Lymphomes T et NK Philippe Gaulard, CHU Henri Mondor, Créteil, France
Lymphomes T et NK 15% des lymphomes (Occident) Identification récente (Kiel, REAL, OMS) Hétérogénéité morphologique ---> relevance clinique? MZL 3% MZL, MALT 8% follicular 22% others 6% anaplastic T/null 2% Plusieurs entités anatomo-cliniques (OMS): - proliférations T et NK - 1/3 = extra-ganglionnaire Biologie mal connue DLBCL 35% PTCL 7% lymphoblastic 2% Burkitt 1% Altérations moléculaires Traitements innovants
D après Feller et al
BIOMED-2 Concerted Action BMH4-CT98-3936: PCR-based clonality studies PCR analysis of TCRG gene rearrangements Vγ Jγ VIf γ V9 γ V10 γ V11 γ Jγ1.3/2.3 Jγ1.1/2.1 V γ family primers J γ primers TCRG tube A: VγIf and Vγ10 primers + Jγ1.1/2.1 primer (blue) and Jγ1.3/2.3 primer (green) polyclonal lymphocytes TCRG tube A: VγIf Vγ10 Jγ1.1/2.1 Jγ1.3/2.3 * monoclonal T-cell leukemia TCRG tube A: VγIf Vγ10 Jγ1.1/2.1 Jγ1.3/2.3 * JJM van Dongen et al. Leukemia, 2003
LYMPHOMES T et NK - CYTOGENETIQUE - T-Lymphoblastique T-Prolymphocytique Anaplasique (systémic) del 1p32 (25%) <-------> TAL1 inv14q(q11-q32) <-----> TCL1 t(x;14)(q28;q11) <---> MTCP1 t(2;5) ou t(2;?) <-------> ALK(2p23) Angio-immunoblastique trisomie 3, trisomie 5 (?) NK, nasal del(6)(q21-q25) (?) Type entéropathie +9q (9q33) (?) Hépatosplénique iso 7q (?)
LYMPHOMES T et NK - Caractères communs - HISTOPATHOLOGIE : - infiltration préférentielle interfolliculaire - pléomorphisme (cell. Tumorales) - hyperplasie vasculaire - polymorphisme (cell. réactionnelles) <--> diagnostic difficile PHENOTYPE : - CD3e + (rarement -), CD20 - - fréquente perte antigénique (marqueur indirect de clonalité?) GENOTYPE : - réarrangement clonal des génes des TCR CD3
HES CD4 CD3 CD7
Precursor T-lymphoblastic lymphoma/leukemia (T-ALL/LBL) T-cell prolymphocytic leukemia T-cell granular lymphocytic leukemia Aggressive NK-cell leukemia Adult T-cell lymphoma/leukemia (HTLV1 +) Peripheral T-cell lymphoma, unspecified Angioimmunoblastic T-cell lymphoma Anaplastic large cell lymphoma, primary systemic type Extranodal NK/T-cell lymphomas, nasal type Enteropathy-type T-cell lymphoma Hepatosplenic (γδ) T-cell lymphoma Subcutaneous panniculitis-like T-cell lymphoma Mycosis fungoides/sezary syndrome Anaplastic large cell lymphoma, primary cutaneous type
T-lymphoblastic lymphoma/leukemia children, young adults mediastinal mass (>70%), with associated symptoms cervical lymphadenopathy (50-60%) abdomnal involvement very unusual high LDH level tendency to involve bone marrow, blood, CNS
Lymphome Lymphoblastique Formol Bouin
T-lymphoblastic lymphoma/leukemia Immature/thymic phenotype, with variation according to stage of thymocyte differentiation: - CD3(cyto) +, CD20 - - TdT +, CD1+ (50% cases), CD10+/- - CD7+, CD2+, CD4-/CD8- or CD4+/CD8+ - High MIB1/Ki67 rate (>70%) Genetics : - clonal rearrangement of TCR genes - translocations at 14q11(α/δ), 7q35(β), 7p14(γ) - deletion/translocation in the TAL1 locus (>25%)
CD20 CD3
Mib1
T-lymphoblastic lymphoma/leukemia - differential diagnosis - B-lymphoblastic lymphoma/leukemia: similar morphology, also Tdt+, CD10+, but B-cell phenotype and different clinical presentation (not mediastinal) Blastic variant of Mantle cell lymphoma Thymoma (cytokeratin; difficult on small biopsies) Neuroendocrine tumours : cytokeratin, chromogranin, CD56 Reactive lymphoid infiltrates (value of mitosis/mib1, cytology) [* The 3 latter diagnosis may be confusing, almost on
T- and NK-cell lymphomas a diagnostic and therapeutic dilemma WHO classification, 2001 leukemic nodal extra-nodal prolymphocytic angioimmunoblastic mycosis/sezary T-LGL leukemia peripheral, unsp. primary cutaneous anaplastic Aggressive NK leuk/lymph ALCL subcutaneous panniculitis ATL/L (HTLV-1) enteropathy-type NK/T nasal(-type) hepatosplenic (γδ) - relies upon clinical, phenotypic, sometimes molecular data
T- CELL LARGE GRANULAR LYMPHOCYTE (LGL) LEUKEMIA Clonal disease of LGLs Blood smears (++) (1,2-2x10 9 L, >6months) Flow cytometry (++) CD3+, CD57+ CD8+,TCRαβ+ CD56-, CD16+ Clonal TCR gene rearrangement IAP 2002, Amsterdam
T- CELL LARGE GRANULAR LYMPHOCYTE (LGL) LEUKEMIA indolent disorder increased number of LGLs (>2x10 9 /L, >6 mo) adults, frequently asymptomatic neutropenia ------> recurrent infections, anemia frequent serologic abnormalities (RF++, ANA,..) moderate splenomegaly (50%) IAP 2002, Amsterdam
T - CELL LARGE GRANULAR LYMPHOCYTE (LGL) LEUKEMIA Cell lineage: -T αβ (++) : * CD3/TCR +, usually CD8+, * CD57+, CD56-, CD16+, * clonal TCR gene rearrangement -T γδ : rare cases - NK (??) : * CD3s-, TCR-, CD3ε+, Activated cytotoxic profile (TIA1+, perforine+, Granzyme B+) IAP 2002, Amsterdam
CD8 CD8 GrB
T - CELL LARGE GRANULAR LYMPHOCYTE (LGL) LEUKEMIA disease entity, limited to mature clonal proliferations of «small» LGL, with indolent clinical presentation proliferation of activated cytotoxic T lymphocytes (CTLs) of unknown antigen specificity alteration of the Fas-Fas ligand pathway (blockade of Fas-dependent apoptosis, Liu JH et al. Blood 2002;100:1449), which could result in: - autoimmune manifestations - lymphoproliferative syndome IAP 2002, Amsterdam
T : CD 3+, CD 3/TCR+, TCR genes rearranged «activated cytotoxic T cells» T-LGL leukemia LGL NK : CD 3s -, CD 3/TCR - no rearrangement of TCR genes EBV,? Nk «indolent» LGL Leukemia? Aggressive NKcell leukémia Both cell subsets mediate «non-mhc» restricted cytotoxicity
Aggressive NK cell Leukemia/lymphoma
AGRESSIVE NK-CELL LEUK/LYMPHOMA Usually presents as disseminated disease with : - hepatosplenomegaly - constant systemic symptoms - cytopenia, + lymphocytosis (mild leukemic phase) - most frequent in Asians common other sites of involvement ( LN, GI tract, skin,...) frequent hemophagocytic syndrome aggressive clinical course cyto/histology: medium and/or large cells, often monotonous systemic proliferation of NK cells
AGRESSIVE NK-CELL LEUK/LYMPHOMA Cytology : «large» atypical lymphocytes with granules CD3/Leu4-, TCR-, CD3ε+ CD5-, CD56+, CD57- TIA1+, perforine+, Gr B+ no TCR gene rearrangement Cytogenetics: del 6q, del 13q EBV association (clonal episomal form)
CD5 CD3ε CD56
AGRESSIVE NK-CELL LEUK/LYMPHOMA Cytology : «large» atypical lymphocytes with granules CD3/Leu4-, TCR-, CD3ε+ CD5-, CD56+, CD57- TIA1+, perforine+, Gr B+ no TCR gene rearrangement Cytogenetics: del 6q, del 13q EBV association
AGRESSIVE NK-CELL LEUK/LYMPHOMA disease entity, restricted to proliferations of atypical (large) NK cells, with aggressive systemic presentation may represent the leukemic/systemic variant of extranodal NK/T cell lymphomas, nasal-type. role of EBV in their pathogeny? - clonal episomal form - viral genes + secretion of cytokines (IFN-γ, TNF-α,...) could promote cell proliferation and favour the occurrence of hemophagocytic syndrome, as recently shown in animal model (Hayashi et al. AJP 2001;158:1533)
EBV LMP- 1 Suppression of hematopoiesis disturbances of lipid metabolism phagocytosis + T/N K TNF-α IFNγ,... MA C + Cytokines (TNFα, INF-γ, Il 1 α) IFN-γ ; TNF-α +? Lay JD et al, J Clin Invest. 1997, 100 : 1969 Herpes virus Papio induces fatal lymphoproliferative disorders with HPS in rabbits. Hayashi et al, Am J Pathol 2001 ; 158 : 1533
Lymphome/Leucémie T de l adulte (HTLV1+) Lymphome T périphérique causé par HTLV1 Epidémique : Sud Japon, Caraïbes Morphologie variable: ptes, moyennes, grandes cellules; noyaux convolutés (en fleur) Phénotype: CD3+, CD4+, CD7-, CD25+ Génotype: intégration clonale du génome HTLV1 Variantes cliniques: «smoldering» chronique lymphomateux aigüe
LYMPHOMES T et NK «MATURES» PRESENTATION GANGLIONNAIRE LYMPHOME T ANGIOIMMUNOBLASTIQUE LYMPHOME T PERIPHERIQUE, sans autre spécificité (Unspecified) LYMPHOME ANAPLASIQUE SYSTEMIQUE (à grandes cellules) (T ou nul)
LYMPHOME T ANGIO-IMMUNOBLASTIQUE Décrit comme une affection dysimmune 20-40% des LTP Tableau clinique particulier: age moyen>60 ans, signes généraux, polyadp, rash cutanés, hyperγglobulinémie, Coombs+,.. Difficulté du diagnostic reposant sur un faisceau d arguments immunomorphologiques (cell. T taille moyenne, IBS- B, prolifération de CFD) et moléculaires (TCR γ R :80%, IgH R :20 40%) Pronostic sombre (30-35% à 5 ans) origine cell? : cell T FH? (Tαβ CD4+) pathogénie? : rôle de cytokines, EBV?, événement oncogènique Ire?
CD3 CD20 EBV CNA-42
HES CD20/CD10 CD10 CD3 ECD 10 0 10 1 10 2 10 3 10 4 The majority (#75%) of AITL express CD10 10 0 10 1 10 2 10 3 10 4 CD10 PE
ANGIOIMMUNOBLASTIC T-CEL LYMPHOMA 158 pts, GELA median age: 62 y B symptoms : 72 % Stage III - IV disease : 81% BM involvement : 47% splenomegaly : 55% hepatomegaly : 31% Skin rash : 44% Tumoral mass >10 cm : 26% IPI score > 2 : 89% Anemia (Hb<12 g/dl) : 65% Coombs test + : 33% Gammaglobulin (>12g/L): 50% Monoclonal gammopathy : 15% Hypoalbulinemia : 50% B2 microglobulinemia >1N : 66% LDH >1N : 66% Median-follow-up = 69 months 5 year OS = 33% Anthracyclin-based chemotherapy: 148 pts (N Mourad et al. GELA, LNH 87 93)
ANGIOIMMUNOBLASTIC T-CELL LYMPHOMA - MORPHOLOGIC VARIANTS - «Classical» (diffuse, patterns II/III of Attygale) Follicular hyperplasia (Patterns II/III of Attygale, «early phase»?) Epithelioïd cell rich Clear cell rich Histologic «progression/transformation» (?) - AITL with significant number of large/clear T cells - «PTCL, unspecified» - Diffuse large B cell Lymphoma (EBV+) Attygale et al. Blood, 2002; Lee et al. Int J Cancer, 2003
AITL, epitheliod cell rich variant
AITL, clear cell rich variant
AILT with hyperplastic germinal centers (pattern I) In a retrospective study of consecutive biopsies, 7/35 cases (20%) showed progression from pattern I to pattern II/III (typical AITL) (Attygale et al. AJSP, 2007) CD10 CD3
AILT and «histological progression» «PTCL-U like, 1/35» «EBV-associated B-cell LPD, 7/35» Attygalle et al. AJSP, 2007 Attygale et al. AJSP, 2007
Molecular signature of AITL : - cell origin? - pathogeny? Principle Component Analysis (PCA) AITL (n=18) PTCL-U (n=16) Affymetrix HG-U133 plus 2.0 L de Leval et al. Blood. 2007
Molecular signature of AITLs Cell to cell communication CD10, CD151, CD200, CD40L, MAL, PDCD1 cadherins, integrins Vascular biology angiopoietin 2, VEGF, PGF, thrombomodulin, alpha-2 antiplasmin THY1, selectin, VCAM, gap junctions proteins Humoral immune response B-cell transcription factor, Ig, syndecan, clusterin, complement components Chemokines and cytokines CCL19, CCL22, CCL24, CCL26, CXCL13, CXCL14, IL4, LIF Extracellular matrix components, matrix modelling Tumor cell genes reported to be TFH-specific Laminin, fibronectin, ladinin, collagens, MMPs, TGFb, FGF, FOXF1 Others NFATC1, PIM2, VAV2 L de Leval et al. Blood 2007
Follicular helper T cells (T FH ) Vinuesa CG et al. Nature Reviews Immunology, 2005 Gene expression signature of CD4+ CD57+ CXCR5+ tonsillar cells Kim CH et al. Blood (2004)104: 1952 Chtanova T et al. J Immunol (2004)173: 68 Chtanova T et al. J Immunol (2005) 175: 7837
A. GS3_TFH_up P = 0.009 AITL signature is enriched in T FH genes C. T subsets AITL PTCL+ AITL SNR PTCL-U B. 42 core genes GS3_TFH_up AITL cell Fold change AILT tissue
Expression of CXCL13 by neoplastic cells in angioimmunoblastic T-cell lymphoma (AITL) Dupuis J. et al. Am J Surg Pathol 2006; 4:490 Grogg KL et al. Blood. 2005; 106:1501-2 Grogg KL et al. Modern Pathol 2006; 19:1107 CD5/CXCL13 CD10/CXCL13
New diagnostic T FH markers useful in routine practice for the diagnosis of AITL PD1 is expressed in 85 95% of AITL PD1 CXCL13 PD1 and CXCL13 are expressed in 85-100% of AITL Dorfman DH et al. Am J Surg Pathol, 2006 Roncador G et al. Haematologica, 2007 H
ANGIOIMMUNOBLASTIC LYMPHOMA - DIFFERENTIAL DIAGNOSIS - 1 - Reactive «dysimmune» lymphadenopathies : --------> look for the presence of atypical (mediumsized, +/-pleomorphic) CD3+ cells 2 - Other T-cell lymphomas: - if numerous pleomorphic T cells: PTCL, unspecified, - if «epitheliod rich»: PTCL, unsp (Lennert s variant) 3 - T-cell rich large B-cell lymphoma 4 - Hodgkin s disease (when atypical polylobated CD30+ cells)
AITL - Diagnostic criteria - Morphological architecture of AITL Clear cells, atypia (moderate) within the CD3+, CD5+ T cells (irregular nuclei, mediumsized): - CD10+ phenotype - Expression of TFH markers (CXCL13, PD1) Demonstration of an FDC meshwork (CD21, CD35, CD23,..) Presence of scattered large CD20+ B cells EBV association (scattered LMP1+ cells) Clonal T cell population (PCR γ ), (however associated to B cell clone (IgH) Clinical and biological features
LYMPHOMES T et NK «MATURES» PRESENTATION GANGLIONNAIRE LYMPHOME T ANGIOIMMUNOBLASTIQUE LYMPHOME T PERIPHERIQUE, sans autre spécificité (Unspecified) LYMPHOME ANAPLASIQUE SYSTEMIQUE (à grandes cellules) (T ou nul) ALK+ LYMPHOME ANAPLASIQUE à grandes cellules (T ou nul) ALK- (entité provisoire;oms, 2008)
LYMPHOME T PERIPHERIQUE, sans autre précision Le plus fréquent des LTP Tableau clinique : adultes, souvent mal. Disséminée (polyadp, BM+, ), Diagnostic d exclusion : - Morphologie variable, svt pléomorphe, avec qq variantes (Lennert s, T-zone, «Tfolliculaire», ) - absence d anaomalie cytogénétique caractéristique Evolution agressive (30% survie à 5 ans) origine cell? : Th1, Th2 pathogénie? Probablement, plusieurs catégories dont la frontière avec T-LAI et ALK- ALCL n est pas définie
PERIPHERAL T-CELL LYMPHOMA (PTCL), UNSPECIFIED MORPHOLOGICAL ASPECTS : «Pleomorphic» : small medium lymphoid cells large Lymphoepithelioid (Lennert s) lymphoma T-zone lymphoma
PTCL-u : Lennert s lymphoma variant Feb 2003 CD8
U1 PTCL-u : molecular heterogeneity U2 PTCL-U3 Histiocytic markers IFNγ /STAT1/ JAK2 pathway HLA-II CD14 CSF1 CCL2 CCL4 CD44 Cath-B Cath-C STAT1 JAK2 CXCL-9 CXCL-10 GBP1 IFI-30 cbl-b Histological correlations: moderate to high amounts of reactive histiocytes (includes so-called Lennert s lymphoma) Ballester B et al. Oncogene, 2006
CD30+ PTCL: a distinct molecular signature with similarities to that of ALKnegative ALCL? Principle Component Analysis (PCA) AITL (n=18) PTCL-U (n=16) Affymetrix HG-U133 plus 2.0
The signature of PTCLs-u compared to that of normal T cells: new targets for therapy? PDGFRa P- PDGFRa Imatinib Histone deacetylase inhibitors PP Piccaluga et al. J Clin Invest, march 2007
An example of CD30+ PTCL-u CD30 EMA-, ALK-, absence of cytotoxic molecules CD2
Un sous-type Type de «lymphome follicular T lymphoma d achitecture» folliculaire, Associé à translocation t(5;9) (SYK/ITK)? Pt 23: t(5;9) positive CD3 #7: CD3+/CD4+/CD10+/CD57+/CXCL13+/PD1+/LMP+ B-immunoblasts CD57
- Conclusion - AITL : a tumour of T FH The demonstration of molecular analogies between AITL and T FH supports the hypothesis that AITL derives from T FH cells CD10/CNA-42 CD10 In agreement with the pathological, clinical and biological features of the disease. Tight interaction between FDC and neoplastic cells CXCL13 induces FDC proliferation, through lymphotoxin secretion by B cells
Follicular «helper» T cells (T FH ) T FH centrocytes BCA-1=CXCL13 CXCR5 CXCL13 Bcl6 Il6R IL21 T-LAI (de Leval et al. Blood 2007) centroblastes CD84 CD40L CD200/OX2 ICOS PTCL-F? T FH cells provide help to germinal-centre B new diagnostic markers (CXCL13, PD1,..) PD1 cells, independently of CD57 expression molecular alterations targeting T FH? Therapeutic targets? Vinuesa CG et al. Nat Rev Immunol, 2005
Non anaplastic T cell Lymphoma 120 Percent Survival 100 80 60 40 20 p = 0.0001 B = 1595 T = 228 0 0 20 40 60 80 100 Months from start of treatment
LYMPHOMES T et NK «MATURES» PRESENTATION GANGLIONNAIRE LYMPHOME T ANGIOIMMUNOBLASTIQUE LYMPHOME T PERIPHERIQUE, sans autre spécificité (Unspecified) LYMPHOME ANAPLASIQUE SYSTEMIQUE (à grandes cellules) (T ou nul) ALK+ LYMPHOME ANAPLASIQUE à grandes cellules (T ou nul) ALK- (entité provisoire;oms, 2008)
LYMPHOME T ANAPLASTIQUE A GRANDES CELLULES (systémique) 10-20% des LTP Tableau clinique : fréquence enfant et sujets jeunes, atteinte ganglionnaire, Morphologie: cell «halmark», distribution intrasinusale/perivasculaire IHC : CD30+ (100%), EMA+, CD3 + (het)/cd20 -, or CD3 -/CD20 -, cytotoxique activé (Perf +/GrB +), ALK + (50-85 %) Translocation t(2,5) ou variante t(2;?) impliquant ALK, de valeur clinique et biologique Bonne réponse au Trt (>70% survie à 5 ans) pour les formes ALK Les LNH «Anaplasiques» ALK+ et ALKn appartiennent à la même entité (classification OMS 2008)? Les ALK- ALCL sont-ils proches des PTCL-U CD30+? CD30
LYMPHOME T ANAPLASTIQUE A GRANDES CELLULES (systémique) CD30 Falini et al. Blood, 1999
ANAPLASTIC LARGE-CELL LYMPHOMA (T-and null-cell types) MORPHOLOGY : Cytology <--> halmark cell : large cell with an eccentric (horse shoe, kidney shaped) nucleus Architecture : - often diffuse and massive, - sometimes interfollicular, - look for intrasinusal infiltration perivascular distribution
Lymphome anaplasique à grandes cellules CD30+, CD20-, CD3-, CD2+, GrB+, ALK1- CD3 0
ANAPLASTIC LARGE CELL LYMPHOMA (SYSTEMIC, T-null) CD30 + (virtually all tumour cells) Most often, EMA + CD3 + (heterogeneous)/cd20 -, or CD3 -/CD20 - Activated cytotoxic profile (TIA1 +, Perf +, GrB +) ALK expression : 50-80 % (*) CD15 and EBV usually negative
EMA CD30 CD30
CD3 GrB
Perforin egranzymes TIA-1 perforine LYSIS (necrosis) - - KIR MHC class 1 granzymes TIA-1 + TC R Ag- MHC DNA fragmentation APOPTOSI S CYTOTOXIC T CELL "NK/T cell" TARGET CELL
ANAPLASTIC LARGE CELL LYMPHOMA (SYSTEMIC, T-null) CYTOGENETICS: - translocation t (2 ; 5): novel fusion gene ALK/NPM with nucleolar accumulation -----> cytoplasmic + nuclear ALK expression - variant translocations (20%) : Alk rearrangement, but not implicating npm -----> cytoplasmic ALK expression - oncogenic properties of ALK - Prognostic relevance of ALK expression NORMAL COUNTERPART?: activated perifollicular T- blasts?
ALK1 From Stein H et al. Blood, 2000 CD30
CD30 ALK1 Falini et al. Blood, 1999
ANAPLASTIC LARGE CELL LYMPHOMA (SYSTEMIC, T-null) ALK+ MORPHOLOGIC VARIANTS : Common-type Lymphohistiocytic Small cell Giant cell «mixed»
ANAPLASTIC LARGE-CELL LYMPHOMA (T-and null-cell types) MORPHOLOGIC VARIANTS : Common-type Lymphohistiocytic Small cell Giant cell «mixed»
ALK1 CD30 EMA
LYMPHOMES ANAPLASIQUES à GRANDES CELLULES (T/nul) - HISTOLOGIE : cell. très grande taille, noyau réniforme topographie sinusale préférentielle - PHENOTYPE : activé (CD30+, CD25+,...), EMA +/- CD3+/-, cytotoxique activé - TROIS ENTITES ANATOMO-CLINIQUES (cytogénétique et présentation clinique): formes systémiques (ALK+) (translocation impliquant ALK (souvent t (2; 5)/NPM-ALK), et bonne réponse à chimiothérapie) formes systémiques (ALK-) formes cutanées primitives (ALK-),
CD4+ cytotoxic T lymphocyte activation? proliferation (Ag, cytokines?...) t (2;5) LYMPHOMATOID PAPULOSIS? SYSTEMIC ALCL (ALK-1+) CUTANEOUS CD30+ LYMPHOMAS?? SYSTEMIC ALCL (ALK-1-) + systemic CD30+ non ALC
Conduite à tenir devant une prolifération tumorale à grandes cellules d allure «lymphoïde» - CD20+ : LNH DIFFUS A GRANDES CELLULES B - CD3+ : LNH-T ---> périphérique, sans spécificité ----> anaplasique (CD30, EMA, ALK) - CD3-, CD20- : CD30+ = LNH anaplasique, Hodgkin LNH Plasmablastique T plasmocytaire (CD138) CD30- S granulocytique T NON HEMATOPOIETIQUE
«MATURE» T/NK CELL NEOPLASMS PREDOMINANTLY EXTRANODAL Mycosis fungoides, Sézary syndrome Primary cutaneous ALCL Subcutaneous panniculitis-like T-cell lymphoma Nasal and «nasal type» NK/T cell lymphoma Enteropathy-type intestinal T-cell lymphoma Hepatosplenic γδ T-cell lymphoma
ALCL (T/NULL) - CLINICAL FEATURES 2 DISTINCT FORMS SYSTEMIC PRIMARY CUTANEOUS LN, extranodal sites only skin children and adults adults CLA-, CLA +, ALK-1 - ALK-1 +/- spontaneous clinically aggresive regression (?), continuous spectrum with lymphomatoid papulosis type A (?)
ALCL Cutané
ALCL Cutané perforin
MYCOSIS FUNGOIDES Epidermotropic CTCL Small, medium sized T-cells, cerebriform nuclei CD3 +, CD4 + αβ T-cells Clinical features IMPORTANT for the diagnosis
SUBCUTANEOUS PANNICULITIS LIKE T-CELL LYMPHOMA Usually multiple subcutaneous masses Histology = «panniculitis-like lesion» Cytotoxic (activated) CD3 + T cells (perf +, GrB +, TIA-1 +) Cell lineage : Tαβ CD8 (# Tγδ, usually CD4-/CD8-, CD56+ and more aggressive) Possible hemophagocytic syndrome Curable (# γδ)
HES
HES Apoptose ++ HES Atypies ++
CD2 GrB CD7 CD8
T- and NK-cell lymphomas WHO classification, 2001 leukemic nodal extra-nodal prolymphocytic angioimmunoblastic mycosis/sezary T-LGL leukemia peripheral, unsp. primary cutaneous ALCL+ Aggressive NK leuk/lymph systemic ALCL subcutaneous panniculitis ATL/L (HTLV-1) enteropathy-type extranodal NK/T nasal(-type) hepatosplenic (γδ) -
ENTEROPATHY TYPE T-CELL LYMPHOMA Adults (median age: 50y) Complication of CD (50%) (loss of response to gluten-free diet), or de novo (50%) HLA DQA1*0501 or DQB1*0201 context Usually jejunal, multifocal lesions; ulcerations, frequently with perforation Frequent mesenteric LN involvement Some cases may present in non intestinal mucosal sites (skin, lung, ) Intraepithelial lymphocytes (IEL) All IELs express αeβ7 integrin (CD103+ /HML1) [ligand = E-cadherin which is expressed on
ENTEROPATHY TYPE T-CELL LYMPHOMA T-cell phenotype (CD3+, CD2+) often CD4 -/CD8 - expression of HML-1/CD103 (α4 β7 intergrin) often activated cytotoxic profile (TIA-1+, GrB+) absence of EBV association clonal γ and β gene rearrangements
Ulcerative jejunitis/ Refractory celiac disease : a «low grade» intraepithelial T-cell lymphoma? CD3 CD8 TIA1
Molecular mechanisms associated with progression from CD to ETL Celiac disease ETL Environmental fr (gliadine,..) HLA context Cytokines (IL-15, ) Refractory Celiac disease + 1q Gain 9q33-34(58%) Loss 9p21,,... Verkarre V et al, Gastroenterology, 2003 Zettl et al, AmJ Pathol, 2002
Prevalence of celiac disease 1/3000 Silent Asymptomatic Celiac disease 1/300
Nasal NK/T cell lymphoma More frequent in Asia, Central and South America Young adults (median age = 41 y), male predominance Peculiar clinical features : Nasal obstruction, usually localized at presentation Histology: necrosis, angiocentrism and angioinvasion; cytological spectrum Phenotype and genotype of NK cells in most instances, with some cases of γδ or αb T cytotoxic origin CD3e+, CD5-, CD56+, TIA1+/GrB+, EBV+ Nasal-type : skin, liver, lung, GI tract, testis,. High risk of HPS, low risk of nodal involvement Poor outcome (around 45% 5 year OS) cell origin : NK >>Tγδ, Tαβ pathogeny : role of EBV, del 6q?
Angiocentrism, angioinvasion Epitheliotropism Variable cytological features Epithéliotropism Angioinvasion
CD3ε EBV+, 100% CD56 EBER ISH CD5 GrB
CD3/TCR complex CD3ε CD3 γ TCR β TCR α CD3 δ CD3ε CD3ζ
Chronic sinusitis IL-9 Nasal NK lymphoma EBV Il-10 Fas Deletions, 6q del, 6p dup 11q del (%)... p53, MDR,.. Hypothetical scheme
LYMPHOME NK/T NASAL - HISTOLOGIE : pléomorphisme angiocentrisme fréquent - CLINIQUE : «granulome malin centrofacial» possibilité autres atteintes (poumon, peau, foie, rate) mauvais pronostic - ORIGINE CELLULAIRE le + souvent NK: CD2 +, CD5 -, CD56 +, CD3ε+,TCR - absence réarrgt des gènes des TCR TIA1+, Perforine+, Granzyme B+ - PATHOGENIE : délétion 6q? rôle oncogènique du virus EB?
LYMPHOME NK/T NASAL - Diagnostic différentiel - - Inflammations, Wegener (Pts peu significatifs+++) - Autres lymphomes T cytotoxiques (entéropathie notamment) - Autres tumeurs CD56+: en particulier hémopathie/hématodermie CD4+/CD56+ (Tumeur à cell. Dendritiques plasmocytoides)
Hématodermie CD4+, CD56+
CD20 CD4 CD123 + CD5 TCL1 CD56
Hématodermie CD4+, CD56+: une nouvelle entité 1. Présentation souvent cutanée (tumeurs) +/- gg régionaux +/- atteinte médullaire 2. Prolifération monotone +/- blastique, non épidermotrope 3. CD4+, CD56+, CD123+ (TCL1+, CD43+) négativité: MPO, CD20, CD3, TIA1/GrB, EBV, CD68: variable 4. Évolution défavorable (LA) 5. Cytogénètique: del5q, del13q,.. 6. Origine cellulaire: cell. Dendritique plasmocytoide 7. Dc #: lymphome NK, sarcome myéloide
γδ T-cell lymphomas Muco cutaneous γδ Hepatosplenic γδ - Skin, usually subcutaneous ( ) Spleen, liver, BM (sinusal/ - mucosal sites: GI, nose, thyroid,.. sinusoidal distribution) Aggressive Aggressive Activated cytotoxic phenotype non activated cytotoxic pheno TIA-1+, Gr B +, Perf + TIA-1 +, Gr B -/ Perf Cell spectrum, apoptosis, Cell spectrum limited (exc, EBV variable, site dependent EBV - blastoid var ) Iso7q? cytogenetics? Iso 7q +, + Trisomy 8 ( ) Cutaneous γδ lymphomas: a separate group (WHO/EORTC classification)
Hepatosplenic (γδ) T-cell Lymphoma TIA1 CD3 γδ vs αβ Context: chronic ag stimulation (post-transplant patients) K Belhadj et al. Blood, 2003
T/NK CELL LYMPHOMAS - CONCLUSIONS - Entités cliniques distinctes ayant une signification clinique (AILD, ALCL,...) Beaucoup d entre elles présentent un spectre cytologique Diversité phenotypique possible (NK, γδ, αβ) à l intérieur de certaines entités (ex: NK/T nasal lymphomas) A l exception du LNH anaplasique ALK1, la plupart des LNH T/NK ont un pronostic péjoratif
Morphol Clinical cell cytotox putative genepresent. origin antigen tics AIL VPC hyper B symptoms T (αβ) -? triso 3 clear cells LN, SMG,.. ALCL kydney nuc LN, skin T +/- (act)? t(2;5) sinus Nasal angiocent "LMG" NK + (act) EBV 6q NK/T necrosis (γδ, αβ) Subcutan lipoph.pann panniculitis T αβ, γδ + (act)?? pannic-like caryorrh. nodule ETL epitheliot. intest perf, IEL +/- (act) gliadin? eosinoph mass, enterop. T αβ, (γδ) Hepato medium-sized SMG, T γδ + (non? iso7q splenic γδ sinuses (BM) thrombo activ) cytop.
T/NK CELL LYMPHOMAS CD3 +, CD20- EBV (LMP-1, EBERs) TIA1, GrB, CD56 Extranodal CD1, tdt T-LBL/ALL FDC (CD21, CNA42...) EBV (EBERs IHS) AIL CD30, EMA ALK1 ALCL (T/N)
T/NK CELL LYMPHOMAS - CONCLUSIONS - importance of the site of origin (homing receptors?) many T/NK lymphomas, specially extranodal, derive from cells with (potential) cytotoxic properties role of an antigen? - EATL : gliadin - nasal : EBV... role of immunodepression?
LYMPHOMES T et NK - PERSPECTIVES - Un certain nombre de «zones d ombre» persiste: ----> heterogeneité à l intérieur d une entité (ALCL) ----> entités mal définies (ex: PTCL unsp, ) Nécessité de : - correlations anatomo-cliniques - travaux biologiques : «biopuces», proteomique,... ------> nouveaux critères de définition ------> nouvelles entités? ------> nouvelles cibles thérapeutiques From gene signature to protein expression