LINFOMAS B AGRESIVOS
Lluís Colomo
Hospital Clínic, Barcelona
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)
• 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)
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
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
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
• 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
BL with plasmacytoid differentiation
BURKITT LYMPHOMA - Variants
Atypical BL / Burkitt-like• Immunodeficiency
• Monotypic cIg
• Ki-67 ~ 100%
• MYC translocation
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
CD20 CD10
bcl-2 Ki-67
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)
Translocation involving MYC is a constant genetic feature in BL
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)
Blum, K. A. et al. Blood 2004;104:3009-3020
Direct and indirect consequences of c-Myc overexpression in Burkitt lymphoma
• 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
AIDS-Related Burkitt’s Lymphoma vs.Diffuse Large B-cell Lymphoma
HAART EraPre–Highly Active Antiretroviral
Therapy (HAART)
J Clin Oncol 2005;23:4430
Diffuse Large B-Cell LymphomaHeterogeneous Disease
• Clinical Characteristics
• Morphology
• Phenotype
• Genetic Alterations
• Oncogenic alterations
CD5CD10
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
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
PrimaryMediastinal Intravascular
PrimaryEffusion
HHV-8
Diffuse Large B-cell LymphomasSubtypes (clinico-pathological entities)
Centroblastic monomorphic
Immunoblastic
Diffuse Large B-cell LymphomasMorphologic Variants
Centroblastic multilobated
Centroblastic polymorphic
T-Cell/Histiocyte rich B-Cell Lymphoma
CD79a
CD57CD3
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
Anaplastic Large Cell Lymphoma
CD20 CD30
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
Monomorphic Polymorphic
PLASMABLASTIC LYMPHOMAMorphologic heterogeneity
kappa lambda
CD45 CD20 CD79a
CD3
EBER
MUM1BCL6
CD138
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
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
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
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
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
PRIMARY EFFUSION LYMPHOMA
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+
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
*
Blood, 2003
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
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
Extramedullary Plasmablastic Plasma Cell Neoplasms (Multiple Myeloma, Plasmacytoma)
Ki-67
CD56 Ciclina D1 CD117
• 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
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
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
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)
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-
Primary Mediastinal (Thymic)Large B-cell Lymphoma
CK
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
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
Primary Mediastinal B-cell Lymphoma Distinct Gene Expression Profile
Rosenwald, J Exp Med 2003
CD30
Mediastinal Gray Zone Lymphoma
Classic HL?
CD15PMBL?
• cHL-NS or PMBL with unusual features
• Composite and metachronous
CD20
Savage, Blood 2003;102:3871Rosenwald, J Exp Med 2003;198:851
PMBL transcriptional profile resembles that of cHL
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
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
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
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
CD20
Retroperitoneal mass
Brain tumor
Extravascular infiltration
Diffuse Large B-Cell LymphomaHeterogeneous Disease
• Clinical Characteristics
• Morphology
• Phenotype
• Genetic Alterations
• Oncogenic alterations
CD5CD10
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
Alizadeh A, et al. Nature 2000;403:503-511
Gene expression–defined DLBCL also likely represent different mechanisms of malignant transformation and
distinct tumor biology
Lossos, JCO 2005
DLBCL Subgroups Recognized by Microarray May Correspond to Different Entities
Rosenwald, NEJM 2002;346:1937-1947
NEJM 2002;346:1937-1947
N=235
DLBCL Subgroups are Genetically Distinct
Beà, Blood 2005;106:3183-90
CD10 Bcl-6
MUM-1 CD138
CD10 -
+ GC
Bcl-6
Non GC
MUM-1
GC
Non GC
-
+ -
+
Diffuse Large B-Cell LymphomaImmunophenotypical approach
Germinal Center profile
Non GC profile
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
-
+ -
+
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 ?
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
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
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
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
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