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Transcript of Burkitt Lymphoma and Plasmablastic Lymphoma - unibo.it · Burkitt Lymphoma and Plasmablastic...
Burkitt Lymphoma and Plasmablastic Lymphoma
Differences and similaritiesLorenzo Leoncini
University of SienaItaly
• Endemic BL was the first human tumor for which a viral association has been shown
• The first human tumor for which a chromosomal translocation resulting in the activation of an oncogene was identified
• The first tumor to be successfully treated with chemotherapy alone
AFTER
A single molecular and morphological entity with variations in clinical presentation
Endemic, Sporadic, Immunodeficiency
Endemic BL
• Equatorial Africa• Correlation with incidence & climatic factors, Malaria• High incidence among children• Peak Incidence, 4-7 yrs, Males : Females 2:1• Sites: Extranodal sites 20% involve jaws,
other facial bones Leukemia rare
• EBV 100%
Sporadic BL• Tumor histologically identical to BL identified in other parts
of the world, including US and Europe
• Approximately 30% of childhood lymphomas
• 1-2% of all lymphomas
• Median age - approximately 12 yrs.
• Male: Female ratio - 2-3:1
• Jaw tumors less frequent
• GI most common site of involvement
• Ovaries, Breast (at pregnancy, puberty)
• EBV 20-30%
Immunodeficiency Associated BL
• Presents early in the course of HIV, often as the initial manifestation of infection
• CD4 counts generally normal
Common Features of BL variants
Immunophenotype
Morphology
Myc rearrangementMost proliferative of all human tumors100% of cells in cycle, 27% in S phase
Bcl6 Bcl2CD 10
c-MYC
The MYC transcription factor is pathologically activated in many human malignancies:
Genomic aberrationsChromosomal amplifications
Mutual translocations
Hummel M et al. Molecular Mechanisms in Malignant Lymphomas Network Project of the Deutsche Krebshilfe A biologic definition of Burkitt's lymphoma from transcriptional and genomic profiling. N Engl J Med. 2006 Jun 8;354(23):2419-30.
Piccaluga et al. Blood 2011
Piccaluga et al. Blood 2011
BCR signaling pathway
Schmitz R et al. Nature 2012
This rate of mutations is significantlylower than that reported in sBL (70%).
This finding seems to be consistent with thehypothesis that an activation of B-cellreceptor through an extrinsic antigen-drivensignaling could be present in eBL and maydepend on the presence of multiplepathogens
Co-factors in endemic Burkitt’s Lymphoma
EBV
• Burkitt’s Lymphoma is endemic in region with mean minimum temperatures> 15,5°C and annual rainfall
• eBL common in wet areas. The altitude gradient is in effect a temperature gradient.
• Shifting foci, space-time case-clusters and seasonality observed in eBL
Lymphoma Belt of Africa
Malaria and EBV are ubiquitous within the lymphoma belt of Africa
Then Burkitt’s Lymphoma should be commoner than it is. Are there other co-factor candidates?
EBV can interact with malaria, planttumour promoters and arboviruses
• EBV and malaria boost eBL incidence by x 100-150 in LB
• VCA levels increased pre eBL up to 6 yrs before. Only antibody which changes before tumour develops
• EBV activated by plant phorbol esters. Interactions include eBL 8:14 t in 1% of cells in Lymphoblastoid Cell Lines
• EBNA1 found to increase HCV replication
BL DLBCL
Terapia specifica
HD-MTX e ARA-C
% Cura
70-90%
Terapia specifica
CHOP-R
% Cura
~50%
Non nota terapia efficaceScarsa efficacia
CHOP-R
% Cura
0%
B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma
(2008) 4th Edition
CLINICA:
Adulti
Sede: prevalentemente extranodale SNC
Presentazione leucemica
IMMUNO :CD20+, CD79a+ CD10+, Bcl6+
Bcl2-, MUM1- /debole
Bcl2 -/+ o +
Mib1 50-100%
GENETICA
MYC R 35-50%
No MYC-IGH
BCL2 R 15% spesso con MYC (double hit)
Raro BCL6 R con o senza MYC e BCL2
Cariotipo complesso
LINFOMA A CELLULE B INCLASSIFICABILE INTERMEDIO TRA DLBCL e BL
Bcl2
Mib1
Categoria eterogenea da non considerare come una distinta entità patologica.Categoria « pratica » per classificare i casi che non soddisfano i criteri diagnostici per BL e DLBCL
CD20-positive aggressive B-cell lymphoma after exclusion of lymphoblastic lymphoma
Phase 1 scoring
Morphology (0-3)BCL2 (2 - neg.; 1- wk.)CD10 (1, if pos.)
Cumulative score:5-6 – BL3-4 – BL not excluded<3 – not BL
Phase 2 scoring
Morphology (0-3)BCL2 (2 - neg.; 1- wk.)CD10 (1, if pos.)Ki-67 (2 - >95%; 1 - 90-95%)CD38 (1, if pos.)CD44 (1, if neg.)
Cumulative score:>8 – BL6-7 – BL not excluded<6 – not BL
Phase 3 scoring
Morphology (0-3)BCL2 (2 - neg.; 1- wk.) CD10 (1, if pos.)Ki-67 (2 - >95%; 1 - 90-95%) CD38 (1, if pos.)CD44 (1, if neg.)FISH (2, if MYC-Ig pos. & BCL2/BCL6 neg.)
Cumulative score:>8 – BL6-7 – BL not excluded*
* Benefit from karyotype, CGH, gene expression and assessment of the impact of each of the parameters
Fase 181,7%
Fase 210,7%
Fase 32,8%
95,2%
RESULTS
RESULTS
N. positive
(%)
N. negative
(%)
Intensity of
staining
Pattern of expression
BL 45(96%)
2 (4%) strong single or multiple droplets into thecytoplasm, clustering around theouter nuclear membrane
notBL
3 (9%) 30 (91%) weak single, very small droplets into thecytoplasm
…close attention to the cellular details helps further distinguish these related but distinct neoplasms… composed of blasts with a light chromatin and one to a few prominent nucleoli and not containing proplasma cells and mature plasma cells …tipical of plasmacytomas.
PBL show a morphological spectrum varying from a diffuse and cohesive proliferation of cells resembling immunoblasts, cells with more obvious plasmacytic
differentiation, which may resemble cases of plasmablastic plasma cells myeloma
PLASMABLASTIC LYMPHOMAHarald Stein, Nancy L. Harris, Elias Campo
Caratteristiche ClinicheINCIDENZA: <1% NHL
ETÀ(media,range): 40aa (7-60) HIV+
60aa (1-80) HIV-
SESSO M/F: 7:1
SEDE: Cavità orale (90% in HIV+)
Extra-orale: Seno Mascellare,Nasofaringe, Tratto Gastrointestinale,Orbita,Cute, Polmone, Tessuti Molli,Osso,Mediastino, Vulva
Nodale: raro (HIV-)
EZIOLOGIA: EBV 60-75% (Cavità orale ~100%)
HIV 80%
HHV8 assente
Immunosoppressione post-trapianto,iatrogena
PROGNOSI: aggressivo, sopravvivenza 1aa dalla diagnosi
Linfoma Plasmablastico secondario
Tumours with features of PBL may occur in patients with prior plasma cell myeloma. Such cases should be considered plasmablastic tranformation of myeloma and distinguishedfrom primary plasmablastic lymphoma.
IstologiaPattern di crescita diffusoFrequente starry skyNumerose mitosi e corpi apoptoticiAree di necrosi confluenti comuni
Proliferazione monotona coesiva di grandi cellule ad aspetto blastico Immunoblasti: grande nucleolo centrale con scarso o assente citoplasma Differenziazione Plasmablastica: nuclei eccentrici, marcato citoplasma basolfiloPresenti elementi Binucleati o MultinucleatiCorpi di Russell e Dutcher assenti
Differenziazione Plasmacitica
Proliferazione polimorfa con cellule di medie e piccole dimensioni con nucleo eccentrico, nucleolo relativamente piccolo,citoplasma abbondante
CD20,PAX5 -
CD79a +/-
Ig citoplasmatiche +
CD38, CD138, MUM-1 +
PRMD1/BLIMP1, XBP1 +
CD45 -/+
CD30, EMA +/-
CD10 +/-CD56 -/+HHV8 -EBV +
EMA
CD138
CD20
Ig
CD45MUM1
Immunofenotipo
Blimp-1
OverlapClinico
MorfologicoImmunofenotipico
LINFOMA PLASMABLASTICO
diagnosi differenziale
DLBCL NosDLBCL Variante ImmunoblasticaLinfoma di Burkitt
PEL
Linfoma Plasmablastico in MCD
Linfoma a Grandi Cellule B ALK+
Mieloma Multiplo PlasmablasticoPlasmacitoma Plasmablastico
Sarcoma MieloideCarcinoma indifferenziatoMelanoma
HHV8
ALK t(2;17) clatrina -ALK
Markers non linfoidi
CD20+ CD20-
Paraproteine sericheBence Jones urinarieBOM positiva alla diagnosiLesioni osteolitiche
Presenza di plasmacellule neoplastiche atipiche e/o mature
EBER-Ki67 più bassoCD56+
Burkitt Lymphomaand Plasmablastic Lymphoma
Two separate entities but with manysimilarities
Extranodal localizationMorphology
Proliferation rateGenetic abnormalities
HIV settingEBV Latency Program
CD10CD20
CD 38 CD 138
Mib-1: 95-100%
t(8;14)(q24;q32) IG/MYC
MYC
BREAK-APART PROBESt(8;14)
c-myc
Why lymphomas in imunocompromised patients show do not show Latency III?
Lymphomas in immunocompromised patients
EBER LMP 1
Latency I
II
Activated B cell
GC
T cell Response
I
III
III
III
EBV Naïve B cell
EBV+ Memory B cell
IIISHM
No SHM
Burkitt cell counterpart?
I = EBNA-1; II = EBNA-1, LMP1/2; III = All EBNAs
Translocation?
Infection
RAG
AID
No T cell Response
Plasmablastic cell counterpart?
Cocco et al. Am J Pathol 2008
The strategy of the virus is to persist in a healthy carrier
• T-cell immunity is believed to play a critical role in the control of EBV infection–Acute infection – T- and NK-cell
LPD–Reactivation memory B-cells – B-
cell-LPD• Oncogenic effect of EBV products
in association with additional genetic, microenviromental and environmental factors
Only expression of EBNA1 (No LMP1, no EBNA2)
Latency I
• Active interplay between virus and hostinvolving miRNAs
• Virus-mediated miRNA dysregulation may beinvolved in several malignancies
Cullen BR, Nature, 2009
MODELS OF miRNA-MEDIATED HOST-VIRUS INTERACTIONS
• Viral transcripts targeting hostmiRNAsMechanism of modulation of host miRNAexpression by viral transcripts
• Viral miRNAs targeting host transcriptsRegulatory role of virus-encoded miRNAson cellular transcriptEBV — host transcripts (associated withapoptosis and tumor suppression)
8/470 hsa-miRNA (3 up, 5 down)
13/44 viRNA (BARTs)
Human and viral miRNA profiling in EBV positive versus EBV negative BLs
miR-192
miR-127
EBV
Antigens
Growth program Latency III
Latency I
Default program Latency II
MYC translocation
EBNA1+AID+miR-127
Latency 0
IgM+ memory B cells
IgG+ memory B cells
Plasma cells
T helper cells
FDC
Apoptosis
High affinity
Low affinity
Naive B cells
EBNA1+AID+miR-??high
Plasmablastic lymphoma
Burkitt lymphoma
Latency I
Proliferation and SHM
Selection
PB ebv+PB ebv-
PC ebv+PC ebv-
12 miRNA cellulari
39 miRNA virali
BL ebv-
PB ebv-PB ebv+
BL ebv+
17 miRNA cellulari
36 miRNA virali
BL ebv+PB ebv+
PB ebv-
ebv-miR-BART- 18-5pebv-miR-BART- 19-5p
hsa-miR-148-3p hsa-miR-148-5phsa-miR-192-5phsa-miR-1304-3p
BL ebv-
BL ebv+
PB
ebv-miR-BART- 18pebv-miR-BART- 19 p
hsa-miR-148a 3p hsa-miR-148a 5phsa-miR-192 5phsa-miR-1304 3p
56aa
M/F: 50%
Extraorale
EBV+ (92%)
HIV- (100%)
46aaM Cavo orale
Seno mascellare
EBV+ (100%)HIV+ (70%)
Secondario a MielomaCD56
IL6TaT
DNMT
TaTProliferazione
Differenziamento
BHLFE41
BRWD1
IL-6
CXCL13
PTRJ
Proliferazione cellulare
Migrazione cellulare
Risposta immunitaria
miR-148a-3p
miR-148a-5p
ApoptosiDifferenziamento
CCNT2GDF11
GDF11 ACVR2B
MAPK6MAP3K
BCL2
PTRJ
MDX1
BRWD1
Regolazione espressione genica
METILAZIONE
DNMT1 DNMT3b
Metabolismo lipidico
FAR2
miR-1304-3pmiR-192-5p
PDP2
PicTar
IL-6
• PBL e BL sono due distinte entita con molte analogie
• miRNA profiling distingue nettamente i PBL dai PC, dato non cosi evidente con i BL
• PBL è una categoria eterogenea che riflette lo stato immunitario del paziente
•I casi HIV + presentano una più marcata differenziazione plasmacitica
• L’ interazione HIV miRNA gioca sicuramente un ruolo importante nella linfomagenesi nelle forme HIV correlate
CONCLUSIONI
University of Siena, Italy
Maria Raffaella AmbrosioCristiana Bellan Giulia De FalcoSara GazaneoStefano LazziLucia Mundo
Polo d'Innovazione di Genomica Genetica e BiologiaPerugia, Italy
G A Z I ER
EBV miRNA BART 18-5p
BCLAF1 Apoptosi
CDKN1C Ciclo Cellulare
TP53INP1 P53 pathway
SOCS3JAK-STAT pathway
PTENAKT-PI3K pathway