Modern classification of lymphomas (2010) VEAB presentation
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Modern classification of lymphomas
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Modern classification of lymphomas (2010) VEAB presentation
- 1. Modern classification of lymphomas András Matolcsy 1st. Department of Pathology and Experimental Cancer Research Semmelweis University Budapest Hungary
- 5. Kiel classification (1974, 1988) Low grade High grade B-cell B-CLL Centroblastoma Immunocytoma B immunoblastoma Centrocytoma B anaplastic large cell Centrocytic-centroblastic Burkitt’s lymphoma T-cell T-CLL T lymphoblastoma T zone lymphoma T immunoblastoma Lymphoepitheloid T anaplastic large cell Angioimmunoblastic Pleomorphic
- 6. REAL- WHO classification (1994-2008) Morphology Phenotype Genotype Clinical course Evidence based ENTITY B-cell lymphomas T/NK-cell lymphomas Precursor cell Matured cell
- 7. REAL- WHO classification (1994-2008) B -cell lymphomas Precursor B-cell neoplasms - B-lymphoblastic leukemia/lymphoma Matured (peripheral) B-cell neoplasms - B-cell chronic lymphocytic leukemia, small lymphocytic lymphoma - B-cell prolymphocytic leukemia - Lymphoplasmocytic lymphoma - Hairy cell leukemia - Plasma cell myeloma/plasmocytoma - Extranodal marginal zone B-cell lymphoma MALT type - Nodal marginal zone B-cell lymphoma (+/- monocytoid B-cells ) - Spleni c marg inal z o n e lymphoma (+/- villous lymphocytes) - Follicular lymphoma - Mantle cell lymphoma - Diffuse large B-cell lymphoma - Mediastinal large B-cell lymphoma - Intravascular large B-cell lymphoma - Primer effusional lymphoma - Burkitt’s lymphoma
- 8. REAL- WHO classification (1994-2008) T/NK-cell lymphomas Precursor T-cell tumors - T-lymphoblastic lymphoma/leukemia Matured (peripheral) T-cell tumors - T-cell prolymphocytic leukemia - T-cell large granular lymphocyte leukemia - Aggressive NK-cell leukemia - Adult T-cell lymphoma/leukemia (HTLV1+) - Extranodal NK/T-cell lymphoma, nasal type - Enteropathy-type T-cell lymphoma - Hepatosplenic T-cell lymphoma - Subcutan panniculitis-like T-cell lymphoma - Mycosis fungoides/Sezary syndrome - Anaplastic large cell lymphoma - Peripheral T-cell lymphoma (not otherwise specified) - Angioimmunoblastic T-cell lymphoma
- 9. The role of basic science in lymphoma classification
- 10. B-cell ontogeny and lymphomagenesis C entroblast Plasma cell Marginal zone B cell Naive B cell Centrocyte Ag-experienced mature B cell Antigene Plasmablast Mantle zone B cell Memory B cell Bone marrow Interfollicular area Follicular area Perifollicular area Peripheral blood Extranodal tissues Progenitor B cell Follicular lymphoma CLL/SLL Precursor ALL/LB DLBCL CG-type Burkitt’s lymphoma DLBCL ABC-type Mantle zone lymphoma Margianal zone lymphoma Multiple myeloma FDC Precursor neoplasms Pre-GC neoplasms GC neoplasms Post-GC neoplasms
- 11. Lymphomas associated with infectious agents Nasal, cutaneous and systemic NK/T-cell lymphomas EBV Adult T-cell leukemia/lymphoma HTLV1 Marginal zone lymphomas H pylori, B burgdorferi, C jejuni, Hepatitis C Primary effusion lymphoma, HHV-8/ KSHV LBCL associated with multicentric C astlemann disease HHV-8/ KSHV Plasmablastic, Burkitt, DLBCL, CHL EBV (subset of cases) Lymphomas with deregulation of apoptosis and survival pathways Follicular lymphoma BCL2/IGH@ MALT lymphomas API2/MALT1 and variants Lymphomas with deregulation of the cell cycle Mantle cell lymphoma CCND1/IGH@ Burkitt’s lymphoma MYC/IGH@ and variants Lymphomas with deregulation of cell signaling or transcriptional regulation Anaplastic large cell lymphoma NPM/ALK and variants Diffuse large B-cell lymphomas BCL6, NFB, Stat6 Lymphomas associated with host susceptibility factors, congenital or acquired Enteropathy-associated T-cell lymphoma Genetics, gliadin allergy Extranodal and systemic EBV T/NK cell lymphomas Genetics, host response to EBV Hepatosplenic T-cell lymphoma I mmunosuppression Lymphomatoid granulomatosis Partial immune dysfunction and EBV Burkitt lymphoma Polyclonal B-cell activation (malaria, HIV) Posttransplant lymphoproliferative ndisorders Iatrogenic immunosuppression Pathogenetic disease-oriented approach to lymphoma classification
- 12. Genetic alterations determine lymphoma entities t(14;18) t(11;14) t(8;2/7/14) t(2;5) IgH/BCL-2 IgH/cyclin D1 / /IgH/cMYC ALK/NPH Follicular lymphoma Mantle cell lymphoma Burkitt lymphoma Anaplastic large cell lymphoma BCL-2 BCL-1/cyclin D1 C-MYC ALK-1
- 13. Anaplastic large cell lymphoma genetic variants ALK Cent Tel Breakpoint cluster Translocation Partner gene Fusionprotein ALK immunreaction Ratio t(2;5)(p23;q35) NPH 80 kDa Nucleus, nucleolus, cytoplasm 75% t(1;2)(q25;p23) TPM3 104 kDa Cytoplasm 18% t(2;3)(p23;q21) TFG 85 (S) 97 (L) 113 kDa Cytoplasm 1% inv(2)(p23;q35) ATIC 96 kDa Cytoplasm 4% t(2;17)(p23;q11ter) CLTC 248 kDa Cytoplasm (granular) 1% t(2;19)(p23;p13.1) TPM4 104 kDa Cytoplasm <1% t(2;X)(p23;q11-12) Moesin 125 kDa Membrane <1% t(2;17)(p23;q25) ALO17 192 kDa Cytoplasm <1% t(2;22)(p23;q11.2) MYH9 220 kDa Cytoplasm <1%
- 14. Anatomic sites in classification of lymphomas „ The clinicopathological entities”
- 15. DLBCL – morphologic variants centroblastic immunoblasic anaplastic T cell/histiocyte rich Kiel classification (1974, 1988) Centroblastoma B-immunoblastoma B-anaplastic large cell Working formulation (1982) Diffuse large cell Diffuse large cell immunoblastic REAL (1994) Diffuse large B-cell lymphoma
- 16. DLBCL 2001-2008 WHO classification WHO (2001) Diffuse large B-cell lymphoma Morphologic variants Centroblastic Immunoblastic Anaplastic T cell/histiocyte-rich Clinicopathologic entities Primary mediastinal large B-cell lymphoma Intravascular large B-cell lymphoma Primary effusion lymphoma Lymphomatoid granulomatosis WHO (2008) Diffuse large B-cell lymphoma Morphologic variants Centroblastic Immunoblastic Anaplastic Rare variants (spindle cell, myxoid ect.) Clinicopathologic entities Primary mediastinal large B-cell lymphoma Intravascular large B-cell lymphoma Primary effusion lymphoma Lymphomatoid granulomatosis T cell/histiocyte-rich DLBCL associated with chronic inflammation ALK + large B-cell lymphoma Plasmablastic lymphoma DLBCL arising in HHV8 + Castleman Primary DLBCL of the CNS Primary cutaneous DLBCL, leg type EBV + DLBCL of the elderly
- 17. Early events in lymphoid neoplasia „Proliferations of uncertain malignant potencial”
- 19. Monoclonal B-cell lymphocytosis +12 del(13q14) IgH
- 20. Monoclonal gammopathy with uncertain significancy (MGUS) HE CD138 Kappa Lambda
- 21. bcl-2 bcl-2 „ In situ” follicular lymphoma bcl-2 CD3 t(14;18)
- 22. „ In situ” mantle cell lymphoma In-situ mantle cell lymphoma—a report of two cases N Aqel, F Barker, K Patel and K N Naresh Histopathology 2008; 52:256 Cyclin D1 Cyclin D1
- 23. Early gastric extranodal marginal zone (MALT) lymphoma CD20 t(11;18)(q21;q21) - API2 / MALT1 t(1;14)(p22;q32) - BCL10 / IgH ) +3 +18 Helicobacter ass. gastritis MALT lymphoma DLBCL HE HE HE Giemsa CD20 CD20
- 25. Lymphomatoid paulosis Type A Type B Type C CD30 CD30 CD30
- 26. Lymphomatoid paulosis Lymphomatoid papulosis Mycosis fungoides Regression
- 27. B-cell lymphomas, unclassifiable intermediate between „ Gray zone lymphomas” DLBCL – Burkitt’s lymphoma DLBCL – classical Hodgkin lymphoma
- 28. Expressional profile analysis of Burkitt and primary mediastinal large B-cell lymphomas N Engl J Med. 2006; 354:2419 J. Exp. Med. 2003, 198:851
- 29. BL Intermediate DLBCL Intermediate cHL Frequent BM, CNS involvement Diffuse proliferation Meduium- to large cells Starry sky pattern Variable nuclear size Resemble to DLBCL or LB CD19, CD20,CD22, CD79a + CD10, BCL6 + BCL2 +/- Ki67 50-100% cMYC rearrangement 35-50% BCL2 rearrangemet 15% cMYC -complex karyotype „ Double hit” Aggressive clinical course B-cell lymphoma, unclassifiable, intermediate between DLBCL-HO, DLBCL-BL Frequent mediastinal disease Sheet like growth of pleomorphic cells Diffúz - focal fibrotic stroma Hodgkin cells, RS cells, lacunar cells Different areas – different morphology Sparse inflammatory infiltrates (eo., ly., hist.) CD45 + (can be inhomogenous) CD20 + (generally diffuse) CD15 +/- CD30 + (can be inhomogenous) PAX5, OCT2, BOB.1 + Overlapping gene expression profile More aggressive than cHL or DLBCL
- 30. H&E Ki67 CD20 CD10 Burkitt lymphoma
- 31. Intermediate between DLBCL and BL BCL-2 Resembling to DLBCL Resembling to LB BL with atypical immunophenotype/genotype „ double hit”
- 32. BL Intermediate DLBCL Intermediate cHL Frequent BM, CNS involvement Diffuse proliferation Meduium- to large cells Starry sky pattern Variable nuclear size Resemble to DLBCL or LB CD19, CD20,CD22, CD79a + CD10, BCL6 + BCL2 +/- Ki67 50-100% cMYC rearrangement 35-50% BCL2 rearrangemet 15% cMYC -complex karyotype „ Double hit” Aggressive clinical course B-cell lymphoma, unclassifiable, intermediate between DLBCL-HO, DLBCL-BL Frequent mediastinal disease Sheet like growth of pleomorphic cells Diffúz - focal fibrotic stroma Hodgkin cells, RS cells, lacunar cells Different areas – different morphology Sparse inflammatory infiltrates (eo., ly., hist.) CD45 + (can be inhomogenous) CD20 + (generally diffuse) CD15 +/- CD30 + (can be inhomogenous) PAX5, OCT2, BOB.1 + Overlapping gene expression profile More aggressive than cHL or DLBCL
- 33. Primary mediastinal large B-cell lymphoma H&E H&E Reticulin CD20
- 34. Classical Hodgkin lymphoma H&E H&E H&E H&E
- 35. Classical Hodgkin lymphoma CD30 CD15 CD45 CD3
- 36. Intermediate between DLBCL and cHO H&E H&E H&E H&E
- 37. CD30 CD30 CD45 CD45 Intermediate between DLBCL and cHO
- 38. CD20 CD20 CD20 CD20 Intermediate between DLBCL and cHO
- 39. Overlapping features between lymphoma entities Mantle cell lymphoma Plasma cell myeloma CD5 CD138 Cyclin D1 Cyclin D1 t(11;14)
- 40. Pro Prognosis of lymphomas
- 41. Gene expression profile of DLBCL PNAS 2003, 100:9991
- 42. Blood 2004, 103:275 Predicting survival according to immunophenotype of DLBCL MUM-1 BCL-6 CD10
- 43. New Engl J Med 2010, 362:1417 Predicting survival according to gene expression in DLBCL
- 44. Prognostic group of mantle cell lymphoma Cancer Cell 2003, 3:185
- 45. Prognostic markers in CLL 1 10 20 30 40 50 60 70 80 90 . . . . . . . . . . CDR1 ______CDR2______ VH251 EVQLVQSGAEVKKPGESLKISCKGSGYSFT SYWIG WVRQMPGKGLEWMG IIYPGDSDTRYSPSFQG QVTISADKSISTAYLQWSSLKASDTAMYYCAR Case 1 .............................. ..... .............. ................. ................................ DP-42 EVQLVETGGGLIQPGGSLRLSCAASGFTVS SNYMS WVRQAPGKGLEWVS VIY-SGGSTYYADSVKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR Case 2 ...... . .... . .................. ..... .............. ...-............. ................................ DP-14 QVQLVQSGAEVKKPGASVKVSCKASGYTFT SNGIS WVRQAPGQGLEWMG WISAYNGNTNYAQKLQG RVTMTTDTSTSTAYMELRSLRSDDTAVYYCAR Case 3 .......................T...... .Y... .............. ...T..D.......F.. ................................ VH4.21 QVQLQQWGAGLLKPSETLSLTCAVYGGSFS GYYWS WIRQPPGKGLEWIG EII-HSGSTNYNPSLKS RVTISVDTSKNQFSLKLSSVTAADTAVYYCAR Case 4 ......................GF..A... ..... .............. ..N-............. ...V......K.L.......N........... VH26 EVQLLESGGGLVQPGGSLRLSCAASGFTFS SYAMS WVRQAPGKGLEWVS AISGSGGSTYYADSVKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAK Case 5 ......................V......K N.... .......R...... G.GA..FQ.F.P..LR. ........TR...S..V.........M...V. Blood 1999, 94:1848 N Engl J Med 2000, 343:1910
- 46. What is the future for lymphoma diagnostics?
- 47. Signaling pathways and targeted therapies in DLBCL p53 modulators - Deliver wild type p53 (Ad-p53) - Restoration wild type p53 (PPIMA-1, CDB3) Targeting BCL-2 - Inhibition BCL-2 transcription (HDAC, PPAR ) - mRNA degradation with antisense oligo (G3139) - Inhibition of BH3 domain (ABT737, TW37) - Activatin of endogenous antagonists (3CI-AHPC) NF-kB inhibitors (IKK inhibitors) -PS1145 - BMS-345 541 - Bay 11-7082 Proteosome inhibitors - PR171 - NPI-0052 - Bortezomib (Velcade) Agonistic ab-s against TRAIL receptors - ETR-1 (mapatumumab) - AMG 655 (lexatumumab)