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Diagnosis of Diffuse Large B-cell Lymphoma L. Jeffrey Medeiros, MD MD Anderson Cancer Center

2008 WHO Classification of Diffuse Large B-cell Lymphoma Diffuse large B-cell lymphoma, NOS Morphologic variants Molecular subgroups (GCB vs ABC) Immunohistochemical subgroups (CD5, GCB vs non-GCB) Diffuse large B-cell lymphoma, subtypes T-cell/histiocyte-rich large B-cell lymphoma Primary DLBCL of the central nervous system Primary cutaneous DLBCL, leg-type EBV+ DLBCL of the elderly

ACCME/Disclosure Dr. Medeiros has nothing to disclose

Anticipated Updates to WHO Classification of DLBCL Diffuse large B-cell lymphoma, NOS Morphologic variants Molecular subgroups (GCB vs ABC) Immunohistochemical subgroups (CD5, GCB vs non-GCB) Diffuse large B-cell lymphoma, subtypes T-cell/histiocyte-rich large B-cell lymphoma Primary DLBCL of the central nervous system Primary cutaneous DLBCL, leg-type EBV+ DLBCL

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 large B-cell lymphoma Plasmablastic lymphoma Large B-cell lymphoma associated with HHV8+ Castleman disease Primary effusion lymphoma

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 large B-cell lymphoma Plasmablastic lymphoma HHV8+ lymphoproliferative disorders (?) Primary effusion lymphoma Large B-cell lymphoma with IRF4 rearrangement

Borderline cases B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and BL B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and CHL

Borderline cases High-grade B-cell lymphoma, NOS (2 subgroups: double hit vs other) B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and CHL

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DLBCL Variants

2008 WHO Classification of DLBCL

Centroblastic (~80%)

Immunoblastic (~10%)

Diffuse large B-cell lymphoma, not otherwise specified Common morphologic variants Centroblastic Immunoblastic Anaplastic Molecular/GEP subgroups Germinal center B-cell-like Activated B-cell-like Immunohistochemical subgroups CD5+ DLBCL Germinal center B-cell-like Non-germinal center B-cell-like WHO book, p. 234

Event-free survival

CB IB

Overall survival

CB IB

> 90% immunoblasts

107 DLBCL assessed using FISH with MYC break-apart and MYC-IGH fusion probes MYC translocations detected in: 13 / 39 (33%) immunoblastic 5 / 68 (7%) centroblastic All immunoblastic DLBCL with MYC translocations had MYC-IGH fusions

Blood 116: 4916, 2010

Am J Surg Pathol 39: 61, 2015

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“Immunoblastic / plasmablastic Variant”

“…we

modified the definition of IB-DLBCL so that these lymphomas should consist of typical CD20-positive immunoblasts and/or plasmablasts/plasmacytoid cells …. and typical centroblasts should not comprise > 10% of the total cell population. Am J Surg Pathol 39: 61, 2015

Diffuse Large B-cell Lymphoma NOS

DLBCL, Anaplastic Variant

Many Morphologic Variants Common Centroblastic (~80%)

Small CB

Immunoblastic (~10%)

Blastoid

Uncommon Anaplastic (~3%) Often sinusoidal and / or CD30+ CD30+ tumors rarely have MYC R

CD30

Rare

Multilobated (~3%)

Spindled Signet ring Myxoid Rosettes

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Starry Sky Pattern in DLBCL

2008 WHO Classification of DLBCL Diffuse large B-cell lymphoma, not otherwise specified Common morphologic variants Centroblastic Immunoblastic Anaplastic Molecular/GEP subgroups Germinal center B-cell-like Activated B-cell-like

Ki-67

Worse prognosis Increased frequency of MYC R

DLBCL Patients Treated with R-CHOP

Immunohistochemical subgroups CD5+ DLBCL Germinal center B-cell-like Non-germinal center B-cell-like

CD5+ DLBCL

CD5+ Correlates with Poorer Survival

CD79A

CD5+ in ~6% of DLBCL Older Women > men Poorer performance status Bulky Higher frequency BM+ and CNS relapse Independent of cell-of-origin classification

OS

CD5

PFS

CD5+ CD5Ken H. Young MD, PhD

~80% ABC / non-GCB type

Oncotarget 6: 5615, 2015

STAT3 and NF-κB activation BCL6 translocations ~25% Low somatic hypermutation (SHM) CD30-, rare MYC R or BCL2 R

Oncotarget 6: 5615, 2015

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Primary DLBCL of the CNS 2008 WHO Classification of DLBCL Diffuse large B-cell lymphoma, subtypes T-cell/histiocyte-rich large B-cell lymphoma Primary DLBCL of the central nervous system Primary cutaneous DLBCL, leg-type EBV+ DLBCL

Definition DLBCL of brain parenchyma including intraocular tumors Exclude Dura IVLBCL Immunodeficiency Secondary Immunophenotype CD20 IFR4 BCL6 CD10 CD138

+ ~90% ~75% 2

15/52

(29%)

LDH >2 normal

18/52

(35%)

IPI >3

28/52

(54%)

MYC/BCL2

65%

MYC/BCL2/BCL6

21%

MYC/BCL6

14%

Prognosis poor for all types

54% MYC R 28% MYC/BCL2 DHL Prognosis bad for all subsets Pei Lin, MD

MYC/BCL2 DHL and triple hit cases similar MYC/BCL6 DHL a little different More often extranodal, non-GCB

Cancer 118: 1566, 2012

Pillai et al. Am J Surg Pathol 37:323, 2013 Landsburg et al. Cancer 122:559, 2016

Gray Zone Lymphoma Two Variants

A B-lineage lymphoma that demonstrates

1. Resembles HL but has immunophenotype more like DLBCL

immunophenotypic features between classical

2. Resembles DLBCL but has immunophenotype more like HL

Hodgkin lymphoma and DLBCL.

3. A mixture of 1 and 2

overlapping clinical, morphological and / or

There is discordance between morphology and immunophenotype 2008 WHO book p.267

2008 WHO book, p.267

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Gray Zone Lymphoma HL-like Intermediate between Classical HL and DLBCL

Gray Zone Lymphoma HL-like

CD15

CD30

LCA

CD20

Gray Zone Lymphoma DLBCL-like

PAX5

What is Best Therapy for Gray Zone Lymphoma ? 24 pats treated with DA-EPOCH-R

CD15 PMBL MGZL

CD20 Median age = 33y (14-59) 63% male 46% mass >10 cm 50% high LDH

CD30

LCA

Correlates of poorer prognosis High dendritic cells (DC-SIGN) High macrophages (CD68) High CD15 Blood 124: 1563, 2014

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CHL vs GZL vs DLBCL What Are Stakes?

Classical HL

ABVD (standard)

DLBCL

R-CHOP + XRT (standard) DA-EPOCH-R (emerging)

GZL

DA-EPOCH-R

112 Patients Median age = 39y M/F = 1.5 IPI 0-2 66% 48 (43%) mediastinal 64 (57%) non-mediastinal

Non-mediastinal GZL pts Older (50 y) >1 extranodal site BM often+ Less often bulky

OS and PFS similar for mediastinal and non-mediastinal groups Rituximab associated with better outcomes DA-EPOCH-R seemed best therapy

Am J Hematol 90: 778, 2015

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