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Lymphomes diffus Lymphomes diffus àà grandes cellules Bgrandes cellules BClassification des diffClassification des diff éérentes entitrentes entit ééss
T. J. MolinaT. J. Molina
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Diffuse large B Diffuse large B cellcell lymphomaslymphomas
Definition
Lymphomas defined by a neoplasm of large lymphoid
B-cells with nuclear size equal to or exceeding normal
macrophage nuclei or more than twice the size of a
normal lymphocyte
That has a diffuse growth pattern
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Immunophénotype
• Les cellules tumorales expriment :– CD20, CD79a, mais peuvent perdre certains
marqueurs
– immunoglobuline intracytoplasmique quand il y a une différenciation plasmocytaire
– CD30 dans les variantes anaplasiques et dans quelques formes non anaplasiques
– CD10 (25-50%), CD5 (10%)
– Ki67; habituellement plus de 40%
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Morphological, biological and clinical studies have subdivided DLBCL into• Morphological variants• Molecular and immunophenotypical
subgroups• Subtypes• Distinct disease entities
WHO 2008 Classification of DLBCL
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Diffuse large B-cell lymphoma subtypesT-cell rich large B-cell lymphomaPrimary DLBCL of the CNS Primary cutaneous DLBCL, leg typeEBV positive DLBCL of the elderly
Other lymphomas of large B-cellsPrimary mediastinal (thymic) large B-cell lymphomaIntravascular large B-cell lymphomaDLBCL associated with chronic inflammation (EBV)Lymphomatoid granulomatosis (EBV)ALK positive DLBCL (ALK )Plasmablastic lymphoma (EBV)Large B-cell lymphoma arising in HHV-8 associatedmulticentric Castleman disease (HHV8)Primary Effusion lymphoma (HHV8, EBV)
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Diffuse Large B-cell lymphomas, not otherwise specified (NOS)
Common morphological variantsCentroblasticImmunoblasticAnaplastic
Rare morphological variantsMolecular subgroups
Germinal centre B-cell like (GC-B)Activated B-cell like (ABC)
Immunohistochemical subgroupsCD5+DLBCLGerminal Centre B-cell like (GCB)Non Germinal centre B-cell like (non-GCB)
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Importance of assessing if this lymphoma arises de novo or is developing from
B-CLL (Richter Syndrome )Follicular lymphomaMarginal zone lymphomaNLPHL (Nodular Lymphocyte
Predominance Hodgkin lymphoma )
Crucial role of the size of the sample +++++
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OTHER DIFFICULT DIFFERENTIAL DIAGNOSES
Mantle cell lymphoma , aggressive , pleomorphic subtypeCyclin D1 DLBCL do exist
CD5+ DLBCL is a phenotypical subtype
Is this a transformed small B-cell lymphoma?Follicular Lymphoma
Marginal zone lymphoma
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Centroblastic
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Centroblastic multilobated
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Immunoblastic
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Anaplastic
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Plasmablastic
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DLBCL NOS , Molecular subgroups
• GC like DLBCL
• Activated like DLBCL
• Other (According to Wright/type III).
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Alizadeh et al, 2000
Cell of Originsignature
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Lenz , NEJM, 2008
Molecular subgroups defined by GEP or QRTPCR impacts on survivalIndepedently from IPI among R-CHOP treated DLBCL patients
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Classification OMS des DLBCL NOS
• Immunohistochemical subgroups– Germinal center B-cell (GC-B)
– Non germinal center B-cell (n-GCB)
– CD5 positive DLBCL
Lymphome à grandes cellules B du médiastin à part (entité)
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C Hans et al, Blood 2004
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PN Meyer, 2011
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GC/nGC according to Hans’algorithmis not reproducibly prognostic in
DLBCL treated by R-CHOP
• Nyman 2007,
• Saito 2007,
• Copie-Bergman 2009,
• Ott G 2010,
• Gutierrez Garcia 2011,
• Salles G, 2011
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Prognostic forMeyer N, JCO, 2011
Not prognostic forGuttierez Garcia, Blood 2011
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Autres algorithmes
• Combiner FISH + IHC : Immunofish, Copie-Bergman, 2009– Mum-1 (30%), foxp1 (0 vs P), FISH bcl6 : 2 parmi trois marqueurs
positifs
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Multivariate analysisIPI : p= 0.04nGC score : p=0.04
Copie-Bergman et al, JCO, 2009
ImmunoFISH négatif
ImmunoFISH positif
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Ces biomarqueurs peuvent ils être prédictifs?
• Identifier la population cible, la plus susceptible de répondre
• Guide parmi les options thérapeutiques
– C Thieblemont : BioCoral
– O3-2B: RACVBP vs RCHOP
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Primary Mediastinal Large B-celllymphoma (PMLBCL)
• Variant of DLBCL derived from a putative thymic B-cell (asteroid variant of thymicmedullary B cell)
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LM A GRANDES CELLULES B PRIMITIF DU MEDIASTIN ( THYMIQUE )
- Clinique• Adulte jeune, F > H• Tumeur médiastinale antérieure
- Histopathologie• LM diffus• Grandes cellules +/- cytoplasme clair
•Cbl, Ibl, parfois de type RS• Sclérose• Lymphocytes réactionnels ,histiocytes, plasmocytes, éosinophiles
-Cellule d’origine
Cellule B intrathymique
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• No expression of immunoglobulins but expression of pu-1, bob2, oct 1
• Activation of NF-κB with nuclear expression of c-rel
• Functional rearrangement of IgH withoutintraclonal variation.
• No rearrangement of bcl-2 and rare bcl-6 rearrangement
Thymus IF CD79a / MAL
Copie Bergman, 2002
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The gene expression signature of PrimaryMediastinal B Cell Lymphoma
A Rosenwald et al. J Exp Med, 2003A Rosenwald et al. J Exp Med, 2003
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RosenwaldJEM, 2003
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Georg Lenz, M.D., and Louis M. Staudt,.N Engl J Med 2010; 362:1417-1429
Mutations of SOCS1 in classicalHodgkin lymphoma are frequent(Wenger et al, Oncogene, 2006)
8/19 HL patients and 3/5 cell lines
A20 is a tumor suppressor gene in CHL And PMBL.( Schmitz R, J Exp Med, 2009)
A20 which negatively regulates NF-KB ismutated in 40% of PMBL and CHL; in CHL, mostly in EBV negative cases.
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MHC Cl II transactivator CIITA is rearranged in 38% PMBL and 15%CHL
STEIDL C , Nature, 2011
• Translocation partner : in PMBL, half of the cases PDL1, PDL2 with overexpression and downregulation of MHC cl II.
• CIITA rearrangement in 4%DLBCL (11% testis) and in 15% NLPHL.
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T-cell Histiocyte Rich large B-cell lymphoma
- Histopathology
• difuse infiltration
• large B-cellsLimited numbers (< 10% cells)Scattered cellsNo sheetsCb, Ibl, anaplastic,rare RS-like cells
• Numerous reactive cellsT lymphocytes histiocytes
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- Immunophenotype• tumor cells
CD20+, EMA +/-CD15-, CD30-, LMP1-
• Reactive cells
CD3 +Low number of PD1+
• No FDC network
- diagnostic différentiel• CHL • NLPHL•T cell lymphoma
CD20
T-cell/ histiocyte rich large B-cell lymphomas
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Immunohistochemical study
• CD20+
• CD30 :2/46
• EMA: 34/38
• CD15 : 0/38
• few CD57+ cells
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Specific Clinical Characteristics of Patients With T-Cell/Histiocyte-Rich Large B-Cell Lymphoma
TCRBCL DLBCL p(n = 50) (n = 150)
Sex, male/female, n 44/6 82/68 < .0001
Cervical 34 33 .90
Axillary 52 24 .0002
Mediastinal 30 46 .02
Lumboaortic 54 38 .02
Mesenteric 32 24 .30
Inguinal 30 21 .20
Pelvis 38 16 .002
Spleen 60 17 < .0001
Bone marrow 31 26 .50
Liver 33 11 .001
Gastrointestinal tract 0 10 .005
Bone 4 12 .01
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Bouabdallah et al, J Clin Oncol 2006; Anthracyclin based therapyWithout rituximab
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• HU 133A et U 133 B, 33 000 gènes• 176 patients (série de validation : 221)• Unsupervised clustering (three profiles highly
reproducible)– oxydative Phosphorylation– BCR proliferation cluster– Host immune response
• No prognostic vaue
Monti, Blood, 2004
Microenvironment and DLBCL
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Gamma interferonInduced lysosomalthiolreductase
FewCD1a or CD123;
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LM B PRIMITIF DES SEREUSES
- Définition• Lymphome se développant
essentiellement dans lescavités des séreuses: pleurale
péricardiqueabdominale
• En l’absence habituelle de massetumorale
• ≠≠≠≠ extension 2 d d’un LM à grandescellules B
- Clinique•Epanchement pleural sans tumeursolide
HIV+, EBV+, HHV8+
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Immunophénotype
• Absence d ’expression de CD19, CD20, CD79a, cIg
• expression de CD45
• expression aberrante de CD3
• protéine latente HHV8, EBER1+, LMP1-
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LM A GRANDES CELLULES B INTRAVASCULAIRE
- CliniqueAdulteLésions cutanéesSymptomes neurologiquesHépatosplénomégaliePancytopénie, CIVD
- Histopathologie• Grandes cellules (Cb, Ib, anaplasiques)• Dans les petits vaisseaux
sinus (moelle osseuse, rate)sinusoïdes (foie)capillaires (peau, cerveau, poumon)
• Histiocytes avec Erythrophagocytose
- ImmunophénotypePan B+
CD20
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Lymphome B de type granulomatose lymphomatoïde
– Lésion lymphoproliférative angiocentrique et angiodestructrice , extranodale, comportant des cellules lymphoïdes B de grande taille associées à l ’EBV et des lymphocytes T le plus souvent nombreux
» grade histologique (I, II, III) selon la proportion de grandes cellulesB.
» Le Grade III est considéré comme une variante de lymphome diffus à grandes cellules B
– Evolution en 2 à 5 ans du grade I au grade III. L ’Alpha-interferon pourrait contrôler les grades I et II.
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– Masses pulmonaires nécrotiques• Nombreux lymphocytes T réactionnels ,
histiocytes et polynucléaires neutrophiles• Vasculite lymphocytaire et nécrose fibrinoïde• grandes cellules lymphoïdes B EBV+ de
morphologie centroblastique ou immunoblastique– dispersées ou de topographie périvasculaires, infiltr ant
la paroi des vaisseaux, réalisant un aspect angiocentrique
– Autres localisations : cerveau (26%), rein(32%), foie (29%),peau (25-50%)
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CD20
LMP1
MIB1 EBER
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Other subtypes/entities
• Primary DLBCL of the CNS– Intracerebral and/or intraocular,mum-1+
• Primary cutaneous DLBCL, leg type– N-GC phenotype, female 7th decade
• EBV positive DLBCL of the elderly– More than 50 year-old, noimmunodeficiency, mum1+, polymorphic
subtype• DLBCL associated with chronic inflammation (EBV)
– Pyothorax associated lymphoma, osteomyelite chronic– More than 10 years inflammation– CD20, CD79a often positive, CD138+/-, T- cell markers
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Other subtypes/entities
• ALK Positive DLBCL– Lymph nodes, Immunoblast with plasma cell
differentiation, CD138, EMA, IgA, CD20 neg, CD79a neg, CD45 neg,mum1+.
• Plasmablatic lymphoma– Oral cavity ,other extranodal sites, HIVpositive, CD138,
CD30, EMA, EBER, IgG• Large B-cell lymphoma arising in HHV-8 associated
multicentric Castleman disease (HHV8)– IgM plasmablast EBER neg IgM lambda present in mantle zone areas
at the beginning
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Borderline cases
B-cell lymphoma, unclassifiable, with featuresintermediate between DLBCL and Burkitt lymphoma
B-cell lymphoma, unclassifiable, with featuresintermediate between DLBCL (PMBL) and classicalHodgkin lymphoma
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LYMPHOME DE BURKITTsous-types, cliniques et génétiques
- EndémiqueAfrique et autres régions tropicalesEnfant++, Mâchoire++Association à EBV: > 90%Rôle de la malaria
- SporadiqueLocalisation intraabdominale+Ganglion, plus fréquent chez l’adulteAssociation à EBV: 20%
- Associé à une immunodéficienceLa plupart HIV+Souvent ganglionnaireAssociation à EBV: 40%
EBER
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- Histopathologie
• Infiltration diffuse• Aspect de ciel étoilé• Cellules cohésives• Cellules de taille moyenne• Fine couronne cytoplasmique
basophile avec des vacuoleslipidiques
• Noyau rond, +/- irrégulier• Chromatine en mottes• Multiples (2-5) nucléoles
centraux, de taille moyenne• Nombreuses mitoses
LYMPHOME DE BURKITT
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LYMPHOME DE BURKITT
- Immunophénotype
Pan B+, sIgM+,
bcl-6+
CD10+, bcl2- , Ki67 > 90%
CD5-, CD23-, TdT-
- Biologie moléculaire
• t(8;14)(q24;32) et variantes
• réarrangement de c-myc
CD10
Mib-1
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BURKITT LYMPHOMA
CD10
Mib-1
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CD10
MIB1 BCL2
Sporadic Burkitt, Child, EBV -
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MIB1BCL2
Diffuse Large B-cell Lymphoma or Intermediate BL/DLBC L?
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Recommandation WHO
• Look for myc rearrangement
• Look for double hit lymphoma ((bcl2/myc, bcl6/myc, bcl2/bcl6/myc).
• Double hit particularly myc/bcl2 have a worseprognosis compared to paired DLBCL – May qualify for intermediate features between BL and
DLBCL
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Controversy
• Intermediate Molecular Burkitt have been definedby GEP and correlated with genome complexity. (Hummel, NEJM, 2006)
• Not by atypical morphology and /or phenotype as in WHO– might increase according to the WHO numbers of
intermediate features
– Therefore, lack of consensus criteria to define thosecases that might benefit from alternative therapy thanclassicalDLBCL.
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Hummel, NEJM, 2006
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Borderline cases
B-cell lymphoma, unclassifiable, with featuresintermediate between DLBCL and Burkitt lymphoma
B-cell lymphoma, unclassifiable, with featuresintermediate between DLBCL (PMBL) and classicalHodgkin lymphoma
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B-cell lymphoma, unclassifiable, withfeatures intermediate between ClassicalHodgkin Lymphoma (CHL) and Diffuse
large B- cell Lymphoma (DLBCL).• Composite or Sequential
– Both entities within the same patient at the same time (C)
– To differentiate from metachronously occurrence of NSHL and PMBCL (S)
• Intermediate features– between CHL and PMBL
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Intermediate Features areExceptional !!
Most often PMBL or CHL
Or other diagnosis…..
In big centers specialised inHematopathology includingLocal cases and consult cases
Max : 1-2 cases per year.
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CD20 CD3
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CD30
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TiA1
CD7EMA
ALK 1
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TTake Home Message
• Except PMLBL, entities of DLBCL are rare+++
• A CD5+ agressive B cell lymphoma :exclude MMantle cell lymphoma aggressive variant
before assessing CD5+ DLBCL
• DLBCL are not rarely transformed
• FISH is important in addition to immunohistochemistry, specially Myctranslocation– Burkitt/ Double hit lymphoma
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Department of Pathology