New Insights from the Lymphoma Landscape: An Update

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The 2008 World Health Organization (WHO) classification of lymphomas made new strides in the recognition of early lesions, molecular subtypes and lymphomas with features intermediate between previously well-recognized entities. In the last five years, additional investigations have led to further understanding and refinement of the proposed categories and have uncovered novel mechanisms of pathogenesis amenable for diagnostic and prognostic stratification as well as targeted therapy. Burgeoning high throughput technologies have been instrumental in shaping much of the new knowledge in the field. This presentation will aim to provide an update of the current state-of-the-art with particular emphasis on the following topics: (1) improved diagnosis and subclassification of low grade B-cell lymphomas; (2) aggressive B-cell lymphomas and borderline categories; (3) diagnostic and therapeutic implications of immunomodulation in high grade B-cell and classical Hodgkin lymphomas with challenges imposed by tumor cell, host response and stromal interactions; and (4) biomarkers in NK/T-cell lymphoma.



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New Insights from the Lymphoma Landscape: An Update

  1. 1. Yaso Natkunam MD PhDStanford UniversityAn Update
  2. 2. Outline•  WHO 2008: New strides in recognition of early lesions,molecular subtypes and borderline categories•  In 2013: High throughput tools uncover novel targetswith implications for diagnosis, prognosis and therapy•  Update on selected topics–  Improved diagnosis of small B-cell lymphomas–  Aggressive B-cell lymphomas and borderline categories–  Immunomodulation and the tumor microenvironment–  NK cell biomarkers
  3. 3. Small B-CellLymphomas•  Follicular lymphoma•  Marginal zone lymphoma•  Lymphoplasmacytic lymphoma•  Chronic lymphocytic leukemia•  Mantle cell lymphomaAnderson & Natkunam, 2010
  4. 4. “Differentiation-Linked Phenotype”TdT+ CD5+CD20+sIgMsIgDTdT+CD10+CD79a+PAX5+ CD20+CD10+BCL6+CD138+cIgGcIgACD20+CD10-BCL6-ANTIGEN Pro-B Pre-B Naïve B Plasma cellGC B Memory BAntigen-Independent Antigen-DependentB-LymphoblasticPost-GCMarginal zoneLymphoplasmacyticDLBCLPlasma cell myelomaGCFollicularBurkittDLBCLHodgkin
  5. 5. TH• Proliferation & clonal expansion• Somatic hypermutation• Class-switch recombinationB BB-cell receptorsignalingFDCB-CellLymphomaGerminal Center
  6. 6. Follicular Lymphoma•  Neoplasm of GC B-cells with at leastpartially follicular growth pattern•  Hallmark t(14;18)(q21;q32) MBR/IgHtranslocation in 90% of FL•  t(14;18) or BCL2 over-expression alone isinsufficient for neoplastic transformationBCL2 - NL BCL2 - FLCentrocyteCentroblast
  7. 7. FL: Prognosis•  Histologic Grading–  Grades 1 & 2 – indolent, incurable, diffuse areas irrelevant–  Grade 3B and/or >25% diffuse areas - worse prognosis–  Grading and proliferation – insufficient to capture heterogeneity•  Cytogenetics/progression of FL–  > 6 chromosomal breaks–  MYC, BCL6 rearrangements and inactivation of TP53–  Recurrent losses in 1p, 6q, 10q, 17p, trisomy 21, gain 1q•  GEP & MicroRNA Profiles–  Importance of microenvironment–  t(14;18) neg FL – late GC phenotype•  FL microenvironment–  Macrophage subsets: CD68 and CD163–  T-cell subsets: FOXp3 (Treg), PD-1 (TFH)•  Perifollicular pattern of Treg a/w poor prognosisHorn et al. Haematologica 2011Leich et al. Blood 2011Koch et al. Hum Pathol 2012
  8. 8. HGALLossos et al, Blood 2004Natkunam et al, Blood 2005Lu et al. Blood 2007Temmins et al. AIMM 2011Romero et al. Nature Commun 2012•  Sensitive/specific for GC B-cells•  HGAL+ DLBCL are low stage•  Regulates GC B-cell motility•  Regulates B-cell receptor signalingby Syk activation leading tolymphoid hyperplasia and massiveamyloidosis in HGAL transgenic miceAmyloidosisWT SCA1-HGALHGALPAX5
  9. 9. HGALInterfollicularComponent•  Positive in CD10- FL•  Not downregulated ininterfollicularcomponent•  Down regulated inbone marrowmicroenvironmentYounes et al. AJSP 2010
  10. 10. In situ Follicular LymphomaBCL2 BCL2BCL2
  11. 11. FLIS•  Scattered strong BCL2+follicles in normal NL–  FL in subset–  Colonization of pre-existingfollicles–  A/W other neoplasia – markerof genomic instability?•  Patients with this findingshould be evaluated forFL but not treated•  High grade BCL2- cases–  Clonal B-cells in normalfollicles–  Circulating t(14:18)+ B-cells in healthy individualsBala et al. 2013 unpublished
  12. 12. •  Most common chronic leukemia; typically in older adults•  Monotonous small B-cells in PB, BM > LN•  Admixed prolymphocytes and paraimmunoblasts•  CLL FISH panel•  Del 13q14 (50%), Trisomy 12 (20%),del 11q22-23, 17p13, 6q21•  Two molecular subtypes•  Ag-naïve: unmutated IgVH•  Ag-experienced: mutated IgVH•  ZAP70 surrogate•  Transformation•  Large cell (Richters)•  Prolymphocytic leukemia•  Classical Hodgkin-likeChronic Lymphocytic Leukemia
  13. 13. •  Whole genome seq–  Recurrent mutations a/w prognosis–  NOTCH1, XPO1, MYD88•  12% CLL, high stage & adverse outcome•  Unmutated IgVH•  Faster progression to DLBCL•  LEF1–  WNT/beta-catenin signaling–  Normal: T-cells & pro-B, not mature B–  CLL: 100%–  Increased: Proimmunoblasts, Richters & DLBCL•  pERK–  Aberrant expansion of anergic B-cells–  Signaling inhibitors induce apoptosisCLL – Signaling MoleculesPuente et a. Nature 2011Gutierrez et al. Blood 2010Tandon et al. Mod Pathol 2011Apollonio et al. Blood 2013LEF1 Richters
  14. 14. Lymphoplasmacytic Lymphoma”Waldenstroms Macroglobulinemia”•  Closely overlapswith MZL inmorphology andimmunophenotype•  MYD88 mutationL265P in 91%–  Not exclusiveTreon et al, NEJM, 2012
  15. 15. Marginal Zone Lymphoma•  Lymphoma of heterogeneous small B-cells•  Three categories: Extranodal, Nodal, Splenic•  Etiology varies with anatomic & geographic location–  H. pylori ~ 60-90% gastric–  Chlamydia sp ~ 10-47% ocular–  Hashimoto thyroiditis ~94%–  Sjogren syndrome ~85%•  Challenges in diagnosis–  No specific marker–  Overlap with other small BCL–  Refractory subtypesMarginal zone
  16. 16. MNDAMarginal zone cellsKanellis et al Leukemia 2009Freud et al. 2013 unpublished
  17. 17. AggressiveB-CellLymphoma•  Burkitt lymphoma•  Diffuse large B-cell lymphoma, NOS•  Primary mediastinal large B-cell•  Intravascular large B-cell lymphoma•  Primary effusion lymphoma•  BCL unclassifiable: DLBCL/Burkitt•  BCL unclassifiable: DLBCL/CHL•  Large B-cell lymphoma arising in HHV8-associated multicentric Castleman disease•  ALK-positive large B-cell lymphoma•  DLBCL a/w chronic inflammation•  Lymphomatoid granulomatosis
  18. 18. DLBCL• Common• Heterogeneous• 40-50% cure rates
  19. 19. WHO 2008: Borderline Categories•  Not distinct entities, but temporary categoriesthat await further study and refinement•  Allows classification of cases not meeting criteriafor distinct diagnostic entities•  Not intended as convenient waste baskets•  Requires a multidisciplinary approach for patientmanagement1.  B-cell lymphoma, unclassifiable, with featuresintermediate between DLBCL and Burkitt lymphoma2.  B-cell lymphoma, unclassifiable, with featuresintermediate between DLBCL and classical Hodgkinlymphoma
  20. 20. •  Morphology–  Intermediate between BL andDLBCL•  Immunophenotype–  CD10+ BCL6+–  Variable Ki-67–  Variable BCL2, often positive•  Genetics–  MYC, BCL2/18q32, BCL6/3q27–  Double hit/triple hit–  Complex karyotypes•  Clinical–  Rare progression of FL–  Aggressive, especially double hitBCL Unclassifiable: DLBCL and BurkittKi67Dave et al. NEJM 2006Hummel et al. NEJM 2006Harris 2008DLBCLABC GC PM UNBkt
  21. 21. •  MYC rearrangement–  IG-MYC common–  Non IG-MYC sometimes•  Double-hit (Triple hit): MYC/8q24 in combination withBCL2/18q21 and/or BCL6/3q27•  MYC-complex karyotype - common•  MYC-simple karyotype - rare•  BCL2 or BCL6 without MYC - rare•  Transformed FL (Blastic FL) - rareBCLU: Genetic Features
  22. 22. “Double-Hit” B-Cell LymphomasAukema et al, Blood 2010Snuderl et al, AJSP 2010Alizadeh et al, ASH, Dec 2010Am. Soc Hematology, Dec 2010•  Incidence difficult to assess•  Patients with poor prognostic factors•  High IPI, elevated LDH, BM and CNS involvement•  Poor outcome despite high intensity chemo or RCHOP -Does worse than Burkitt or DLBCL•  Prognosis not explained by myc/8q24 alone•  Additional hits – BCL2 or karyotypic complexity•  In Children, Ig/MYC breakpoints and simplekaryotypes are common and are best diagnosed asBurkitt lymphoma
  23. 23. •  Aggressive mature B-cell lymphomas shouldbe systematically studied using ancillarytests, in particular, FISH•  Features that are worrisome•  GCB-immunophonotype with BCL2 expression•  High growth fraction•  BM or CNS involvement•  Proliferation index (Ki-67 IHC) is not a goodindicator of aggressivity or double-hit cases“Double-Hit” B-Cell LymphomasRecommendationsJohnson et al, Blood 2009Aukema et al, Blood 2010
  24. 24. THB BB-cell receptorsignalingFDCB-CellLymphomaHost/ImmuneMicroenvironment• Co-stimulatory molecules• Immune microenvironmentIdentification of Risk GroupsTumor CellBiomarkers• LMO2• HGAL
  25. 25. Two-Gene Model• LMO2 – Tumor cell• CD137 – Immune microenvironment• Multiple GEP datasets on total of 787 DLBCL patientsLMO2 green, CD79a redNatkunam et al. Blood 2007Natkunam et al. JCO 2008Alizadeh et al. Blood 2011
  26. 26. Inducible Co-Stimulatory Target• Stimulation of CD137 enhances anti-lymphoma activity ofanti-CD20 antibodies• Synergy between anti-CD137 and anti CD20 may reduce oreliminate the need for chemotherapyKohrt et al. Blood 2011
  27. 27. 750 HematopoieticNeoplasmsCD137+Follicular dendritic tumor 86%Classical Hodgkin 86%T-cell lymphoma 58%Extranodal NK/TCL 37%Anderson et al. AJP 2012CD137CD137 redCD3 greenCD137 redOCT2 green
  28. 28. CD137 LigandZhao et al. AJSP 2012CD137L red, CD137 greenCD137L red, PAX5 greenPrimaryfolliclesSecondaryfollicles•  Majority of B-cell lymphoma•  Not in classicalHodgkinlymphoma•  Good marker ofmantle celllymphoma•  Marker ofmemory B-cells
  29. 29. HRS Cells and Immune MicroenvironmentGascoyne EHA 2012Natkunam et al. Blood 2007Juszczynski et al. PNAS 2007Green et al. Blood 2010Steidl et al. NEJM 2010Azambuja et al. Ann Onc 2012Anderson et al. AJP 2012Sanchez-Espiridion et al. Hematologica 2012HGAL Galectin-19p24.1 amplificationPD-L1/L2 & JAK2TAM and CD68CD137
  30. 30. Mature T and NK LymphomasWHO 2008•  Predominantly Nodal–  Peripheral TCL, NOS–  Angioimmunoblastic TCL–  Anaplastic large cell lymphoma, ALK+–  Anaplastic large cell lymphoma, ALK-–  Adult T-cell leukemia/lymphoma•  Predominantly Leukemic–  T-cell LGL leukemia–  Chronic LPD of NK cells–  Aggressive NK-cell leukemia–  Sezary syndrome•  Predominantly Extranodal–  NK/T-cell lymphoma, nasal type–  Enteropathy-associated TCL–  Hepatosplenic TCL–  Subcutaneous Panniculitis-like TCL–  Systemic EBV+ T-cell LPD of childhood•  Predominantly Cutaneous–  Mycosis Fungoides–  Primary cutaneous CD30+ T-cell LPD–  Primary cutaneous gamma/delta TCL
  31. 31. • Natural killer (NK) cells arelarge granular lymphocytes• 5-15% of blood lymphocytes;<1-2% of lymph node cells• Traditionally considered partof innate immune system• Recognize and kill malignant orinfected cells• Secrete chemokines, cytokinesand other molecules to promoteimmunityNK Cells
  32. 32. CD335 in NK CellsCD2CD7CD56CD16CD57CD161KIRCD2CD7CD56CD16CD57CD161KIRCD2CD56CD16CD2CD7CD56CD16CD56NK cell T cell Monocyte Myeloid Plasma cellCD335 CD335 CD335 CD335CD56 CD335 CD335 CD335• NK cells express pan-NKsurface antigens and lack non-NK markers (CD3, CD19)• These markers are not specificto NK cells• CD335 (NKp46) is an activatingreceptor on mature NK cells• It selectively labels CD3-CD56+ NKcells in normal adult blood• CD335 was evaluated to assesspotential diagnostic utility(CD3-)
  33. 33. CD335 is a Specific Marker of NK CellsCD56 CD335CD335 CD335(CD3-)Normal adult blood· CD335 is a highly specific markerof human NK cells (CD3-CD56+) andis expressed in at least a subset ofNK cell neoplasms (ENKL)· CD335 is aberrantly expressed in asubset (20%) of mature T cellneoplasms (T-LGL, ALCL, ALK+, MF,PTCL, NOS)·  Flow cytometry and IHC data showpromising utility of this marker inthe diagnostic evaluation of NK andT cell neoplasiaFreud et al, 2013 unpublished
  34. 34. THB BB-cell receptorsignalingFDC B-CellLymphomaUnderstanding Disease HeterogeneityTumor CellBiomarkers• Co-stimulatory molecules• CD137-CD137L signaling• PD1-PD-L1/L2 signaling• Tumor infiltrating cells• Regulatory T-cells• Th1, Th2, Th17• Macrophage subsets• Dendritic cell subsets• NK cellsHost/ImmuneMicroenvironment
  35. 35. StanfordPathology OncologyRoger Warnke Ronald LevyShuchun Zhao Ash AlizadehMatthew Anderson Ranjana AdvaniCaroline Temmins Holbrook KohrtAharon Freud Debra CzerwinskiDita Gratzinger Behnaz TaidiRyan MetcalfSheren YounesStatistics & InformaticsRobert TibshiraniRobert MarinelliAcknowledgementsU Miami, FloridaIzidore S LossosGerald ByrneRio de Janeiro, BrazilDenize AzambujaNelson SpectorGuatemala CityHernan Molina Kirsch

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