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Principles of pathology and microscopic. The paradigm of diffuse large B cell lymphoma Luca Mazzucchelli Istituto cantonal...
Lymphoma subtype frequencies Histopathology 2011, 58:4-14 DLBCL
DLBCL categories <ul><li>DLBCL specifed by site </li></ul><ul><li>DLBCL with characteristic histologic, immunophenotypic o...
<ul><ul><li>Primary mediastinal lymphoma </li></ul></ul><ul><ul><li>Intravascular lymphoma </li></ul></ul><ul><ul><li>DLBC...
<ul><ul><li>T-cell/histicyte-rich-B-cell lymphoma </li></ul></ul><ul><ul><li>Anaplastic Lymphoma (ALK+) </li></ul></ul><ul...
<ul><ul><li>EBVpositive DLBCL of the elderly </li></ul></ul><ul><ul><li>DLBCL associated with chronic infection </li></ul>...
<ul><ul><li>Common morphologic variants </li></ul></ul><ul><ul><ul><li>centroblastic </li></ul></ul></ul><ul><ul><ul><li>i...
Diffuse large B-cell lymphoma A Alizadeh AA et al.: Distinct type of diffuse large  B-cell lymphoma identified by gene exp...
Decision tree for classification of DLBCL based on immunohistochemistry CD10 MUM1 bcl6 GCB GCB Non-GCB Non-GCB + + + - - -...
Immunohistochemical algorithms  (Hans, Blood 2004)  in the CHOP-treatment era <ul><li>Blood 2004; 103:275 </li></ul><ul><l...
Gene expression-based distinction of DLBCL in subgroups Gene expression-based distinction between GCB and ABC DLBCL carrie...
Clin Cancer Res 2009; 15:5494 Concordance rate with GEP of 93% versus 86%
CHOP R-CHOP GEP New Algorithm Overall Srvival Overall Srvival Clin Cancer Res 2009; 15:5494
Immunoblastic morphology but not the immunohistochemical GCB/non-GCB classifier predicts outcome in diffuse large B-cell l...
G Ott et al. Blood 2010, prepublished online August 24
G Ott et al. Blood 2010, prepublished online August 24
<ul><li>Gene expression profiling may divide DLBCLs in prognostically important subgroups </li></ul><ul><li>The applicatio...
<ul><ul><li>Common morphologic variants </li></ul></ul><ul><ul><ul><li>centroblastic </li></ul></ul></ul><ul><ul><ul><li>i...
MYC <ul><li>MYC  is a transcription factor controlling the expression of a large set of target genes involved in cell cycl...
<ul><li>303 DLBCL, all treated with R-CHOP </li></ul><ul><li>35 (14%) with  MYC -R </li></ul><ul><li>Combination with othe...
J Clin Oncol 2010; 28:3360 Univariate Kaplan-Maier analysis of overall survival in the MYC-R versus non rearranged patients
<ul><li>MYC -R occurs in 3-16% of DLBCL </li></ul><ul><li>The presence of a  MYC -R is a strong adverse prognostic factor ...
Double hit B-cell lymphomas <ul><li>B-cell lymphomas characterized by a recurrent chromosomal translocation in combination...
Double hit B-cell lymphomas <ul><li>Complex karyotypes </li></ul><ul><li>Gene expression profile intermediate between Burk...
Aukema SM et al Blood  feb. 2011, 117:2319-2331
Timing and synergy of translocation in DH lymphomas <ul><li>BCL2  and  CCND1  breakpoints are most likely mediated by RAG1...
Timing and synergy of translocation in DH lymphomas Follicular Lymphoma Mantle cell lymphoma BCL2+/MYC+ DH Lymphoma CCND1/...
How can the aggressive course of DH lymphomas be explained? <ul><li>MYC  and  BCL2  translocation may be detected in norma...
Aukema SM et al Blood  feb. 2011, 117:2319-2331
<ul><ul><li>B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and BL   </l...
DLBCL BL Burkit-like lymphoma Atypical Burkitt lymphoma Gray-zone lymphoma B-cell lymphoma unclassifiable Borderline lymph...
Adv Anat Pathol 2011, 18:219-228 Lymphoma MYC Rearrangement BL Present in >90% of cases; Primary genetic event. Translocat...
Proposed algorithm for highly aggressive lymphomas Cogliatti S et al. Br J Heamatol 2006; 134:294 (modified) Burkitt lymph...
<ul><li>Lymphoma in the gray zone between BL and DLBCL in children </li></ul><ul><ul><li>IG-MYC-positive mature aggressive...
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LLA 2011 - L. Mazzucchelli - Principles of pathology and microscopic diagnosis of lymphoma

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LLA 2011 - L. Mazzucchelli - Principles of pathology and microscopic diagnosis of lymphoma

  1. 1. Principles of pathology and microscopic. The paradigm of diffuse large B cell lymphoma Luca Mazzucchelli Istituto cantonale di patologia, Locarno ESO Course, Leukaemia and Lymphoma, Ascona, June 12-14, 2011
  2. 2. Lymphoma subtype frequencies Histopathology 2011, 58:4-14 DLBCL
  3. 3. DLBCL categories <ul><li>DLBCL specifed by site </li></ul><ul><li>DLBCL with characteristic histologic, immunophenotypic or genotypic features </li></ul><ul><li>DLBCL associated with EBV o HHV8 infection </li></ul><ul><li>DLBCL, NOS </li></ul><ul><li>Lymphoma non classifiable </li></ul>DLBCL
  4. 4. <ul><ul><li>Primary mediastinal lymphoma </li></ul></ul><ul><ul><li>Intravascular lymphoma </li></ul></ul><ul><ul><li>DLBCL of the CNS </li></ul></ul><ul><ul><li>Testicular lymphoma </li></ul></ul><ul><ul><li>Large B-cell skin lymphoma, leg-type </li></ul></ul><ul><li>DLBCL specified by site </li></ul><ul><li>DLBCL with characteristic histologic, immunophenotypic or genotypic features </li></ul><ul><li>DLBCL associated with EBV o HHV8 infection </li></ul><ul><li>DLBCL, NOS </li></ul><ul><li>Lymphoma non classifiable </li></ul>
  5. 5. <ul><ul><li>T-cell/histicyte-rich-B-cell lymphoma </li></ul></ul><ul><ul><li>Anaplastic Lymphoma (ALK+) </li></ul></ul><ul><ul><li>DLBCL CD5+ </li></ul></ul><ul><li>DLBCL specified by site </li></ul><ul><li>DLBCL with characteristic histologic, immunophenotypic or genotypic features </li></ul><ul><li>DLBCL associated with EBV o HHV8 infection </li></ul><ul><li>DLBCL, NOS </li></ul><ul><li>Lymphoma non classifiable </li></ul>
  6. 6. <ul><ul><li>EBVpositive DLBCL of the elderly </li></ul></ul><ul><ul><li>DLBCL associated with chronic infection </li></ul></ul><ul><ul><li>DLBCL with pyothorax </li></ul></ul><ul><ul><li>Plasmablastic lymphoma </li></ul></ul><ul><ul><li>Lymphomatoid granulomatosis </li></ul></ul><ul><ul><li>Primary effusion lymphoma </li></ul></ul><ul><ul><li>Large B-cell lymphoma arising in HHV8 associated multientric Castleman disease </li></ul></ul><ul><ul><li>Post-transplant lymphoma </li></ul></ul><ul><li>DLBCL specified by site </li></ul><ul><li>DLBCL with characteristic histologic, immunophenotypic or genotypic features </li></ul><ul><li>DLBCL associated with EBV o HHV8 infection </li></ul><ul><li>DLBCL, NOS </li></ul><ul><li>Lymphoma non classifiable </li></ul>
  7. 7. <ul><ul><li>Common morphologic variants </li></ul></ul><ul><ul><ul><li>centroblastic </li></ul></ul></ul><ul><ul><ul><li>immunoblastic </li></ul></ul></ul><ul><ul><ul><li>anaplastic </li></ul></ul></ul><ul><ul><li>Molecular subgroups </li></ul></ul><ul><ul><ul><li>Germinal centre B-cell-like (GCB) </li></ul></ul></ul><ul><ul><ul><li>Activated B-cell-like (ABC) </li></ul></ul></ul><ul><ul><ul><li>Unclassified </li></ul></ul></ul><ul><ul><li>Cytogenetic alterations </li></ul></ul><ul><ul><ul><li>Bcl2 </li></ul></ul></ul><ul><ul><ul><li>Bcl6 </li></ul></ul></ul><ul><ul><ul><li>C-myc </li></ul></ul></ul><ul><li>DLBCL specified by site </li></ul><ul><li>DLBCL with characteristic histologic, immunophenotypic or genotypic features </li></ul><ul><li>DLBCL associated with EBV o HHV8 infection </li></ul><ul><li>DLBCL, NOS </li></ul><ul><li>Lymphoma non classifiable </li></ul>
  8. 8. Diffuse large B-cell lymphoma A Alizadeh AA et al.: Distinct type of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 2000, 403:503
  9. 9. Decision tree for classification of DLBCL based on immunohistochemistry CD10 MUM1 bcl6 GCB GCB Non-GCB Non-GCB + + + - - - Hans et al. Blood 2004
  10. 10. Immunohistochemical algorithms (Hans, Blood 2004) in the CHOP-treatment era <ul><li>Blood 2004; 103:275 </li></ul><ul><li>Mod Pathol 2005; 18:1113 </li></ul><ul><li>Arch Pathol Lab Med 2006; 130:1819 </li></ul><ul><li>J Pathol 2006; 208:714 </li></ul><ul><li>Blood 2007; 109:4930 </li></ul><ul><li>Eur J Haematol 2007; 79:501 </li></ul><ul><li>J Clin Oncol 2006; 24:4135 </li></ul><ul><li>Histopathology 2007; 51:70 </li></ul><ul><li>Blood 2003; 101:78 </li></ul><ul><li>J Clin Oncol 2005; 23:7060 </li></ul><ul><li>Haematologica 2007; 92:778 </li></ul><ul><li>J Clin Oncol 2008; 26:447 </li></ul><ul><li>Ann Oncol 2007; 18:931 </li></ul>It works... It doesn‘t work...
  11. 11. Gene expression-based distinction of DLBCL in subgroups Gene expression-based distinction between GCB and ABC DLBCL carried a prognostic impact in the CHOP and R-CHOP treatment era Lenz G et al. N Engl J Med 2008; 359:2313
  12. 12. Clin Cancer Res 2009; 15:5494 Concordance rate with GEP of 93% versus 86%
  13. 13. CHOP R-CHOP GEP New Algorithm Overall Srvival Overall Srvival Clin Cancer Res 2009; 15:5494
  14. 14. Immunoblastic morphology but not the immunohistochemical GCB/non-GCB classifier predicts outcome in diffuse large B-cell lymphoma in the RICOVER-60 trial of the DSHNHL. G Ott et al. Blood 2010, prepublished online August 24 Extension of the study published in Heamatologica 2009; 15:5494 Immunoblastic lymphoma Immunoblastic lymphoma with plasmablastic features
  15. 15. G Ott et al. Blood 2010, prepublished online August 24
  16. 16. G Ott et al. Blood 2010, prepublished online August 24
  17. 17. <ul><li>Gene expression profiling may divide DLBCLs in prognostically important subgroups </li></ul><ul><li>The application of the Hans‘s immunohistochemical algorithm for OS prediction gives contradictory results </li></ul><ul><li>The application of new immunohistochemical algorithms must be validated in prospective studies </li></ul><ul><li>Immunoblastic morphology may predict outcome of DLBCLin CHOP and R-CHOP treated patients (multivariate analyses, but validation in prospective studies is still lacking) </li></ul>
  18. 18. <ul><ul><li>Common morphologic variants </li></ul></ul><ul><ul><ul><li>centroblastic </li></ul></ul></ul><ul><ul><ul><li>immunoblastic </li></ul></ul></ul><ul><ul><ul><li>anaplastic </li></ul></ul></ul><ul><ul><li>Molecular subgroups </li></ul></ul><ul><ul><ul><li>Germinal centre B-cell-like (GCB) </li></ul></ul></ul><ul><ul><ul><li>Activated B-cell-like (ABC) </li></ul></ul></ul><ul><ul><ul><li>Unclassified </li></ul></ul></ul><ul><ul><li>Cytogenetic alterations </li></ul></ul><ul><ul><ul><li>Bcl2 </li></ul></ul></ul><ul><ul><ul><li>Bcl6 </li></ul></ul></ul><ul><ul><ul><li>C-myc </li></ul></ul></ul><ul><li>DLBCL specified by site </li></ul><ul><li>DLBCL with characteristic histologic, immunophenotypic or genotypic features </li></ul><ul><li>DLBCL associated with EBV o HHV8 infection </li></ul><ul><li>DLBCL, NOS </li></ul><ul><li>Lymphoma non classifiable </li></ul>
  19. 19. MYC <ul><li>MYC is a transcription factor controlling the expression of a large set of target genes involved in cell cycle regulation, metabolism, DNA repair, stress response and protein synthesis (10% of human genes) </li></ul><ul><li>MYC is highly regulated at the transcriptional and posttranscriptional level, and it is involved in the regulation of miRNA expression </li></ul><ul><li>Genomic alterations of the MYC gene include chromosomal translocations, mutations affecting regulatory and promoter regions, as well as copy number increase </li></ul><ul><li>Most chromosomal breakpoints involving MYC are mediated by activation induced cytidine deaminase (ACIDA) and not by RAG1/2 gene </li></ul>
  20. 20. <ul><li>303 DLBCL, all treated with R-CHOP </li></ul><ul><li>35 (14%) with MYC -R </li></ul><ul><li>Combination with other rearrangements ( BCL2 , BCL6 ) </li></ul><ul><li>MYC -R is a strongly adverse prognostic factor (in combination with age and IPI) </li></ul>
  21. 21. J Clin Oncol 2010; 28:3360 Univariate Kaplan-Maier analysis of overall survival in the MYC-R versus non rearranged patients
  22. 22. <ul><li>MYC -R occurs in 3-16% of DLBCL </li></ul><ul><li>The presence of a MYC -R is a strong adverse prognostic factor in CHOP and R-CHOP treated patients </li></ul><ul><li>MYC -R in combination with IPI and patient‘s age accurately predict clinical outcome </li></ul><ul><li>The presence of MYC -R can not be predicted by lymphoma‘s morphology </li></ul><ul><li>MYC in DLBCL is rarely found as the sole genetic abnormality (Double-Hit lymphoma) </li></ul>J Clin Oncol 2010; 28:3360 Blood 2009; 114:3533 J Clin Pathol 2009; 62:754
  23. 23. Double hit B-cell lymphomas <ul><li>B-cell lymphomas characterized by a recurrent chromosomal translocation in combination with a MYC /8q24 breakpoint </li></ul><ul><li>DH lymphomas are rare (0-12%) </li></ul><ul><li>Most DH lymphomas have a BCL2+/MYC + combination </li></ul><ul><li>There are no unifying morphological features of DH-lymphomas </li></ul><ul><li>Most DH lymphomas have a GC phenotype (CD10+, bcl6+, bcl2+, high ki67) </li></ul>
  24. 24. Double hit B-cell lymphomas <ul><li>Complex karyotypes </li></ul><ul><li>Gene expression profile intermediate between Burkitt lymphoma and DLBCL </li></ul><ul><li>Frequent non IGH partner of MYC </li></ul><ul><li>Median age 51-65 years </li></ul><ul><li>Highly aggressive clinical behaviour </li></ul><ul><li>Elevated LDH, bone marrow and CNS involvement, high IPI score </li></ul><ul><li>Resistent to chemotherapy (median survival of only 0,2-1,5 years) </li></ul>
  25. 25. Aukema SM et al Blood feb. 2011, 117:2319-2331
  26. 26. Timing and synergy of translocation in DH lymphomas <ul><li>BCL2 and CCND1 breakpoints are most likely mediated by RAG1/2 in precursor cells </li></ul><ul><li>Most MYC breakpoints are likely mediated by AICDA in mature B cells (erroneous somatic hypermutation or class switch) </li></ul><ul><li>5% of FL with BCL2 breakpoints will acquire MYC breakpoint during the course of disease </li></ul><ul><li>Sporadic cases of lymphomas with two clones with different breakpoints have been reported </li></ul><ul><li>Secondary MYC breakpoints affect the Ig light chain whereas primary MYC breakpoints (BL) affect the Ig haevy chain </li></ul><ul><li>MYC breakpoint is most likely a secondary event in the case of BCL2 or CCND1 breakpoint </li></ul>
  27. 27. Timing and synergy of translocation in DH lymphomas Follicular Lymphoma Mantle cell lymphoma BCL2+/MYC+ DH Lymphoma CCND1/MYC+ DH Lymphoma
  28. 28. How can the aggressive course of DH lymphomas be explained? <ul><li>MYC and BCL2 translocation may be detected in normal B cells </li></ul><ul><li>FL are often indolent </li></ul><ul><li>Adult BL have a more favorable prognosis than DH lymphomas </li></ul>BCL2 is anti-apoptotic without mediating proliferative signals MYC drives cells in active and proliferative state Mature B cells PROLIFERATION APOPTOSIS
  29. 29. Aukema SM et al Blood feb. 2011, 117:2319-2331
  30. 30. <ul><ul><li>B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and BL </li></ul></ul><ul><li>DLBCL specified by site </li></ul><ul><li>DLBCL with characteristic histologic, immunophenotypic or genotypic features </li></ul><ul><li>DLBCL associated with EBV o HHV8 infection </li></ul><ul><li>DLBCL, NOS </li></ul><ul><li>Lymphoma non classifiable </li></ul>
  31. 31. DLBCL BL Burkit-like lymphoma Atypical Burkitt lymphoma Gray-zone lymphoma B-cell lymphoma unclassifiable Borderline lymphoma Intermediate between DLBCL and BL (WHO 2008) This is a heterogeneous category that is not considered a distinct disease entity, but is useful in allowing the classification of cases not meeting criteria for classical BL or DLBCL
  32. 32. Adv Anat Pathol 2011, 18:219-228 Lymphoma MYC Rearrangement BL Present in >90% of cases; Primary genetic event. Translocations involve Ig partner genes only: 85% t(8;14), 15% t(2;8) or t(8;22). Not associated with “double hit” lymphoma DLBCL Present in 7-14% of de novo cases. Usually a secondary genetic event. Translocations involve IG (70%) and non-IG (30%) partner genes. Associated with “double hit” lymphoma BCLU Present in 35-50% of cases. Translocations rarely involve IGH as a partner gene. Translocations involve IGk , IG  or non-IG partner genes. Associated with “double hit” lymphoma PBL Present in approximately 50% of cases. Translocations involve IG partner genes in the majority of cases, usually IGH . Not associated with “double hit” lymphoma
  33. 33. Proposed algorithm for highly aggressive lymphomas Cogliatti S et al. Br J Heamatol 2006; 134:294 (modified) Burkitt lymphoma MYC+ DLBCL Intermediate lymphoma Intermediate lymphoma
  34. 34. <ul><li>Lymphoma in the gray zone between BL and DLBCL in children </li></ul><ul><ul><li>IG-MYC-positive mature aggressive B-cell lymphoma </li></ul></ul><ul><ul><li>IG-MYC-negative mature aggressive B-cell lymphoma </li></ul></ul><ul><li>Lymphoma in the gray zone between BL and DLBCL in adults </li></ul><ul><ul><li>MYC negative mature aggressive B-cell lymphomas with typical Burkitt morphology and/or phenotype </li></ul></ul><ul><ul><li>MYC positive mature aggressive B-cell lymphomas lacking typical Burkitt morphology and/or phenotype </li></ul></ul><ul><ul><ul><li>IG-MYC-positive with simple karyotype </li></ul></ul></ul><ul><ul><ul><li>IG-MYC-positive with complex karyotype </li></ul></ul></ul><ul><ul><ul><li>Non-IG-MYC positive </li></ul></ul></ul><ul><ul><ul><li>Double hit lymphomas </li></ul></ul></ul><ul><ul><li>MYC-negative mature aggressive lymphomas with features intermediate between DLBCL and BL </li></ul></ul>Salaverria I and Siebert R. JCO 2011, 29:1835
  35. 35. Thank you

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