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Plasma cell myelomaand other plasma cell neoplasmsExciting new facts about an old
diseaseA report from the SH/EAHP Workshop 2009
Cleveland OH
Falko FendUniversity of Tübingen
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Plasma Cell DisordersPlasma cell is the dominant and proliferatingneoplastic population, +/- M-componentMultiple myeloma
Smouldering and indolent MMPlasma cell leukemiaOsteosclerotic MM (POEMS syndrome)
MGUS (monoclonal gammopathy of unknown significance)Solitary plasmacytoma
OsseousPrimary extraosseous plasmacytoma (EMP)
Primary amyloidosis
The Spectrum of Immunoproliferative Disorders andthe Border Between B-Cell Lymphoma and PlasmaCell Neoplasms
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SH/EAHP workshopCleveland 2009 - a reminiscence
„Everything with plasma cell differentiation and look-alikes...“
More than 220 cases were submittedPlasma cell myeloma and related neoplasms (53cases)
Plasmablastic lymphoma and other large cell lymphomaswith plasmablastic morphology/differentiation
Nodal marginal zone B-cell lymphoma
Lymphoplasmacytic lymphoma
Non-nodal marginal zone lymphomas
Other small B-cell lymphomas with plasma cell differentiation
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Plasma cell myeloma...and its borders and problem zones
t(11;14)+ PCM (12 cases, plus others)PCM and other B-NHL/MBLExtramedullary plasmacytoma and extramedullarymanifestations of PCMPlasmablastic PCM (21 cases)Plasma cell leukemiaEBV+ plasma cell neoplasms in immunocompetentpatientsSystemic plasma cell neoplasms in HIV infectionothers
AmyloidosisCrystal-storing histiocytosisOsteosclerotic PCM
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11q13 CCND1 (15-20%)4p16.3 FGFR3/MMSET (10-20%)8q24 C-MYC (10%, sec. alteration)
6p21 CCND3 (<5%)
16q23 C-MAF (2-5%)
20q11 MAFB (2%)
6p25 MUM1/IRF4 (rare)
1q21 IRTA1/IRTA2 (1-2%)
Represent 90% of translocation-pos. MM (50-70%)
Approx. equal frequency in MGUS
IgH translocation partners in MM
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Case 54 (D. Visnavantha)
CD20 Pax5 CyclinD1
Anemia, no osteolyticLesionsCD20+, CD19+, Pax5+CD38+, CD138sIg and cIgIgGk paraprot.t(11;14)
Initially DiagnosedAs LPL
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2 groups of t(11;14)+ MMidentified by gene expressionprofiling:
- Lymphoplasmacytic variantwith expression of B-cellmarkers (CD20, Pax 5 etc.)
- conventional form
CD20
Cyclin D1
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Cyclin D1
CD138 IgM
t(11;14)+ MM IgM positiveUsually conventional variant
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CD20
IgM
kappaIn LPL: CyD1-, no homogeneous expressionof PC markers, mixed morphology, often IgM
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t(11;14)(q13;q32) in MMt(11;14)(q13;q32) due to errors in Ig heavy chainswitch recombination results in Cyclin D1 overexpression
Cyclin D1+ MM usually well differentiated, oftenlymphoplasmocytoid (40%), frequently CD20+ (50-66%)
Only strong and homogeneous Cyclin D1 is diagnosticof t(11;14)
Frequent in IgM, IgE and nonsecretory MM
Equally common in MGUS
More commonly leukemic
BUT: otherwise usually classical PCM (CRABlesions)
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Zhan, F. et al. Blood 2006;108:2020-2028
Gene expression patterns in MMShow strong imprint of cytogenetics
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0
10
20
30
40
50
Rel
ativ
e G
ene
Exp
ress
ion
1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49 51 53 55
S1
Correlation of Cyclin D1 mRNA and FISH
MM group 2 MM group 3MM group 1
100 2.5 - 20 0 - 2.5Cyclin D1 mRNA
Specht et al, Blood 2004
t(11;14)
+11
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Plasma cell myeloma...and its borders and problem zones
t(11;14)+ PCM (12 cases, plus others)PCM and other B-NHL/MBLExtramedullary plasmacytoma and extramedullarymanifestations of PCMPlasmablastic PCM (21 cases)Plasma cell leukemiaEBV+ plasma cell neoplasms in immunocompetentpatientsSystemic plasma cell neoplasms in HIV infectionothers
AmyloidosisCrystal-storing histiocytosisOsteosclerotic PCM
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PCM and other B-celllymphoproliferative disorder or monoconal B-cell
lymphocytosis (MBL)
Case 276, M. Salama
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Flow cytometry dot plot: Plasma cells(red), Monoclonal B‐cells (blue)
69 yo female presented withanemia, renal failure ¶proteinemia• CBC: WBC 4 K/μL, Hgb 7.1 g/dL,Plts 122K/μl.• Serum protein studies:– TP 9.3 g/dL with 4 g/dL paraprotein– IgG 7 g/dL, with suppressed IgA & IgM
Sorted PC CLL cell13q22
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PCM and other B-celllymphoproliferative disorder or monoconal B-cell
lymphocytosis (MBL)
Differential diagnosis:PCM with lymphoplasmacytic morphologyB-cell NHL with plasmacytic differentiation
LPL, MZL, CLL with cIg
Clues for diagnosis:Aberrant immunophenotype of PC (CD56) and lackof B-cell antigens on PCAberrant immunophenotype of B-cells (CD5)Discordant light chain expressionClinical featuresCytogenetics (Seegmiller et al. AJCP 2007;127:176-81)
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Plasma cell myeloma...and its borders and problem zones
t(11;14)+ PCM (12 cases, plus others)PCM and other B-NHL/MBLPlasma cell leukemiaExtramedullary plasmacytoma and extramedullarymanifestations of PCMPlasmablastic PCM (21 cases)EBV+ plasma cell neoplasms in immunocompetentpatientsSystemic plasma cell neoplasms in HIV infectionothers
AmyloidosisCrystal-storing histiocytosisOsteosclerotic PCM
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Plasma cell leukemia (PCL)Plasma cell leukemia (PCL)>20% PC in PB diff. count or >2x109/L
Primary (2-5% of all MM) or secondary during course of the disease
Broad cytological spectrum
51-Xie 247-Chen 280 - Roepke
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PCL – clinical featuresSex, age distribution, incidence of osteolysis similar to MM
More often light chain only, IgD or IgE, non-secretory
Higher incidence of adverse prognostic features
Organomegaly and high tumor mass, more common extramed.
Disease (25-75%)
Unfavorable cytogenetics
More common t(11;14) (case 151 Tadesse-Heath & Jaffe: both
t(11;14) and C-MYC)
Higher ß2-MG, LDH, PC labelling index, sIL6-R, calcium
Pellat-Deceunynck 1998; Garcia-Sanz 1999; Avet-Loiseau 2001; Saccaro 2005Dimopoulos 1994
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PCLPhenotype and Prognosis
PCLPhenotype and Prognosis
Garcia-Sanz et al, Blood 1999Pellat-Deceunynck et al, Leukemia 1998
Common absence of CD56More common CD20+
Poor prognosis similar to high-riskMM under standard therapy (8 vs 11 vs 36 mo)
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Plasma cell myeloma...and its borders and problem zones
t(11;14)+ PCM (12 cases, plus others)PCM and other B-NHL/MBLPlasma cell leukemiaExtramedullary plasmacytoma andextramedullary manifestations of PCMPlasmablastic PCM (21 cases)EBV+ plasma cell neoplasms in immunocompetentpatientsSystemic plasma cell neoplasms in HIV infectionothers
AmyloidosisCrystal-storing histiocytosisOsteosclerotic PCM
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Primary extramedullary plasmacytoma vs.Extramedullary extension of PCM
Often a diagnostic problem for pathologist, less so forclinician
Extramedullary extension of PCM usually aggressiveend-stage disease
Evidence of end-organ damage
No morphological, phenotpyical or cytogenetic criteria fordistinction in the literature
Can we derive the clinical behaviour of plasmacytomafrom morphology or immunophenotype?
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Case 91, J. Frater
80-year-old male with recurrentnasal obstructionIgG? paraprotein of 1.4g/dlNo bone lesionsNormal PB countsDiscrete polyclonal plasma-cytosis of bone marrow
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CD45 CD138
kappa lambda
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KI 67 EBER
CD56 CD79a
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59 y/o male presented with vomiting,diarrhea, weakness & renal failure.Endoscopy: prominent gastric folds.Bx:PC-rich MALT lymphoma
15 mo later, hip pain. CTmultiple bony lesions• Serum protein studies:– Panhypogammaglobinemia– l FLC at 21,700 mg/L• IgH PCR (gastric bx): +• API2/MALT1 PCR: -• FISH (fem head) : del(13q)
Case 230 R. Ryan
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Primaryextramedullary plasmacytoma
>80% in upper respiratory tract
indolent, good prognosis following local therapy
local recurrence in 15-30%, transformation tomultiple myeloma rare
no clearcut prognostic features for risk oftransformation to MM
No morphological differentiation from extramedullaryMM manifestation (eMM), but usually welldifferentiated
MALT lymphoma with plasmacytic differentiation?
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Immunophenotypeof EMP vs. eMM
Primary EMPand eMM showsimilar PCphenotype
Lack of CD56and cyclin D1 inEMP
eMM commonlyof higher grade,high MIB1 indexand p53 andp21 expression
EMP
EMP CD56
eMM
eMM CD56
Cyclin D1
Kremer et al, J Pathol 2005
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AB
D
F
B C
E F
Trisomy 9 & 15Monosomy 13q
Break 14q32 Fusion FGFR3/IgH
FISH in EMP Common IgH breaksNo t(11;14)t(4;14) in samefrequency as MMCommon polysomiesCommon deletion/monosomy 13qNo MALT-typeaberrations
Similar to MM, butdifferences intranslocation partnerslack of prognosticsignificance
Bink et al, Hematologica 2008
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Plasma cell myeloma...and its borders and problem zones
t(11;14)+ PCM (12 cases, plus others)PCM and other B-NHL/MBLPlasma cell leukemiaExtramedullary plasmacytoma and extramedullarymanifestations of PCMPlasmablastic PCM (21 cases)EBV+ plasma cell neoplasms in immunocompetentpatientsSystemic plasma cell neoplasms in HIV infectionothers
AmyloidosisCrystal-storing histiocytosisOsteosclerotic PCM
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Multisteppathogenesis of PCM
(Bergsagel & Kuehl. J Clin Oncol)
90% of MM patientsshow M-protein in earlier serum samples(Weiss et al, Blood 2009)
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MGUSMGUS IntramedullaryMM
IntramedullaryMM
Extramedullary MMand Plasma cell
leukemia
Extramedullary MMand Plasma cell
leukemia
BM stromal cellBM stromal cell
TNFa,TGFß..
IL-6IGF-1
OsteolysisAngio-genesis
Osteo-clasts
karyotype instability
13q deletion
c-myc alterationsRas, p53 mutations
Mutations in noncanonicalNFkB pathwayChromosome 1p-, 1q+Gene methylation
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#312 Sidhu86-year-old female1y history of myelomaRenal insufficiency, anemia,IgG/l M-prot.Massive retroperitoneallymphadenopathyCD138+, Lambda+, MUM1+,MIB1 80%CD20-, CD79a-, EBERs-
Extramed. Plasma cellmyeloma, plasmablastic
MIB1
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314 Burke PB 317 Nepalli PB 317 Nepalli PB
325 Fend PB 351 Djokic PB 368 Zhang PB HIV+, EBV+
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Plasmablastic subtype in PCM(Greipp et al, Blood 1985; 65:305-10)Plasmablastic subtype in PCM(Greipp et al, Blood 1985; 65:305-10)
Definition:> 2% plasmablastic myeloma cells
Diffuse chromatin patternnucleus > 10µm or nucleolus > 2µmHigh N/C ratioCentrally placed nucleus, no/little perinuclearhof
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Bone marrowhistology in myeloma
(Bartl et al, AJCP 1987)
Bone marrowhistology in myeloma
(Bartl et al, AJCP 1987)
Definition ofplasmablastic myeloma
predominance of cellsLarge nuclei withvery prominent,central nucleoliHigh N/C ratio, faintperinuclear hof
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Comparison ofGrading SystemsComparison of
Grading SystemsBartl et al (Munich)Predominantly histology-basedBased on predominant cell type
Greipp et al (Mayo Cl.)Exclusively cytology-based2% cut-off for „plasmablasts“
Mostly based on old series, relatively limited data undernew therapy regimens
Bartl et al, AJCP 1987
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Plasma cell myeloma plasmablastic
Cytology-based, 2%threshold (Greipp et al)
• Histology-based, pred. cell-type (Bartl et al)
Do diagnose „plasmablastic“ PCM (but use the correctclassification with respect to material!) – probablyidentifies high risk disease (high risk genetics)
Other high grade morphology may be identified
High MIB1 index does not define „plasmablastic“
Morphological diagnosis, however, two different definitions in use
#122Spier
#351Djokic
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C-myc breaks and p53 loss inplasmablastic PCM
18 workshop cases examined (break-apart probe)8/16 (50%) cases positive for c-myc3 cases with deletion of p53
Frequency in PCM in general 15%Prognostic significance uncertain, but hints to moreaggressive behaviour
Thought to be secondary event, often very complex,with varying breakpoints>90% human myeloma cell lines show c-myc (orN/L-MYC) rearrangements, 40% with non Ig partners
Avet-Loiseau 2001, Dib 2008, Gabrea 2008
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Plasma cell myeloma...and its borders and problem zones
t(11;14)+ PCM (12 cases, plus others)PCM and other B-NHL/MBLPlasma cell leukemiaExtramedullary plasmacytoma and extramedullarymanifestations of PCMPlasmablastic PCM (21 cases)EBV+ plasma cell neoplasms inimmunocompetent patientsSystemic plasma cell neoplasms in HIV infectionothers
AmyloidosisCrystal-storing histiocytosisOsteosclerotic PCM
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CD56 x400
kappa x400
EBER x400
51-year-old male, multiple bone lesions, noM-protein
Positiv: CD56, CD117, CD138, bcl-2, MUM1,EMA, p53, kappa, 90% Ki-67.
Negativ: CD10, CD20, CD30, CD43, CD45,CD79a, CD99, LMP1, cyclin D1, PAX5, HHV8,IgA, IgD, IgG, or IgM.
Chuang et al, AJCP 2007
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11-year-old (!) female, multiple osteolytic lesionsCourtesy of Carlos Ortiz, Hosp. ABC, Mexico City
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MUM1
CD56Cyclin D1
CD138
No breaks in C-MYC, CCND1
EBERs
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EBV+ plasmacell neoplasms
Chang et al (AJCP 2007):1/4 extramedullary plasmacytomas (ENT region)3/54 multiple myelomas (2 plasmablastic)
Colomo et al (AJSP 2004)2/8 plasmablastic myelomas / plasmacytomas
Aguilera et al (Mod Pathol 95)3/23 EMP of head and neck
Dong et al, (AJSP 2005)14 cases of EBV+ lymphomas in HIV+ patients withplasmablastic features
4/14 with overlap features with plasma cell myeloma4/4 with bone and soft tissue lesions, 2/4 with BM involvement
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Differential DiagnosisExtram.
PCMPrimary
EMPPBL
Morphology Often plasmablastic Mostly plasmacytic Plasmablasticlarge cell/immunobl.
M-protein Most cases 20-30%, low levels Rare
Osteolytic lesions Common Occasional localbone
Rare
Lymphadenopathy Rare Very unusual,usuallyaerodigestive tract
In minority of cases
Bone marrow Yes No May occur
CD56 70-80% <20%, weak Some positive
Cyclin D1 / t(11;14) 15-20% Neg. Neg.
C-mycrearrangement
common Neg common
P53 Common Rare common
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Robert Lorsbach & Eric Hsithe other members of theCleveland Workshop panel
The submitters to the 2009SH Workshop Cleveland
Katja SpechtEugenia HaralambievaIna KochJulia SlottaMarcus KremerGerman OttPhilip KluinLeticia Quintanilla-Martinez