISH t(4;14)*Cytogenetic Deletion 13 or hypodiploidyPCLI >3%,3 years,5 years,7-10 years,,mSMART 2.0: Treatment of Active MM,Novel approachesNew drugs“TT3 like” approach for p53 deletion ?,Regimen which provid

24、es a high ORR and which minimizes early toxicity HDM could be delayed in patients achieving CR Lenalidomide maintenance,Bortezomib basedcombinationHDM +/- consolidationLenalidomide maintenanceTargeted

25、therapy,High-Risk,Intermediate-Risk,Standard-Risk,GEP分層對TT3預(yù)后的影響,,TT4方案：更強(qiáng)調(diào)分層治療和強(qiáng)化治療,低危組,,,,,高危組,,,,,TT3組,TT3-LITE組,,,同前,誘導(dǎo):VDT-PACE×1,鞏固:VDT-PACE×1,維持：VRD,,,,1療程劑量遞增VDT-PACE,,,,,,采集PBSC,(加大強(qiáng)度和密度的VDT-PACE+PBS

26、C)×4,,,M-VRD×4(mel 10mg d1-4+VRD) ±PBSC,VRD/月×3年,[MEL 100 mg/m2 d1,4,7 +VRD+ASCT d8],VRD,,[MEL 100 mg/m2 d1,4,7 +VRD+ASCT d8],,,,分層主要根據(jù)GEP,Best Pract Res Clin Haematol. 2007 Dec;20(4):761-81,≥nCR