Lymphadenopathies mimicking lymphoma and vice versa. Session 3
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- Clifton Heath
- 5 years ago
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1 Lymphadenopathies mimicking lymphoma and vice versa Session
2 T/ NK Cell System The human and rodent T and NK cell system is characterized by many highly specialized cell suopulations and functions, that are regulated by cellular and molecular interactions with multiple partners( T cells,b cells, macrophages, dendritic cells,endothelial cells a.o.).these interactions are presumed to occur also in the neoplastic counterparts and may even obscure the neoplastic process.
3 Lymphoid tissue extranodal Central lymphoid tissue Precursor T-cells Peripheral lymphoid tissue Peripheral (mature)t-and NK-cells Bone marrow Progenitor T-cell/ Prothymocyte NK gdt-cell Spleen Mucosa Peripheral blood Skin Skin Innate Immunity Subcapsular cortical thymocyte Common thymocyte ab CD4+ CD8+ Thymus CD4 Medullary thymocytes CD8 T lymphoblastic lymphoma/leukaemia Naive T cell CD4 CD8 Naive T cell AG Memory T cell CD4 CD4 Effector T cell T reg Memory T cell CD8 CD8 Effector T cell Adaptive Immunity Follicle FDC Peripheral (mature) T-cell and NK-cell lymphomas/leukaemias TFH
4 Functional subtypes of T and NK cells g/d T H T H CTL NK T Reg T FH Identification TCRd + CD4 8 bf + CD4 + 8 bf + CD4 8 + CD CD4 8 CD CD FOXP + CXCL + Antigen recognition frequent antigens w/o MHC restriction MHC II restricted extracellular antigens MHC I restricted intracellular antigen NKR IgG (ADCC) TCR MHC MHCII Transcription factor T-bet GATA MAF BCL6? Costimulatio n IL IL4? IFNg Recruitment Resident in epithelia, blood,spleen CXCR CCR5 CCR4 Resident in blood, spleen CCR4 CCR5 CD6L CXCR5 Effector arm Granz.B Perforin FASLl IFNg IL4, IL5, IL Granz.B Perforin FASL Granz.B Perforin IL IL IL CD4L Functional consequence s Lysis apoptosis Activation of Mf CTL DTH Defense against helminths Allergy Perforin: lysis GranzymeB: apoptosis FASL: apoptosis Control of autoimmunity Help for GCB-cells and more new TH effector cell subsets: Th9 ; TH 7 ; Th
5 Mature T-cell differentiation CD45RA + CD45R CD7 + CCR7 + L y m p h CCR7 + Non effector CD45RA CD45R + CD7 + CCR7 + Central memory cell T naïve N o d e CCR7 Effector FAS Effector memory cell CD45RA /+ CD45R +/ CD7 CCR7 BCL- Adapted from: Sallusto et al: Annu Rev Immunol. 4;:745-6
6 Mature T-cell development: Recall Responses CD45RA + CD45R CD7 + CCR7 + L y m p h CCR7 + Non effector Lymph node CD45RA CD45R + CD7 + CCR7 + Central memory cell T naïve N o d e CCR7 Effector FAS Effector memory cell CD45RA /+ CD45R +/ CD7 CCR7 BCL-
7 Diagnostic approach in PTCL Structural tumor features imply suspicion of PTCL Lack of B cell markers on supposed tumor cells (CD ; Pax5 ) Suspicious Tumor cells express Pan T cell markers( CD ; CD5; CD;, CD7; bf; CD ) Lack of markers present on normal T cells Proliferation status Clonality analysis
8 Peripheral T/NK-cell lymphoma classification: Clinical approach Localization very important Clinical syndromes (e.g. ITL, AILT) Predominantly leukemic/disseminated Predominantly extranodal Predominantly nodal Anaplastic large cell lymphoma Angioimmunoblastic T-cell lymphoma Peripheral T-cell lymphoma, NOS
9 CHAPTER Mature T- and NK-cell Neoplasms T-cell prolymphocytic leukaemia T-cell large granular lymphocytic leukaemia Chronic lymphoproliferative disorders of NK cells Aggressive NK cell leukaemia EBV-positive T-cell lymphoproliferative disorders of childhood Adult T-cell leukaemia/lymphoma Extranodal NK/T cell lymphoma, nasal type Enteropathy-associated T-cell lymphoma Hepatosplenic T-cell lymphoma Subcutaneous panniculitis-like T-cell lymphoma Mycosis fungoides Sezary syndrome Primary cutaneous CD positive T-cell lymphoproliferative disorders Primary cutaneous gamma-delta T-cell lymphomas Peripheral T-cell lymphoma, NOS Angioimmunoblastic T-cell lymphoma Anaplastic large cell lymphoma (ALCL), ALK positive Anaplastic large cell lymphoma (ALCL), ALK negative
10 ALCL%
11 S u r v i v a l ILCP : Overall Survival..9.8 ALCL ALK DLBCL PTCL Years
12 Proportion Overall survival of PTCL ALK + ALCL ALK - ALCL PTCL-NOS AILT Time
13 Diagnostic approach c td Only recent interest into normal counterparts of PTCL tumor cells. Methodological problems Conceptual problems ( mycosis fungoides, extranodal T/NK cell lymphomas): overinterpretation of clinical features? No relevance for treatment??
14 A practical problem in peripheral T cell Lymphomas (PTCL-NOS)
15 PTCL-NOS What T cell suopulation is the tumor cell? CD4-.jpg CD4 Proliferation CD8
16 In some tumors ( esp. certain malignant lymphomas) most cells are reactive concomitant infiltrates: Hodgkin Lymphomas, T cell rich B cell lymphomas, most peripheral T cell lymphomas
17 PTCL-NOS contain many reactive T cells T- cell rich T cell lymphomas The identification of neoplastic cells in peripheral T cell lymphomas within biopsies is still very unprecise! Methodological solution : Identification of tumor cell clone Functional characterization of neoplastic cells
18 Each T cell has an idiotypic T cell receptor: Genetic polymorphism and organization of the TCR b gene family Vß Vß Vßn Dß Jß Cß Dß Jß Cß 65 Vb segments; 47 functional; 5 Vb -families Rearrangement Vß9 Dß Jß CDR Complex Cß Expression T-cell
19 . Step: Definition of the TCRb segment in the lymphoma tissue: Vß Vß Vßn Dß Jß Cß Dß Jß 5 Vß primer Jß primer Jß primer Cß 5 PCR reactions V V6 4 V 4 V V V7 4 V 4 V V V8 4 V 4 V V4 4 V 4 4 V V V V5 4 V V 5 V 4 5 V 4 5 V V4 5 4 V5. Step: Detection of the specific TCRb segment in by IHC : IHC and double staining by LSM TCRVb CD4 CD T-cell Geissinger E et al: J Mol Diagn; 5
20 TCRVb PTCL-NOS
21 TCRVb CD45RA - PTCL-NOS
22 PTCL-NOS - subset TCRVb CD45R + TCRVb CD45RA CD7 + TCRVb CCR7 +
23 Differentiation pathway of mature T cells CD45RA + CD45R CD7 + CCR7 + L y m p h CCR7 + Non effector CD45RA CD45R + CD7 + CCR7 + Central memory cell T naïve N o d e CCR7 Effector FAS Effector memory cell CD45RA /+ CD45R +/ CD7 CCR7 BCL- Adapted from: Sallusto et al: Annu Rev Immunol. 4;:745-6
24 (ALCL) 8 (ALCL) (ALCL) (ALCL) 4 (ALCL) 9 (ALCL) 8 (ALCL) (ALCL) (ALCL) (ALCL) (ALCL) 9 (ALCL) 5 (ALCL) 6 (ALCL) 7 (ALCL) (NOS) 5 (NOS) 7 (NOS) (NOS) 6 (NOS) 4 (NOS) 9 (NOS) 8 (NOS) (AILT) 7 (AILT) 5 (AILT) 6 (AILT) (AILT) 4 (AILT) (AILT) Cluster Analyse CCR4 -,5,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5,5 -,5 -,5 -,5 -,5,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 CXCR -,5,5 -,5 -,5 -,5,5,5,5,5,5 -,5,5 -,5,5,5,5 -,5,5,5 -,5,5 -,5,5 -,5,5 -,5,5,5 -,5,5 GrB,5 -,5 -,5 -,5 -,5,5 -,5,5 -,5,5,5,5 -,5,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5,5 -,5 -,5 -,5 -,5 TIA,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5,5,5,5,5,5,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5,5 -,5 -,5 -,5 -,5 CD8 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 CD5,5,5,5,5,5,5 -,5,5 -,5 -,5 -,5,5 -,5 -,5,5,5,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 HLA-DR,5,5,5,5,5,5,5,5,5,5,5,5,5 -,5,5,5 -,5 -,5 -,5 -,5 -,5 -,5,5 -,5 -,5 -,5 -,5 -,5 Perforin,5 -,5,5,5 -,5,5,5,5,5,5,5,5,5,5,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 FASL -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5,5 -,5 -,5 -,5 -,5 -,5,5,5 -,5,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 FAS -,5,5,5 -,5,5 -,5,5 -,5 -,5 -,5,5 -,5,5,5 -,5,5,5,5,5,5 -,5,5,5,5,5,5,5,5,5,5 CD69 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5,5,5,5,5 -,5 -,5,5 -,5 -,5 -,5,5,5 -,5,5,5 CTLA-4 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5,5,5 -,5,5,5,5 CD4 -,5,5 -,5,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5,5 -,5 -,5 -,5,5,5,5,5,5 -,5 -,5,5,5,5,5,5,5 -,5 BCL -,5,5 -,5 -,5 -,5,5,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5,5,5,5,5,5,5 -,5,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 CD -,5 -,5 -,5 -,5 -,5 -,5,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5,5,5,5,5,5 -,5,5 -,5,5,5,5,5,5 -,5 CD7 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5,5,5,5,5,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 CCR7 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5,5,5,5,5,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 CD8 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5,5 -,5,5 -,5,5,5 -,5 -,5 -,5,5 -,5 -,5 -,5 -,5 -,5 CD45R -,5,5,5,5,5,5,5 -,5 -,5,5,5 -,5 -,5 -,5,5 -,5,5,5,5,5,5,5,5,5,5,5,5,5,5,5 CD45RA -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 negative <%positive -8% positive >8% positive Geissinger E et al. J Pathol 6; :7
25 (ALCL) 8 (ALCL) (ALCL) (ALCL) 4 (ALCL) Nodal PTCL are derived from Antigen-experienced cells 9 (ALCL) 8 (ALCL) (ALCL) (ALCL) (ALCL) (ALCL) 9 (ALCL) 5 (ALCL) 6 (ALCL) 7 (ALCL) (NOS) 5 (NOS) 7 (NOS) (NOS) 6 (NOS) 4 (NOS) 9 (NOS) 8 (NOS) (AILT) 7 (AILT) 5 (AILT) 6 (AILT) (AILT) 4 (AILT) (AILT) CCR4 -,5,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5,5 -,5 -,5 -,5 -,5,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 CXCR -,5,5 -,5 -,5 -,5,5,5,5,5,5 -,5,5 -,5,5,5,5 -,5,5,5 -,5,5 -,5,5 -,5,5 -,5,5,5 -,5,5 GrB,5 -,5 -,5 -,5 -,5,5 -,5,5 -,5,5,5,5 -,5,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5,5 -,5 -,5 -,5 -,5 TIA,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5,5,5,5,5,5,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5,5 -,5 -,5 -,5 -,5 CD8 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 CD5,5,5,5,5,5,5 -,5,5 -,5 -,5 -,5,5 -,5 -,5,5,5,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 HLA-DR,5,5,5,5,5,5,5,5,5,5,5,5,5 -,5,5,5 -,5 -,5 -,5 -,5 -,5 -,5,5 -,5 -,5 -,5 -,5 -,5 Perforin,5 -,5,5,5 -,5,5,5,5,5,5,5,5,5,5,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 FASL -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5,5 -,5 -,5 -,5 -,5 -,5,5,5 -,5,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 FAS -,5,5,5 -,5,5 -,5,5 -,5 -,5 -,5,5 -,5,5,5 -,5,5,5,5,5,5 -,5,5,5,5,5,5,5,5,5,5 CD69 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5,5,5,5,5 -,5 -,5,5 -,5 -,5 -,5,5,5 -,5,5,5 CTLA-4 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5,5,5 -,5,5,5,5 CD4 -,5,5 -,5,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5,5 -,5 -,5 -,5,5,5,5,5,5 -,5 -,5,5,5,5,5,5,5 -,5 BCL -,5,5 -,5 -,5 -,5,5,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5,5,5,5,5,5,5 -,5,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 CD -,5 -,5 -,5 -,5 -,5 -,5,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5,5,5,5,5,5 -,5,5 -,5,5,5,5,5,5 -,5 CD7 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5,5,5,5,5,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 CCR7 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5,5,5,5,5,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 CD8 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5,5 -,5,5 -,5,5,5 -,5 -,5 -,5,5 -,5 -,5 -,5 -,5 -,5 CD45R -,5,5,5,5,5,5,5 -,5 -,5,5,5 -,5 -,5 -,5,5 -,5,5,5,5,5,5,5,5,5,5,5,5,5,5,5 CD45RA -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 negative <%positive -8% positive >8% positive
26 (ALCL) 8 (ALCL) (ALCL) (ALCL) 4 (ALCL) 9 (ALCL) 8 (ALCL) (ALCL) (ALCL) (ALCL) (ALCL) 9 (ALCL) 5 (ALCL) 6 (ALCL) 7 (ALCL) (NOS) 5 (NOS) 7 (NOS) (NOS) 6 (NOS) 4 (NOS) 9 (NOS) 8 (NOS) (AILT) 7 (AILT) 5 (AILT) 6 (AILT) (AILT) 4 (AILT) (AILT) A subset of PTCL-NOS is derived from central memory cells CCR4 -,5,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5,5 -,5 -,5 -,5 -,5,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 CXCR -,5,5 -,5 -,5 -,5,5,5,5,5,5 -,5,5 -,5,5,5,5 -,5,5,5 -,5,5 -,5,5 -,5,5 -,5,5,5 -,5,5 GrB,5 -,5 -,5 -,5 -,5,5 -,5,5 -,5,5,5,5 -,5,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5,5 -,5 -,5 -,5 -,5 TIA,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5,5,5,5,5,5,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5,5 -,5 -,5 -,5 -,5 CD8 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 CD5,5,5,5,5,5,5 -,5,5 -,5 -,5 -,5,5 -,5 -,5,5,5,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 HLA-DR,5,5,5,5,5,5,5,5,5,5,5,5,5 -,5,5,5 -,5 -,5 -,5 -,5 -,5 -,5,5 -,5 -,5 -,5 -,5 -,5 Perforin,5 -,5,5,5 -,5,5,5,5,5,5,5,5,5,5,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 FASL -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5,5 -,5 -,5 -,5 -,5 -,5,5,5 -,5,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 FAS -,5,5,5 -,5,5 -,5,5 -,5 -,5 -,5,5 -,5,5,5 -,5,5,5,5,5,5 -,5,5,5,5,5,5,5,5,5,5 CD69 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5,5,5,5,5 -,5 -,5,5 -,5 -,5 -,5,5,5 -,5,5,5 CTLA-4 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5,5,5 -,5,5,5,5 CD4 -,5,5 -,5,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5,5 -,5 -,5 -,5,5,5,5,5,5 -,5 -,5,5,5,5,5,5,5 -,5 BCL -,5,5 -,5 -,5 -,5,5,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5,5,5,5,5,5,5 -,5,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 CD -,5 -,5 -,5 -,5 -,5 -,5,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5,5,5,5,5,5 -,5,5 -,5,5,5,5,5,5 -,5 CD7 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5,5,5,5,5,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 CCR7 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5,5,5,5,5,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 CD8 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5,5 -,5,5 -,5,5,5 -,5 -,5 -,5,5 -,5 -,5 -,5 -,5 -,5 CD45R -,5,5,5,5,5,5,5 -,5 -,5,5,5 -,5 -,5 -,5,5 -,5,5,5,5,5,5,5,5,5,5,5,5,5,5,5 CD45RA -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 negative <%positive -8% positive >8% positive
27 (ALCL) 8 (ALCL) (ALCL) (ALCL) 4 (ALCL) 9 (ALCL) 8 (ALCL) (ALCL) (ALCL) (ALCL) (ALCL) 9 (ALCL) 5 (ALCL) 6 (ALCL) 7 (ALCL) (NOS) 5 (NOS) 7 (NOS) (NOS) 6 (NOS) 4 (NOS) 9 (NOS) 8 (NOS) (AILT) 7 (AILT) 5 (AILT) 6 (AILT) (AILT) 4 (AILT) (AILT) AILT and ALCL are derived from different subsets of effector cells CCR4 -,5,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5,5 -,5 -,5 -,5 -,5,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 CXCR -,5,5 -,5 -,5 -,5,5,5,5,5,5 -,5,5 -,5,5,5,5 -,5,5,5 -,5,5 -,5,5 -,5,5 -,5,5,5 -,5,5 GrB,5 -,5 -,5 -,5 -,5,5 -,5,5 -,5,5,5,5 -,5,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5,5 -,5 -,5 -,5 -,5 TIA,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5,5,5,5,5,5,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5,5 -,5 -,5 -,5 -,5 CD8 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 CD5,5,5,5,5,5,5 -,5,5 -,5 -,5 -,5,5 -,5 -,5,5,5,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 HLA-DR,5,5,5,5,5,5,5,5,5,5,5,5,5 -,5,5,5 -,5 -,5 -,5 -,5 -,5 -,5,5 -,5 -,5 -,5 -,5 -,5 Perforin,5 -,5,5,5 -,5,5,5,5,5,5,5,5,5,5,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 FASL -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5,5 -,5 -,5 -,5 -,5 -,5,5,5 -,5,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 FAS -,5,5,5 -,5,5 -,5,5 -,5 -,5 -,5,5 -,5,5,5 -,5,5,5,5,5,5 -,5,5,5,5,5,5,5,5,5,5 CD69 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5,5,5,5,5 -,5 -,5,5 -,5 -,5 -,5,5,5 -,5,5,5 CTLA-4 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5,5,5 -,5,5,5,5 CD4 -,5,5 -,5,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5,5 -,5 -,5 -,5,5,5,5,5,5 -,5 -,5,5,5,5,5,5,5 -,5 BCL -,5,5 -,5 -,5 -,5,5,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5,5,5,5,5,5,5 -,5,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 CD -,5 -,5 -,5 -,5 -,5 -,5,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5,5,5,5,5,5 -,5,5 -,5,5,5,5,5,5 -,5 CD7 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5,5,5,5,5,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 CCR7 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5,5,5,5,5,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 CD8 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5,5 -,5,5 -,5,5,5 -,5 -,5 -,5,5 -,5 -,5 -,5 -,5 -,5 CD45R -,5,5,5,5,5,5,5 -,5 -,5,5,5 -,5 -,5 -,5,5 -,5,5,5,5,5,5,5,5,5,5,5,5,5,5,5 CD45RA -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 -,5 negative <%positive -8% positive >8% positive
28 CD45RA + CD45R CD7 + CCR7 + L y m p h CCR7 + Non effector Central memory cell PTCL-NOS subset CD45RA CD45R + CD7 + CCR7 + T naïve N Effector memory cell o d e CCR7 Effector Angioimmunoblastic T-cell lymphoma Anaplastic large cell lymphoma CD45RA /+ CD45R +/ CD7 CCR7
29 Workshop Case No. (H9567/8) Age Sex Localization Clinical data 87 years female inguinal lymph node CT: supra- and infradiafragmental lymphadenopathy. Unsuspicious spleen.
30
31
32
33
34
35
36 Case No. 4 - phenotype Tumor cells: Background infiltrate: TCRg clonality assay: CD+, CD+, CD5+, CD4+ CD7 partial+ PD+ CD+ CD5+ polyclonal plasma cells (k/l) CD+ FDC networks EBER+ B-cells monoclonal
37 CD
38 CD
39 PD
40 PD
41
42
43 Roncador, G. et al. Haematologica 7;9:59-66
44 KI 67
45 CD
46 LMP
47 EBER
48 CD
49 Diagnosis H9567-8: Angioimmunoblastic T Cell Lymphoma ( AILT) EBV related B LPD?
50 AILT Diagnostic criteria Clinics Systemic disease Morphology Polymorphous infiltrate High endothelial venules Follicular dendritic cells Molcular data TCR rearrangement not of prognostic value Immunophenotype EBV-infected B-cells in the background
51 Proportion Overall and Failure-free Survival. Angioimmunoblastic Cases Time CENSOR FAIL TOTAL MEDIAN FFS OAS
52 Angioimmunoblastic T-cell lymphoma CD
53 Angioimmunoblastic T-cell lymphoma CD
54 Angioimmunoblastic T-cell lymphoma CD CD
55 Angioimmunoblastic T-cell lymphoma CD4 CD8
56 AILT-secondary B-cell proliferations CD
57 CD LMP
58
59 > 8 % positiv () -8 % positiv () < % positiv () negativ () PD ICOS CXCR5 CCR7 Bcl6 Bcl Fas CD - NOS* 6- NOS 9- NOS - NOS 8- NOS - NOS 7- NOS - NOS* 5- NOS 4- AILT 5- AILT 8- AILT 9- AILT - AILT - AILT - AILT 6- AILT 7- AILT - pf. T-NHL - AILT Cluster-Analysis of T FH Markers on tumor cells of nodal PTCL AILT PTCL-NOS
60 > 8 % positiv () -8 % positiv () < % positiv () negativ () PD ICOS CXCR5 CCR7 Bcl6 Bcl Fas CD - NOS* 6- NOS 9- NOS - NOS 8- NOS - NOS 7- NOS - NOS* 5- NOS 4- AILT 5- AILT 8- AILT 9- AILT - AILT - AILT - AILT 6- AILT 7- AILT - pf. T-NHL - AILT Cluster-Analysis of T FH Markers on tumor cells of nodal PTCL AILT PTCL-NOS
61
62 PD Vb AILT PTCL-NOS PD Vb
63
64 Angioimmunoblastic T cell Lymphoma AILT and Follicular/ Perifollicular T Cell Lymphoma are derived from Follicular T Helper Cells
65 CD45RA + CD45R CD7 + CCR7 + L y m p h CCR7 + Non effector CD45RA CD45R + CD7 + CCR7 + Follicular TH Cell lymphoma- Variant of PTCL-NOS T naïve N Effector memory cell o d e CCR7 Effector Angioimmunoblastic T Cell Lymphoma AILT CD45RA /+ CD45R +/ CD7 CCR7
66 Literature Zettl A, Lee SS, Rüdiger T, et al. Epstein-Barr virus-associated B-cell lymphoproliferative disorders in angloimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma, unspecified. Am J Clin Pathol. ;7(): de Leval L, Gisselbrecht C, Gaulard P. Advances in the understanding and management of angioimmunoblastic T-cell lymphoma. Br J Haematol. ;48(5): Federico M, Rüdiger T, Bellei M, et al. Clinicopathologic Characteristics of Angioimmunoblastic T-Cell Lymphoma: Analysis of the International Peripheral T-Cell Lymphoma Project. J Clin Oncol.. Leich E, Haralambieva E, Zettl A, et al. Tissue microarray-based screening for chromosomal breakpoints affecting the T-cell receptor gene loci in mature T-cell lymphomas. J Pathol. 7;():99-5. Rüdiger T, Zettl A, Adam P, Bonzheim I, Geissinger E, Muller-Hermelink HK. Periphere NK/T-Zell Lymphome. Pathologe. 7;8(): Geissinger E, Bonzheim I, Krenacs L, et al. Nodal peripheral T-cell lymphomas correspond to distinct mature T-cell populations. J Pathol. 6;():7-8.
67 Literature c td Rüdiger T, Geissinger E, Müller-Hermelink HK. 'Normal counterparts' of nodal peripheral T-cell lymphoma. Hematol Oncol. 6;4(4):75-8. Reimer P, Rudiger T, Wilhelm M. The role of high-dose therapy in peripheral T-cell lymphomas. Clin Lymphoma Myeloma. 6;6(5):7-79. Geissinger E, Bonzheim I, Krenacs L, et al. Identification of the tumor cells in peripheral T-cell lymphomas by combined polymerase chain reaction-based T-cell receptor beta spectrotyping and immunohistological detection with T-cell receptor beta chain variable region segment-specific antibodies. J Mol Diagn. 5;7(4): Geissinger E, Odenwald T, Lee SS, et al. Nodal peripheral T-cell lymphomas and, in particular, their lymphoepithelioid (Lennert's) variant are often derived from CD8(+) cytotoxic T-cells. Virchows Arch. 4;445(4):4-4. Rüdiger T, Weisenburger DD, Anderson JR, et al. Peripheral T-cell lymphoma (excluding anaplastic large-cell lymphoma): results from the Non-Hodgkin's Lymphoma Classification Project. Ann Oncol. ;():4-49. Rüdiger T, Ichinohasama R, Ott MM, et al. Peripheral T-cell lymphoma with distinct perifollicular growth pattern: a distinct subtype of T-cell lymphoma? Am J Surg Pathol. ;4():7-.
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