Aggressive B-cell Lymphoma 2013

Aggressive B-cell Lymphoma 2013 Diffuse Large B-Cell Lymphoma Burkitt Lymphoblastic lymphoma Gray zone Intermediate DLBCL/HL Intermediate BL/DLBCL

Diffuse Large B-cell lymphoma Common morphology: diffuse pattern, large B-cells Unique clinical staging system: IPI, R-IPI Most of them treated with R-CHOP, but Diverse clinical presentation, molecular pathogenesis immunophenotype response to therapy

The International Prognostic Index (IPI) Age >60 years Ann Arbor stage III or IV Serum LDH level Above normal Extranodal sites >1 ECOG 2

DLBCL subtypes T-cell/histiocyte-rich large B-cell lymphoma Primary DLBCL of the CNS Primary cutaneous DLBCL, leg type EBV-positive DLBCL of the elderly Other lymphomas of large B-cells Primary mediastinal (thymic) large B-cell lymphoma Intravascular large B-cell lymphoma DLBCL associated with chronic inflammation Lymphomatoid granulomatosis ALK-positive LBCL Plasmablastic lymphoma Large B-cell lymphoma arising in HHV8-associated multicentric Castleman disease Primary effusion lymphoma

Rosenwald et al N Engl J Med 2001

DLBCL: Prognostic markers: Morphology: CB vs. IB Phenotype: GCB vs. ABC Double C-MYC/BCL2 expression mirna signature expression CD30 expression

DLBCL: Prognostic markers: Morphology: CB vs. IB Phenotype: GCB vs. ABC Double C-MYC/BCL2 mirna signature CD30 expression Low reproducibility Only for R-CHOP, low reproducibility Solid, but unconfirmed Solid, but unconfirmed Unconfirmed

DLBCL: Predictive markers: GCB vs. ABC Bortezomib Unconfirmed CD30 Brentuximab Unconfirmed

BCR pathway members and PKC as potential targets in the treatment of DLBCL. Friedberg J W Clin Cancer Res 2011;17:6112-6117 2011 by American Association for Cancer Research

Age-related EBV+ DLBCL Age > 50 years No other causes of immunodeficiency or prior lymphoma More advanced stage More than one extranodal involvement Higher IPI risk group Poorer response to initial treatment Variable polymorpic infiltrate, necrosis EBV+ large cell lymphoma are excluded from this category, if Associated with chronic inflammation LyG, PBL, PEL

n 11 n 23-1 n 29-2 n 29-1

EBV-EBER EBV-LMP1 EBV-EBER EBV-LMP1

Survival estimates Age related AR-EBV+ DLBCL vs EBV- DLBCL control series EBV- DLBCL <60 y EBV- DLBCL <60 y EBV- DLBCL >60 y EBV- DLBCL >60 y AR-EBV+ DLBCL AR-EBV+ DLBCL P < 0.001 P < 0.001 EBV+ 0 12 24 36 48 60 72 84 96 108 120 N patients at risk 35 8 5 4 1 1 1 0 0 0 0 EBV- < 60y 0 12 24 36 48 60 72 84 96 108 120 N patients at risk 95 70 47 29 12 8 6 4 1 0 0 EBV- > 60y 0 12 24 36 48 60 72 84 96 108 120 N patients at risk 141 106 63 39 16 10 3 1 0 0 0 EBV+ 0 12 24 36 48 60 72 84 96 108 120 N patients at risk 34 5 3 2 1 0 0 0 0 0 0 EBV- < 60y 0 12 24 36 48 60 72 84 96 108 120 N patients at risk 95 58 37 21 10 8 6 4 1 0 0 EBV- > 60y 0 12 24 36 48 60 72 84 96 108 120 N patients at risk 141 91 54 35 13 7 3 1 0 0 0

Burkitt Lymphoma

Burkitt Lymphoma t8;14 positive medium size B-cell lymphoma, with Ki67>90% Frequent extranodal presentation, intestinal, ovarian,. 2 nd decade, bit can be seen at any age Characteristic morphological features, starry-sky, medium-size cytology,. CD20+ CD10+ Tdt- Most cases are BCL2-, but some may be positive EBV+ in endemic forms, HIV and immunodeficiency Other C-MYC translocations: peculiar features

Burkitt leukemia - 3. Peter Maslak, ASH Image Bank 2011; 2011-1118 Copyright 2011 American Society of Hematology. Copyright restrictions may apply.

bcl2

CD10

KI67

MYC

MYC

MYC

C-MYC translocation t8;14 involving IGH and C-MYC is typical for Burkitt, classical Can be seen in other B-cell lymphomas, such as DLBCL Aggressive forms of FL, CLL, MCL, CLL In classical BL usually this is the only translocation Is usually associated with increased C-MYC expression detectable by IHC But, the opposite is not always true Translocations involving IGK or IGL and C-MYC are more typical for Intermediate BL/DLBCL forms Cases lacking t8;14 are more probably intermediate BL/DLBCL

WHO 4 th Edition Clinical Advisory Committee (2007) Many cases, especially in adults, cannot be definitively classified as abl vs DLBCL Should not contaminate the categories of BL and DLBCL with these cases, which may be biologically and clinically different Provisional category: High-grade B-cell lymphoma, unclassifiable, intermediate between BL and DLBCL A heterogeneous category that needs to be further refined; not a distinct entity Allows classification of cases not meeting criteria for classical BL or DLBCL.

B-Cell Lymphoma, Unclassifiable, with Features Intermediate Between DLBCL and BL Highly proliferative lymphomas with morphological and phenotypic features between Burkitt and DLBCL Increased genomic complexity Adult cases are clinically aggressive at least three subgroups: Double hit involving c-myc and bcl2 (some of them may represent progressed FL or transformed DLBCL) Childhood DLBCL cases with MYC translocation BL cases lacking C-MYC translocation

Ki67

Double hit, MYC/BCL2

Double hit, MYC/BCL6

B-cell lymphoma with features intermediate between DLBCL and classical HL Young men with mediastinal mass but also other locations Both intermediate morphology and immunophenotype B-cell transcriptional program B(OB1, Oct2 and PAX5 +) Activation antiogens (CD30, CD15) Metachronus and composite chl and DLBCL Confluent sheets of large and pleomorphic cells with fibrosis and inflammatory infiltrate More aggresive behaviour than chl or PMBL CD20 CD30 Undefined treatment protocol Histopathology 2005; 47:101-110 Am J Surg Pathol. 2005;29:1411-21 CD15 BOB1

B-cell lymphoma with features intermediate between DLBCL and classical HL NSCHL and PMBL are 2 common young adult mediastinal lymphomas Share immunophenotypic and genetic features Ig-, loss of B-cell receptor signaling Activation of cytokine JAK-STAT pathway TNF family members expressed CD30, TRAF1 Constitutive NF-kappa B activation crel nuclear localization Aberrant activation of tyrosine kinases and activation of the PI3K/ATK pathway PMBL and CHL cell lines share gene expression profile Savage et al, Rosenwald et al, 2003

B lymphoblastic Leukemia/Lymphoma Neoplasm of lymphoblasts committed to B-cell differentiation Clinical features: Most cases <20 yrs (75% <6 años), but can be seen at any age Rarely, pure tumoral forms (initial diagnosis or relapse), in skin, bone, lymph node

B lymphoblastic Leukemia/Lymphoma Leukemic (ALL) or tumoral (LL) presentations, but one single disease Arbitrarily, the therm lymphoma is used when Process is confined to a mass lesion, and BM blast count < 25% Corresponds to ALL L1 and L2 (FAB) Leukemic Burkitt (L3) is a different condition

B lymphoblastic Leukemia/Lymphoma Morphology: characteristic, with small/medium size, round or cleaved nuclei, condensed chromatin, scarce cytoplasm Immunophenotype: Tdt+, CD19+, PAX5+, CD79a+, CD10+/-,CD20-/+, CD34+/-. Some CD99+ cases. Myeloperoxidase - Tdt

Pro-B-ALL (B-I) Common ALL (B-II) Pre-B-ALL (B-III) Mature/transicional pre-b-all TdT ++ + ++ ++ CD10 - + - + CD19 + + + ++ CD20 - + ++ ++ CD79a + + + ++ CD34 + - + + HLA-DR + -/+ + ++ c-ig - - + +

B lymphoblastic leukemia/lymphoma B-cell maduration Stem Pro-B Early-B Pre-B Naive-B H0L0 CD34 HLA-DR H0L0 ccd79a CD19 CD22 HxL0 ccd79a CD19 CD21 CD10 HxL0 ccd79a CD19 CD22 CD20 CD21 CD10 HrL0 ccd79a CD19 CD22 CD20 CD21 cμ HrLr scd79a CD19 CD22 CD20 CD21 sμ/sδ

B lymphoblastic leukemia/lymphoma Structural change Genes % Prognosis t(9;22)(q34;q11.2) BCR/ABL 3-4% Poor t11q23 MLL 2-3% Poor t(12;21)(p13;q22) TEL/AML1 15-30% Favourable Hyperdiploidy (>50) 20-25% Favourable Hypodiploid 5% Poor t(5;14)(q31;q32) IL3-IGH <1% Average t(1;19)(q23;p13.3) E2A-PBX1 6% Improved

22 yrs, leukemic infiltration

CD34 TdT

CD79a CD20 PAX5

43 yrs. Cervical lymphadenopathy

Varón 43 a. Linfoma / Leucemia linfoblástico B CD20 TDT

33 yrs, cutaneous nodules CD79a TdT

48 yrs female, gallblader

CD79a TdT

B-cell lymphoblastic lymphoma Differential diagnosis T-cell lymphoblastic lymphoma/leukemia Other neoplasms with blastic cytology: Myeloid sarcoma/aml Other B-cell lymphomas Leukemic Burkitt lymphoma Blastoid variant of MCL and FL Double hit lymphoma PNET..

Challenges/opportunities Aggressive B-cell lymphoma classification includes Rare disorders, some with paradoxical clinical behavior Gray areas, with low reproducibility in diagnosis New targeted therapies are in a very early stage, morbidity and mortality are still high Reference experts laboratories and clinical centers are required for proper diagnosis and treatment Close integration of efforts is required