High grade B-cell lymphomas (HGBL): Altered terminology in the 2016 WHO Classification (Update of the 4 th Edition) and practical issues Xiao-Qiu Li,

Transcription

1 High grade B-cell lymphomas (HGBL): Altered terminology in the 2016 WHO Classification (Update of the 4 th Edition) and practical issues Xiao-Qiu Li, M.D., Ph.D. Fudan University Shanghai Cancer Center April 8, 2016, Beijing

2 High grade B-cell lymphomas (HGBL) Refer to a group of heterogeneous B-NHL entities (usually featuring large cells or blastoid appearance, very high proliferation rate, and clinically highly aggressive) May include (but not restricted to) BL, B- cell lymphoma, unclassifiable, with features intermediate between DLBCL and BL (BCLU), some DLBCL subtypes (both NOS and specified), and B-lymphoblastic leukemia/lymphoma (LBL)

3 The 2016 WHO Classification of Lymphomas (LYM4+) Monoclonal B-cell lymphocytosis MGUS, IgM diseases In situ follicular neoplasia Duodenal type FL In situ mantle cell neoplasia Paediatric nodal MZL Paediatric type FL +LBCL with IRF4 rearrangement Systemic EBV+ T-cell lymphoma of childhood Hydroa vacciniform-like lymphoproliferative disorder +Monomorphic epitheliotropic intestinal T-cell lymphoma +Indolent T-cell lymphoproliferative disorder of the GI tract, NOS +EBV+ MCU, rare subtypes positive DLBCL, NOS High grade DHL or NOS +Burkitt-like lymphoma with 11q aberrations +follicular T-cell lymphoma +Nodal PTCL with TFH phenotype +Breast implant-associated ALCL

4 Burkitt lymphoma (BL)

5 Characteristics of typical BL Young patients CD10+, BCL6+, BCL2- t(8)(q24)/c-myc Ki-67 index > 95% High level expression of MYC protein MYC gene fusion with IG Absence of BCL2 or BCL6 translocation Low chromosomal complexity

6 BL: What s new? Mutations in TCF3 or its negative regulator ID3 present in 70% of sporadic and immunodeficiency-related cases and 40% of endemic ones New provisional entity in the 2016 WHO LYM4+ classification: Burkitt-like lymphoma with 11q aberration - Resemble BL morphologically, phenotypically and by GEP - Lack MYC rearrangements, but have 11q alterations (proximal gains and telomeric losses) - Frequently a nodal presentation, a certain degree of cytological pleomorphism, lower levels of MYC expression Schmitz R, et al. Nature 2012; 490: 116 Salaverria I, et al. Blood 2014; 123: 1187

7 Sometimes it s rather difficult to distinguish DLBCL from BL BL DLBCL

8 Hummel M, et al. N Engl J Med 2006; 354:

9 B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and BL (BCLU) Aggressive lymphomas having morphological and genetic features of both DLBCL and BL, but for biological and clinical reasons cannot be put into either category A provisional heterogeneous category rather than a distinct entity listed in the 2008 WHO classification Frequent complex karyotypes: some are double or triple hit lymphomas with concurrent MYC and BCL2 and/or BCL6 rearrangements; but some lack double/triple hit High grade, aggressive lymphomas resistant to therapies

10

11 CD10 BCL2 BCL6 Ki-67

12 BCL6 C-MYC t(3)(q27)/bcl-6 t(8)(q24)/c-myc

13 Double/triple-hit lymphoma (DHL) Refers to a B-cell lymphoma (other than FL or LBL) with 8q24/MYC rearrangement in combination with a translocation involving another one or two genes (e.g., BCL2, BCL6, BCL1/CCND1) The most common form is MYC/BCL2 DHL - Morphologically resemble BCLU or conventional DLBCL - Usually GCB phenotype, high proliferation rate, complex karyotype - Aggressive clinical course and poor prognosis The spectrum of MYC/BCL2 DHL has been recently broadened to include those have concurrent MYC and BCL2 cytogenetic abnormalities other than translocations Most DHLs overexpress MYC and BCL2 protein, however, most DLBCL co-expressing MYC and BCL2 (DEL) do not carry MYC and BCL2 chromosomal alterations

14 Expression of MYC protein in DLBCL Wang WG, et al. Unpublished data from FUSCC

15 Classification of DHLs Aukema SM, et al. Blood 2011; 117: 2319

16

17 BCL2 Ki-67 t(8)(q24)/c-myc

18 Double expressor lymphoma (DEL) Johnson NA, et al. Concurrent expression of MYC and BCL2 in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol 2012; 30(28): Green TM, et al. Immunohistochemical double-hit score is a strong predictor of outcome in patients with diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol 2012; 30(28):

19 Prognostic significance of DELs Green TM, et al. J Clin Oncol 2012; 30(28):

20 DHL behaves worse than DEL among DLBCLs Johnson NA, et al. J Clin Oncol 2012; 30(28):

21

22 DHL behaves worse than DEL among DLBCLs Hu S, et al. Blood 2013; 121(20):

23 DHL: Does histologic subtype (DLBCL,NOS v.s. BCLU) have prognostic relevance? DLBCL, NOS MYC IHC- MYC IHC+ BCLU DLBCL, NOS Snuderl, et al. Am J Surg Pathol 2010 BCLU Cook, et al. Am J Surg Pathol 2014

24 MYC translocation partner gene determines survival in DLBCL DH+, non-ig DH- DH+, IG Pedersen, et al. Eur J Haematol 2014

25 The 2016 WHO decision for the terminology of BCLU/HGBL The criteria for BCLU are vague and the diagnosis has not been used uniformly, limiting its utility as a diagnostic category In contrast, DHL should be unified in a single category so that they can be further studied in clinical trials All LBCL with DH can be labeled as high grade B-cell lymphoma (HGBL), with MYC and BCL2 and/or BCL6 rearrangements, and optional to further designate as DLBCL, NOS or Burkitt-like in morphology in comments Those BCLU cases lack a MYC and BCL2 and/or BCL6 rearrangement can be placed in the category of HGBL, NOS

26 Practical issues about HGBL/DLBCL Should all HGBL/DLBCL cases be submitted for an immunohistochemical detection of MYC and BCL2 expression? What a cut-off for MYC and BCL2 expression is appropriate for the diagnosis of a DEL? Can double expression of MYC and BCL2 proteins predict a DHL? Should all HGBL/DLBCL have genetic (FISH) studies for the detection of MYC, BCL2 and BCL6 rearrangements?

27 WHO LYM4+ classification of DLBCL Diffuse large B-cell lymphoma (DLBCL), NOS Germinal center B-cell type Activated B-cell type T-cell/histiocyte-rich large B-cell lymphoma Primary DLBCL of the CNS Primary cutaneous DLBCL, leg type EBV-positive DLBCL, NOS EBV-positive mucocutaneous ulcer DLBCL associated with chronic inflammation Lymphomatoid granulomatosis Primary mediastinal (thymic) large B-cell lymphoma Intravascular large B-cell lymphoma ALK-positive large B-cell lymphoma Plasmablastic lymphoma Primary effusion lymphoma HHV8-positive DLBCL, NOS HGBL, with MYC and BCL2 and/or BCL6 rearrangements HGBL, NOS B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical HL

28 Distinct types of DLBCL identified by GEP GCB v.s. ABC Rosenwald A, et al. N Engl J Med 2002; 346(25):

29

30 Immunohistochemistry algorithm

31 Scott DW, et al. Blood 2014; 123(8): Nanostring platform for GEP of DLBCL: Highly robust and reproducible method to distinguish between GCB and ABC subgroups

32 WHO LYM4+ classification of DLBCL, NOS Recommend to classify into GCB and ABC/non-GCB subtypes - Either by IHC or molecular method (specifying method used) - Important for prognostication - Important for treatment (with promising response of ABC subtype to regimens with added bortezomib, ibrutinib or lenalidomide Retain morphologic variants but not needed in the diagnosis, add the blastoid variant Avoid misinterpreting focal follicular involvement by DLBCL as a FL component Deal with double expressor (MYC, BCL2) as a prognostic indicator, not as a specific subtype, which is also not a surrogate for looking for evidence of MYC and BCL2 or BCL6 rearrangements

33 OxPhos: Enriched in genes involved in oxidative phosphorylation, mitochondrial function, and electron transport chain; higher levels of BCL2 family members BCR/proliferation: Has more abundant expression of cell-cycle regulatory genes (CDK2, MCM family members, etc.); increased expression of DNA repair genes (PMS2, H2AX, PTIP, P53); higher levels of BCR signaling cascade components (CD19, Ig, CD79a, SYK, BLK) and B-cell-related transcription factors (PAX5, OBF-1, E2A, BCL6, STAT6, MYC) HR: Enriched for markers of T-cell-mediated immune response and classical complement pathway; increased expression of an overlapping set of inflammatory mediators and connective tissue components The three consensus clusters have similar 5-yr-survivals, suggesting the clusters may be more useful for identifying potential pathogenetic mechanisms and cluster-specific therapeutic targets than predicting responses to combination CT

34 Ibrutinib Fostamatinib Idelalisib GS1101

35

36

37 EBV+ DLBCL, NOS EBER This term replaces EBV+ DLBCL of the elderly in the WHO LYM4+ classification because EBV+ DLBCL can occur in all age groups EBV+ DLBCL, NOS occurring in young patients - Often show a T-cell/histiocyte -rich large B-cell lymphoma morphology (Some overlaps with EBV+ Classical HL?) - Better prognosis than elderly patients

38

39

40 CD20 LMP1

41 Survival of EBV+ DLBCL, NOS with different therapeutic regimens CHOP RCHOP Case No. DFS OS Case No. DFS OS EBV < < EBV < < EBV- EBV- EBV+ EBV+ CHOP RCHOP Bi R, et al. Unpublished data from FUSCC

42 EBV+ DLBCL-related differential genes Gene symbol P value FDR Geom mean of intensities in EBV+ BLNK NFKBIA BLNK BCL LRMP CDC SCYA EBV+ Geom mean of intensities in EBV- Foldchange EBV- Bi R, et al. Unpublished data from FUSCC

43 Thank you