LINFOMAS B AGRESIVOS - SEAP
Transcript of LINFOMAS B AGRESIVOS - SEAP
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LINFOMAS B AGRESIVOS
Lluís Colomo
Hospital Clínic, Barcelona
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Linfomas Indolentes y Agresivos Características histopatológicas
• Células pequeñas
• Baja actividad proliferativa
• Crecimiento no destructivo
• Respuesta a influenciasreguladoras
• Células grandes
• Actividad proliferativa alta
• Crecimiento destructivo
• Crecimiento Autonomo
Indolente (Bajo grado) Agresivos (Alto grado)
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• Curso clinical indolente
• Supervivencia larga
• No curable con quimioterapia
• Ausencia de “plateau” en las curvas de supervivencia
• Curso clinical agresivo
• Supervivencia corta sin tto
• Posible larga superviencia(curación)
• “Plateau” en las curvas de supervivencia
Linfomas Indolentes y Agresivos Características Clínicas
Indolente (Bajo grado) Agresivos (Alto grado)
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REAL/WHO Classification
Histological distribution
2%
8%
6%
36%1% 2%
7%
7%
7%
24%
LymphocyticLymphoplasmocytoidMALTFollicularMantle-cellDiffuse large-cellBurkittAnaplasticPeripheral T-cellOther
NHL Classification Project, 1997
N=1.403
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BURKITT LYMPHOMA
• Highly aggressive
• Extranodal or acute leukemia
• Monomorphic medium-sized B-cells
• High number of mitotic figures
• Translocation MYC
• Epstein-Barr virus frequent WHO, 2001
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ENDEMIC
• Equatorial Africa, New Guinea
• Children (4-7 years)
• M:F 2-3:1
• Jaws, orbit 50-60%• Ovary (bilateral)• Ileo-coecal region, omentum, breast, kidney
• EBV+ 95%• Malaria as cofactor
SPORADIC
• Elsewhere (North Africa, South America)
• Median age 30 years(younger)
• Abdominal tumors (ileo-coecal region)• Ovary, breast, kidney
• EBV+ 20% (60-80%)
IMMUNODEFICIENCY
• HIV infection
• Nodal• Bone marrow
• EBV+ 30-40%
BURKITT LYMPHOMA - Clinical Variants
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• Extranodal
• Depend on involved site ? CNS involvement
• Bulky Disease ? very short doubling time
• Acute Leukemia
• High LDH and Uric acid ? renal failure
• Stages III-IV 70%
BURKITT LYMPHOMA - Clinical Features
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BL with plasmacytoid differentiation
BURKITT LYMPHOMA - Variants
Atypical BL / Burkitt-like• Immunodeficiency
• Monotypic cIg
• Ki-67 ~ 100%
• MYC translocation
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PLASMA CELL
NAIVE -BLYMPHOCYTE
MCLt(11;14)CCND1
CLL
FLt(14;18)
bcl-2
MEMORY CELL
BLt(8;14)c-myc
MALTt(11;18)API2-MLTALL/LBL
LCLt(3q)bcl-6
CLLMCL
BL has the phenotype of a germinal center cell
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CD20 CD10
bcl-2 Ki-67
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CD20
CD10
bcl-2
Ki-67
CD3
bcl-6
EBERs
BURKITT LYMPHOMA - Phenotype
• CD19, CD22, CD79a
• sIg (IgM > IgG, IgA)
• cIg (plasmacytoid variant)
• T-cell markers negative
• CD5-, CD23-
• TdT-, CD34-
• LMP1- / EBERs+ (Latency pattern I)
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Translocation involving MYC is a constant genetic feature in BL
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14q32 (IgH)
Fusion Translocation Probes Break Apart Rearrangement Probes
normal t(8;14)
t(8;14)(q24;q32)
8q24 (c-myc)
normal
8q24 (c-myc)
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Blum, K. A. et al. Blood 2004;104:3009-3020
Direct and indirect consequences of c-Myc overexpression in Burkitt lymphoma
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• Prolonged ALL-like regimens are ineffective
• Early-stages ? CR rates of 100%
• Advanced stages ? CR 85-90%
• Relapse occurs within first year
• Radiotherapy has not primary role in BL treatment
BURKITT LYMPHOMA - Treatment
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AIDS-Related Burkitt’s Lymphoma vs.Diffuse Large B-cell Lymphoma
HAART EraPre–Highly Active Antiretroviral
Therapy (HAART)
J Clin Oncol 2005;23:4430
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Diffuse Large B-Cell LymphomaHeterogeneous Disease
• Clinical Characteristics
• Morphology
• Phenotype
• Genetic Alterations
• Oncogenic alterations
CD5CD10
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Diffuse Large B-Cell Lymphoma
• Large B-cells (size equal to macrophage nuclei or more than twice of lymphocytes)
• Diffuse growth• 30-40% of adult NHL• Extranodal 40%
(gastrointestinal / any site)• Tumor mass in extranodal sites• De novo or progression of a
low grade lymphoma
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Diffuse Large B-cell LymphomasMorphologic Variants
CENTROBLASTIC
IMMUNOBLASTIC
T-CELL/HISTIOCYTIC RICH
ANAPLASTIC LARGE CELL LYMPHOMA
PLASMABLASTIC LYMPHOMA
FULL-LENGTH ALK POSITIVE
Cb
TCR ALCLB ALK
Imb
PBL
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PrimaryMediastinal Intravascular
PrimaryEffusion
HHV-8
Diffuse Large B-cell LymphomasSubtypes (clinico-pathological entities)
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Centroblastic monomorphic
Immunoblastic
Diffuse Large B-cell LymphomasMorphologic Variants
Centroblastic multilobated
Centroblastic polymorphic
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T-Cell/Histiocyte rich B-Cell Lymphoma
CD79a
CD57CD3
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T-Cell/Histiocyte rich B-Cell Lymphoma
• Age <60 years
• Stages III-IV?75%
• High LDH ?50-60% DLBCL (GELA)
• Hepatomegaly 30% 12%• Splenomegaly 60% 17%• Bone marrow + 35% 26%
• CR after treatment 58% 73%5-year follow-up• Event Free Survival 58% 52%• Overall Survival 63% 66%
Rüdiger, Ann Oncol 2002;13(S1):44-51
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Anaplastic Large Cell Lymphoma
CD20 CD30
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Plasmablastic Lymphoma of the Oral Cavity
• HIV+ (15/16)• Monomorphic blasts • CD45, CD20 -/w; VS38c+• No serum M-component• EBV+ (60%)• Unfavorable outcome
Delecluse et al., Blood 1997;89:1414-20
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Monomorphic Polymorphic
PLASMABLASTIC LYMPHOMAMorphologic heterogeneity
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kappa lambda
CD45 CD20 CD79a
CD3
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EBER
MUM1BCL6
CD138
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Plasmablastic Lymphoma/DifferentiationA term for many uses
Morphological Differentiation- Large Cell Lymphomas with secretory/plasmacytic
differentiation- Dedifferentiated/Plasmablastic Myeloma
Phenotypical Differentiation
- Large Cell Lymphomas with terminal B-celldifferentiation profile (CD20- CD38/CD138 +)
Different Disease Entities- PBL oral cavity- PBL Castleman disease/HHV-8 associated
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PBL of “Oral Mucosa type”23 cases (19M / 4F)
Age 48y (11-86)HIV+ 73% (16/22)
Other: 2 postTx / 1 steroids (SLE) / 2 >80y
Sites:11 oral 5 maxillary sinus
12 extraoral 1 skin / 1 anal / 1 soft tissues
3 nodal / 1 bone marrowEBV + 17/23 (74%)
HHV8 + 0/19 (0%)
8/10 high stage at presentation / 7 DOD (1-28 months)
Am J Surg Pathol 2004;28:736–747
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CD138
• Morphological plasma cell differentiation
• Nodal & Extranodal
• HIV + (33%)Other immunodeficiencies
• EBV 60%
• Similar to extramedullary highgrade plasma cell tumors
• Extensive bone dissemination, occasional IgG M component
Plasmablastic Lymphoma with Plasmacytic Differentiation
EBER
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DLBCL with Terminal Differentiated B-cell Phenotype A heterogeneous spectrum
Immunosupressed patients (HIV+/ HIV-)? Plasmablastic Lymphomas
- Oral cavity type
- PBL with plasmacytic differentiation
? HHV-8 Associated Large B-Cell Lymphomas- Primary effusion lymphoma
- Extracavitary (Solid) variant of PEL
- HHV-8 +/Castleman associated plasmablastic lymphoma
Immunocompetent patients? Extramedullary presentation of Plasma cell neoplasms (Multiple
Myeloma, Plasmacytoma)
? DLBCL expressing ALK
Differential Diagnosis? Pyothorax associated lymphoma
? DLBCL with secretory/plasmablastic differentiation
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PRIMARY EFFUSION LYMPHOMA
• Rare
• Pleural, peritoneal and pericardial cavities
• No lymphadenopathy or organomegaly
• Associated with HHV8 infection
• Coinfection with EBV in most cases
• HIV infection >> elderley males
• Associated with Kaposi sarcoma, Castleman disease
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PRIMARY EFFUSION LYMPHOMA
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Tran
sfor
med
SS
C
Forward Scatter0 64 128 192 256
064
128
192
256
CD
45
->
CD30 ->100 101 102 103 104
100
101
102
103
104
CD
19
->
CD30 ->100 101 102 103 104
100
101
102
103
104
CD
5->
CD20 ->100 101 102 103 104
100
101
102
103
104
CD
56
->
CD38 ->100 101 102 103 104
100
101
102
103
104
CD
10
->
CD45 ->100 101 102 103 104
100
101
102
103
104
Lam
bd
a ci
top
l->
Kappa citopl ->100 101 102 103 104
100
101
102
103
104
CD
79
aci
top
l->
CD3 citopl ->100 101 102 103 104
100
101
102
103
104
INMUNOFENOTIPO
Grandes CD45débil CD30++ CD38++ CD138- CD2- CD3-/+ CD5- CD7-CD19- CD20- CD10- CD79a- ?&? – CD56- CD15- EMA+
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The neoplastic cells are positive for HHV8/KSHV in
all cases (WHO,2001)
Ladd
er
Case
Cont
rol
-Co
ntro
l +H 2
O
LANA-1
*
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Blood, 2003
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Solid Extracavitary PEL
• Before, concomitant with or after PEL
• HIV+ / HHV8 + / EBV +
• Immunoblastic ? polymorphic
• B-cell markers (4/8 patients)
• Aberrant CD3 expression
• LN ? disseminated disease (stages III-IV)
Beaty, Am J Surg Pathol 1999;23:992Chadburn, Am J Surg Pathol 2004;28:1401
HHV-8
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k l
IgM
HHV-8
HHV-8 is associated with a plasmablastic variant of Castleman disease that is linked to HHV-8-positive plasmablastic lymphoma
Dupin N, Diss TL, Kellam P, Tulliez M, Du MQ, Sicard D, Weiss RA, Isaacson PG, Boshoff C Blood 2000;95:1406-12
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Extramedullary Plasmablastic Plasma Cell Neoplasms (Multiple Myeloma, Plasmacytoma)
Ki-67
CD56 Ciclina D1 CD117
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• Young males
• Immunocompetent
• Generalized LN
• ALK-1+
• EMA, CD138
• IgA+
• CD30-
• t(2;19); t(2;5)
• Poor prognosis
DLBCL With Expression of ALK
ALK-1
EMACD138
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Pyothorax-associated Lymphoma
• History of chronic pyothorax
• Adults (median age 64 years)
• Thoracic pain + fever
• Pleural 80% (tumoral mass)
• Immunoblastic large cells
• Most cases CD20+
• Association with EBV (latency III pattern)
• 5-year survival rate ?20%
Nakatsuka et al, J Clin Oncol 2002;20:4255
CD20
LMP1
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DLBCL with Terminal Differentiated B-cell Phenotype A heterogeneous spectrum
Immunosupressed patients (HIV+/ HIV-)? Plasmablastic Lymphomas
- Oral cavity type
- PBL with plasmacytic differentiation
? HHV-8 Associated Large B-Cell Lymphomas- Primary effusion lymphoma
- Extracavitary (Solid) variant of PEL
- HHV-8 +/Castleman associated plasmablastic lymphoma
Immunocompetent patients? Extramedullary presentation of Plasma cell neoplasms (Multiple
Myeloma, Plasmacytoma)
? DLBCL expressing ALK
Differential Diagnosis? Pyothorax associated lymphoma
? DLBCL with secretory/plasmablastic differentiation
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MORPHOLOGIC VARIANTS CentroblasticImmunoblasticT-cell Rich B-cell LymphomaPlasmablastic LymphomaALK positive DLBCLLymphomatoid Granulomatosis
SUBTYPES
Primary Mediastinal B-cell Lymphoma
Intravascular Lymphoma
Primary Effusion Lymphoma
DLBCL (WHO)
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B95-8039
Primary Mediastinal (Thymic)Large B-cell Lymphoma
•5% of aggressive lymphomas
•Young females (median 30-35 years)
•Anterior mediastinal mass involving the thymus with local agressive growth
•Vena cava syndrome 30%
•Localised disease ? rare distant spread
•Disseminate to extranodal sites (kidney, adrenal, liver, skin, brain)
•EBV-
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Primary Mediastinal (Thymic)Large B-cell Lymphoma
CK
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Primary Mediastinal (Thymic)Large B-cell Lymphoma
• Asteroid medullary B-cell population
• CD19, CD20, CD79
• DO NOT EXPRESS s/c Ig
• CD10-/+, Bcl-6+/-, MUM1+/-, CD138-
• CD30w+, CD15-
• Bcl-2+, CD21-• BOB.1+, Oct-2+ • PAX5+, PU.1+ • MAL protein 70%
• Somatic IgVH mutations and BCL6mutations
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Primary Mediastinal (Thymic) Large B-cell Lymphoma
Lack of HLA class I products is the cause of the low levels of ß2-microglobulin in serum
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Primary Mediastinal B-cell Lymphoma Distinct Gene Expression Profile
Rosenwald, J Exp Med 2003
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CD30
Mediastinal Gray Zone Lymphoma
Classic HL?
CD15PMBL?
• cHL-NS or PMBL with unusual features
• Composite and metachronous
CD20
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Savage, Blood 2003;102:3871Rosenwald, J Exp Med 2003;198:851
PMBL transcriptional profile resembles that of cHL
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Mediastinal Gray Zone Lymphoma
• Intermediate between PMBL and cHL
• Lack of Ig expression
• Low levels of BCR signalling molecules
• Activation of the NF-kB pathway
• Similar gene expression profiles
• Common genomic aberrancies (2p15-REL, 9p24-JAK2 )
• B-cell transcription factor expression resemble PMBL
Environmental factors could play a favourable roleClinical studies are necessary
García, Histopathology 2005;47:101Poppema, Eur J Haematol Suppl. 2005;66:45
Traverse-Glehen, Am J Surg Pathol 2005;29:1411
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INTRAVASCULAR LARGE B-CELL LYMPHOMA
• Uncommon (<1% of NHL)
• Adults (median age 70 years)
• Extranodal (brain, skin > other sites)
• High LDH, B symptoms
• Hepatosplenic involvement (26%)
• Bone marrow infiltration (32%)
• Disseminated at diagnosis
• Overall survival usually poor
Ferreri, Br J Haematol, 2004;127:173
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CD20
INTRAVASCULAR LARGE B-CELL LYMPHOMA
• Large cells in small vessels
• CD19, CD20, CD22, CD79a
• CD5+, CD10+ few cases
• Rarely T-cell phenotype
• Abnormal or absent expressionof adhesion molecules
• IgH rearrangement
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INTRAVASCULAR LARGE B-CELL LYMPHOMA - Variants
CUTANEOUS
• Localised
• Younger patients
• Better prognosis
ASIATIC
• Haemophagocytic syndrome
• Liver, spleen
• Bone marrow CD20 CD68
Ferreri, Br J Haematol, 2004;127:173
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CD20
Retroperitoneal mass
Brain tumor
Extravascular infiltration
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Diffuse Large B-Cell LymphomaHeterogeneous Disease
• Clinical Characteristics
• Morphology
• Phenotype
• Genetic Alterations
• Oncogenic alterations
CD5CD10
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LNH AGRESIVOSINDICE PRONÓSTICO INTERNACIONAL (IPI)
Supervivencia global a 5 años, estratificados por grados de riesgo
Shipp. N Engl J Med. 1993;329:987
100
75
50
25
0
0 2 4 6 8 10
H
HILI
L
Pac
ient
es(%
)
Años
5 años5 años
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Alizadeh A, et al. Nature 2000;403:503-511
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Gene expression–defined DLBCL also likely represent different mechanisms of malignant transformation and
distinct tumor biology
Lossos, JCO 2005
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DLBCL Subgroups Recognized by Microarray May Correspond to Different Entities
Rosenwald, NEJM 2002;346:1937-1947
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NEJM 2002;346:1937-1947
N=235
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DLBCL Subgroups are Genetically Distinct
Beà, Blood 2005;106:3183-90
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CD10 Bcl-6
MUM-1 CD138
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CD10 -
+ GC
Bcl-6
Non GC
MUM-1
GC
Non GC
-
+ -
+
Diffuse Large B-Cell LymphomaImmunophenotypical approach
Germinal Center profile
Non GC profile
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Hans et al. Blood. 2004;103:275
Chang et al. Am J Surg Pathol 2004;28:464
Tzankov et al. J Clin Pathol, 2003;56:747–752
Diffuse Large B-Cell LymphomaImmunophenotypical approach
CD10 -
+ GC
Bcl-6
Non GC
MUM-1GC
Non GC
-
+ -
+
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Diffuse Large B-Cell Lymphoma Phenotype as prognostic factor
GC-like DLBCL
“Centroblastic”
CD10+ / bcl6+
Bcl2+ t(14;18)
Bcl6 expression not useful
CD5-
Extranodal
BETTER PROGNOSIS ?
ABC-like DLBCL
“Immunoblastic”
MUM1+ / CD138?
Bcl2+ BCL2 amplification
Bcl6 expression not useful
CD5+
Nodal / Specific sites
POOR PROGNOSIS ?
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Linderoth et al. Clin Cancer Res 2003.better76%CD40
Drillenburg et al. Leukemia 1999.worse76%CD44
Harada et al. Leukemia 1999.Linderoth et al. Clin Cancer Res 2003.worse
17%9%CD5
Hermine et al. Blood 1996.Hill et al. Blood 1996.Colomo et al. Blood 2003.
worse45%55%59%
Bcl-2
Years
Prob
abili
ty
.2
.4
.6
.8
1
0 2 4 6 8 10 12 14
Bcl-2-negative
Bcl-2-positive
Mounier et al. Blood 2003
p=0.004
Bcl-2 +R-CHOP
CHOP
Diffuse Large B-Cell Lymphoma Phenotype as prognostic factor
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Location in Lymphoma Classification
• Primary mediastinal large B-cell lymphoma
• Primary cutaneous large B-cell lymphoma
• DLBCL of Immnunoprivileged sites (SNC, testes)
• Follicular lymphoma
– Children
– Extranodal sites
– Duodenum (IgA)
• Skin T-cell lymphomas
• Cell of origin
• Site related immunological function
• Tumor- host Interaction
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Conclusions and Perspectives
• New information has clarified different categories and suggestedpotential new variants and entities
• Broad categories still remain heterogeneous and need additional progress
• New concepts are emerging that may be important in future efforts to define new disease entities
- Anatomic site as a parameter for classification- Identification of new entities based on expression profiles- Identification of new markers useful for the daily practice
• New information regarding pathogenesis will have significant implications for the design of clinical trials and the development of new therapeutic approaches
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http://www.ncbi.nlm.nih.gov/entrez/query.fcgihttp://www.ncbi.nlm.nih.gov/gquery/gquery.fcgi
http://www.hlda8.org/HLDAtoHCDM.htm
http://mpr.nci.nih.gov/prow/
http://www.nordiqc.org/
http://www.uscap.org/http://www.hematology.org/
LINKS