5/23/2013 Double Hit Lymphomas Double Hit Lymphomas • What are double hit lymphomas? • Historical perspectives • Recognizing DHLs among Burkitt Burkitt Lymphoma Double Hit DLBCL and Burkitt-like lymphomas Lymphoma • Recognizing DHLs among DLBCL MYC BCL2 • Beyond Double Hits: Recognizing “double hit biology” by IHC Patrick Treseler, MD, PhD University of California San Francisco BCL2 BCL2 BCL2 BCL2 MYC MYC MYC MYC BCL6 BCL6 BCL6 BCL6 or or or or Double Hit Lymphomas 1
5/23/2013 Double Hit Lymphoma � DHL is a genotype associated with a very poor prognosis in various B-cell neoplasms � Lymphomas with double-hit genotype: – Burkitt or Burkitt-like lymphoma (most common) (many in WHO “gray zone” category B-UNC/DLBCL/BL) – Diffuse large B-cell lymphoma (less common) – TdT+ B-cell lymphoblastic leukemia/lymphoma (occ.) Friedberg J W JCO 2012;30:3439-3443 – Low-grade follicular lymphoma (rare) Fluorescent in situ hybridization of tumor cells demonstrating (A) presence of t(14;18) and (B) split at MYC locus (red 5 ′ and – Plasmablastic lymphoma (rare) green 3 ′ regions). Double Hit Lymphoma Is MYC the second hit? � Many DHLs arise in patients with prior follicular lymphoma, often with known BCL2 translocations Historical Perspectives � BCL2 translocations mediated by recombinase activating gene 1/2 (RAG1/2) in precursor B-cells; MYC translocations mediated by activation induced cytidine deaminase (AICDA) in mature B-cells � MYC translocations in DHL often to IG light chain genes or non-IG genes 2
5/23/2013 Cytogenetics and Survival in HG Burkitt-Like Lymphoma . High-Grade Burkitt-Like Lymphoma (Adults & Children) Macpherson et al. J Clin Oncol 17:1558; 1999 High-Grade Burkitt-like (REAL 1994): Generally resembles Burkitt lymphoma but has: � Younger � – “Morphologic features intermediate between large MYC only Low-stage � cell lymphoma … and typical Burkitt’s lymphoma” Simpler � karyotypes Noted to have frequent translocations of BCL2 � (unusual in typical Burkitt lymphoma) Older � High-stage � MYC + BCL2 dual Complex (double hit) � karyotypes Normal Single Green=Ig balanced AJSP 29: 1652; 2005 Red=MYC Ig/MYC Multiple MYC Ig/MYC amplification Ig/MYC & MYC amplification McClure et al. AJSP 29: 1652; 2005 Li et al. Mod Pathol 25:145 3
5/23/2013 McClure et al. AJSP 29: 1652; 2005 AJSP 29: 1652; 2005 AJSP 29: 1652; 2005 P = 0.03 P = 0.003 P = 0.03 P = 0.003 Both! (“Double hit”) McClure et al. AJSP 29: 1652; 2005 P = 0.008 P = 0.008 P = 0.32 (NS) P = 0.32 (NS) McClure et al. AJSP 29: 1652; 2005 Snuderl et al. AJSP 34: 327; 2010 AJSP 29: 1652; 2005 BL P = 0.03 P = 0.003 DLBCL Double Hit P = 0.32 (NS) P = 0.008 Snuderl et al. AJSP 34: 327; 2010 4
5/23/2013 Double Hit Lymphoma � DHL may explain difference in long-term survival between pediatric & adult BL/BLL – Pediatric: 70-80% Recognizing DHLs Among – Adult: 15-25% Lymphomas Resembling � DHL tends to: � Occur in older patients (30%) Burkitt Lymphoma � Show very complex karyotypes BCL2 � Show strong staining for BCL2 � But some adults with BL/BLL will have genetically simple single-hit disease – important for us as pathologists identify these different populations! HGBL vs. Gray Zone � High-Grade Burkitt-like (REAL 1994): Generally resembles BL but has: – “Morphologic features intermediate between large Burkitt cell lymphoma … and typical Burkitt’s lymphoma” Lymphoma “Gray Zone” Lymphoma DLBCL � B-UNC/DLBCL/BL (WHO 2008): ( B-UNC/DLBCL/BL) Generally resembles BL (most cells Burkitt-like), but has either: – significant population of large cells, or – abnormal immunophenotype (esp. BCL2+) 5
5/23/2013 Typical BL Typical BL Typical BL Acceptable for BL 6
5/23/2013 Too Many Large Cells DLBCL Burkitt Lymphoma � Typical immunophenotype: “I entirely agree with you (and feel myself CD20 + supported by many others like Elaine Jaffe) CD10 + that from a morphologic point of view, we BCL6 + really should be liberal in diagnosing Burkitt BCL2 - lymphoma as long as the tumor cells have a CD10 typical phenotype and MYC breakpoint (and CD43 + lack a BCL2 and BCL6 breakpoint).” CD5 - - Philip Kluin, 2011 (personal communication) TdT - sIg + BCL6 BCL2 7
5/23/2013 Molecular Diagnosis of Burkitt Lymphoma (Hummel et al. NEJM 354: 2419; 2006) Pathologic Features of molecular BL Cases CD10+ 100% BCL6+ 100% BCL2+ 19% ← BL can be BCL2+? Any MYC trans. 91% ← 9% will lack MYC! Ki-67 ≥ 95% 66% ← 34% Ki-67 <95%! Dave SS et al. N Engl J Med 2006;354:2431-2442 . Burkitt Lymphoma Burkitt Lymphoma � Typical karyotype: Guidelines & rules of thumb for diagnosis � Be liberal in diagnosing Burkitt lymphoma as long as Most have translocations the tumor cells have a typical phenotype and MYC linking MYC to Ig genes: translocation (and lack BCL2 & BCL6 translocations) - t(8;14) → MYC-IGH � DLBCL morphology excludes Burkitt lymphoma - t(2;8) → MYC-IGL-κ � Burkitt lymphoma will lack MYC translocation in 10% - t(8;22) → MYC-IGL- λ of cases; diagnosis still permitted if all other features completely typical � But… � Non-IG translocations rare in true Burkitt lymphoma − Non-IG partner favors DHL (34%) over BL (2%) � Complex karyotype by standard cytogenetics argues − 10% BL will lack MYC translocations by FISH, against Burkitt lymphoma 2008 WHO still permits dx of BL provided case is “otherwise completely typical” 8
5/23/2013 Finding DHLs Among DLBCLs The Problem… � DLBCLs that are DHLs often present with high-stage Recognizing DHLs Among disease, but so do many other DLBCLs � No distinctive morphology or immunophenotype Diffuse Large B-Cell � Most CD10+ BCL6+ MUM1- by IHC, consistent with Lymphomas “good prognosis” DLBCL subgroup per Hans et al., yet have highly lethal with median survival <1 year � DHLs only ~5% of DLBCLs, so FISH testing of all DLBCL cases would yield manly negative results � Yet DLBCL so much more common than Burkitt lymphoma that DLBCL DHLs nearly as numerous as Burkitt-like DHLs in total number Finding DHLs Among DLBCLs The Solution? � New antibody recently developed that correlates well Beyond Double Hits: with MYC protein levels in tissue by IHC � Long known that translocation only one mechanism Detecting “Double Hit Biology” of MYC activation (amplification, mutation, miRNA by Immunohistochemistry dependent mechanisms are others) � MYC protein expression may be “final common pathway” for all MYC activation mechanisms. � Three IHC studies recently published to test whether IHC for MYC and BCL2 protein could be as good or better than FISH to detect “double hit biology.” 9
5/23/2013 Detecting DHL in DLBCL by IHC Detecting DHL in DLBCL by IHC Green et al. J Clin Oncol 30:3460; 2012 Johnson et al. J Clin Oncol 30:3452; 2012 MYC MYC BCL2 “Double Hit Score” (DHS): ▪ MYC ≥40% cells (median): ▪ BCL2 ≥70% cells (median): 1 point − Survival difference by IHC score IHC Scoring: ▪ Total point range: 1 point ▪ MYC+: independent of IPI score, COO subtype, 0-2 points ▪ BCL2+: ≥50% cells ≥40% cells & presence of true double-hit by FISH − High level MYC staining insignificant unless BCL2 overexpressed as well Increased identification of patients with “double hit biology” from 6% to 29%! − 2/3 DHL long-term survivors MYC <40% Detecting DHL in DLBCL by IHC Double-hit B-cell Lymphomas with BCL6 and MYC Translocations Horn et al. Blood 121:2253; 2013 Pillai R. et al. American Journal of Surgical Pathology 37(3):323-332, March 2013 IHC Scoring: ▪ MYC high (>40% cells): ▪ BCL2 high: >0% cells 1 point ▪ BCL6 high: >25% cells “Sum Score”: ▪ MYC hi (>40% cells): 1 point ▪ BCL2 hi (>0% cells): ▪ BCL6 hi (>25% cells): 1 point 1 point ▪ Sum point range: 0-3 points Overall Survival (Months) 10
5/23/2013 Diffuse Large B-Cell Lymphoma BCL2 BCL2 BCL2 BCL2 Prognostic Markers MYC MYC MYC MYC BCL6 BCL6 BCL6 BCL6 � CD10 or or or or “Cell of origin” � BCL6 per Hans et al. � MUM1 � MYC “Double hit score” per Green et al. � BCL2 AJSP 29: 1652; 2005 P = 0.03 P = 0.003 McClure et al. AJSP 29: 1652; 2005 P = 0.32 (NS) P = 0.008 11
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