Modern classification of lymphomas (2010) VEAB presentation

12,036 views

Published on

Modern classification of lymphomas

Published in: Health & Medicine
5 Comments
26 Likes
Statistics
Notes
  • Please, i need this presentation for teaching purpose
       Reply 
    Are you sure you want to  Yes  No
    Your message goes here
  • Are you able to share your slides for teaching of residents? I like how you approach the history of lymphoma classification. Thank you.
       Reply 
    Are you sure you want to  Yes  No
    Your message goes here
  • i need this presentation for teaching purpose
       Reply 
    Are you sure you want to  Yes  No
    Your message goes here
  • i need this presentation for teaching purpose
       Reply 
    Are you sure you want to  Yes  No
    Your message goes here
  • Excellent presentation for non expert pathologists.
    Please fix some slides that did not convert.
    Do you have a presentation with voice? Or where can I go to expand? Some or these items are hard to follow for a non-hematopathologist.
    Thanks a lot!
       Reply 
    Are you sure you want to  Yes  No
    Your message goes here
No Downloads
Views
Total views
12,036
On SlideShare
0
From Embeds
0
Number of Embeds
88
Actions
Shares
0
Downloads
0
Comments
5
Likes
26
Embeds 0
No embeds

No notes for slide

Modern classification of lymphomas (2010) VEAB presentation

  1. 1. Modern classification of lymphomas András Matolcsy 1st. Department of Pathology and Experimental Cancer Research Semmelweis University Budapest Hungary
  2. 3. Historical background of lymphoma classification <ul><li>Kiel classification 1974 </li></ul><ul><li>Working formulation 1982 </li></ul><ul><li>Kiel classification update 1988 </li></ul><ul><li>REAL classification 1994 </li></ul><ul><li>WHO classification 2001 </li></ul><ul><li>WHO classification 2008 </li></ul>Morphology/clinical Immunhistochemistry Cytogenetics, FISH Molecular biology Expressional profile
  3. 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
  4. 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
  5. 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
  6. 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
  7. 9. The role of basic science in lymphoma classification
  8. 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
  9. 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
  10. 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
  11. 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%
  12. 14. Anatomic sites in classification of lymphomas „ The clinicopathological entities”
  13. 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
  14. 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
  15. 17. Early events in lymphoid neoplasia „Proliferations of uncertain malignant potencial”
  16. 18. Early events in lymphoid neoplasia „Proliferations of uncertain malignant potencial” <ul><li>Monoclonal B-cell lymphocytosis (MBL) </li></ul><ul><li>Monoclonal gammopathy with uncertain significancy (MGUS) </li></ul><ul><li>In situ follicular lymphoma </li></ul><ul><li>In situ mantle cell lymphoma </li></ul><ul><li>Early gastric extranodal marginal zone (MALT) lymphoma </li></ul><ul><li>Lymphomatoid papulosis </li></ul>
  17. 19. Monoclonal B-cell lymphocytosis +12 del(13q14) IgH
  18. 20. Monoclonal gammopathy with uncertain significancy (MGUS) HE CD138 Kappa Lambda
  19. 21. bcl-2 bcl-2 „ In situ” follicular lymphoma bcl-2 CD3 t(14;18)
  20. 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
  21. 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
  22. 24. Lymphomatoid paulosis
  23. 25. Lymphomatoid paulosis Type A Type B Type C CD30 CD30 CD30
  24. 26. Lymphomatoid paulosis Lymphomatoid papulosis Mycosis fungoides Regression
  25. 27. B-cell lymphomas, unclassifiable intermediate between „ Gray zone lymphomas” DLBCL – Burkitt’s lymphoma DLBCL – classical Hodgkin lymphoma
  26. 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
  27. 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
  28. 30. H&E Ki67 CD20 CD10 Burkitt lymphoma
  29. 31. Intermediate between DLBCL and BL BCL-2 Resembling to DLBCL Resembling to LB BL with atypical immunophenotype/genotype „ double hit”
  30. 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
  31. 33. Primary mediastinal large B-cell lymphoma H&E H&E Reticulin CD20
  32. 34. Classical Hodgkin lymphoma H&E H&E H&E H&E
  33. 35. Classical Hodgkin lymphoma CD30 CD15 CD45 CD3
  34. 36. Intermediate between DLBCL and cHO H&E H&E H&E H&E
  35. 37. CD30 CD30 CD45 CD45 Intermediate between DLBCL and cHO
  36. 38. CD20 CD20 CD20 CD20 Intermediate between DLBCL and cHO
  37. 39. Overlapping features between lymphoma entities Mantle cell lymphoma Plasma cell myeloma CD5 CD138 Cyclin D1 Cyclin D1 t(11;14)
  38. 40. Pro Prognosis of lymphomas
  39. 41. Gene expression profile of DLBCL PNAS 2003, 100:9991
  40. 42. Blood 2004, 103:275 Predicting survival according to immunophenotype of DLBCL MUM-1 BCL-6 CD10
  41. 43. New Engl J Med 2010, 362:1417 Predicting survival according to gene expression in DLBCL
  42. 44. Prognostic group of mantle cell lymphoma Cancer Cell 2003, 3:185
  43. 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
  44. 46. What is the future for lymphoma diagnostics?
  45. 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)

×