High grade B-cell lymphomas (HGBL): Altered terminology in the

Transcription

High grade B-cell lymphomas (HGBL): Altered terminology in the
High grade B-cell lymphomas
(HGBL): Altered terminology in the
2016 WHO Classification (Update of
the 4th Edition)
and practical issues
Xiao-Qiu Li, M.D., Ph.D.
Fudan University
Shanghai Cancer Center
April 8, 2016, Beijing
High grade B-cell lymphomas
(HGBL)

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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, Bcell lymphoma, unclassifiable, with features
intermediate between DLBCL and BL
(BCLU), some DLBCL subtypes (both NOS
and specified), and B-lymphoblastic
leukemia/lymphoma (LBL)
The 2016 WHO Classification of Lymphomas (LYM4+)
Monoclonal B-cell lymphocytosis
MGUS, IgM
diseases
Paediatric nodal MZL
In situ follicular neoplasia
Duodenal type FL
In situ mantle
cell neoplasia
Systemic EBV+ T-cell lymphoma of childhood
Hydroa vacciniform-like lymphoproliferative disorder
Paediatric type FL
+LBCL with IRF4
rearrangement
+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
Burkitt lymphoma (BL)
Characteristics of typical BL

Young patients

CD10+, BCL6+, BCL2-

Ki-67 index > 95%

High level expression of
MYC protein

MYC gene fusion with IG

Absence of BCL2 or BCL6 translocation

Low chromosomal complexity
t(8)(q24)/C-MYC
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
Sometimes it’s rather difficult to
distinguish DLBCL from BL
BL
DLBCL
Hummel M, et al. N Engl J Med 2006; 354: 2419-30
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
CD10
BCL2
BCL6
Ki-67
BCL6
t(3)(q27)/bcl-6
C-MYC
t(8)(q24)/c-myc
“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
Expression of MYC protein in DLBCL
Wang WG, et al. Unpublished data from FUSCC
Classification of DHLs
Aukema SM, et al. Blood 2011; 117: 2319
BCL2
Ki-67 t(8)(q24)/c-myc
“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):
3452-9
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): 3460-7
Prognostic significance of DELs
Green TM, et al. J Clin Oncol 2012; 30(28): 3460-7
DHL behaves worse than DEL
among DLBCLs
Johnson NA, et al. J Clin Oncol 2012; 30(28): 3452-9
DHL behaves worse than DEL
among DLBCLs
Hu S, et al. Blood 2013; 121(20): 4021-31
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
MYC translocation partner gene
determines survival in DLBCL
DH+, non-IG
DH-
DH+, IG
Pedersen, et al. Eur J Haematol 2014
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”
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?
WHO LYM4+ classification of DLBCL
















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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
Distinct types of DLBCL identified by GEP
GCB v.s. ABC
Rosenwald A, et al.
N Engl J Med 2002;
346(25): 1937-47
Immunohistochemistry algorithm
Nanostring platform
for GEP of DLBCL:
Highly robust and
reproducible method
to distinguish
between GCB and
ABC subgroups
Scott DW, et al. Blood 2014; 123(8): 1214-7
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
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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
Ibrutinib
Fostamatinib
Idelalisib
GS1101
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
CD20
LMP1
Survival of EBV+ DLBCL, NOS with
different therapeutic regimens
CHOP
Case No.
EBV+
14
EBV-
79
DFS
< 0.001
RCHOP
OS
< 0.001
Case No.
10
62
DFS
OS
< 0.001
< 0.001
EBVEBV-
EBV+
EBV+
CHOP
RCHOP
Bi R, et al. Unpublished data from FUSCC
EBV+ DLBCL-related differential genes
Gene
symbol
P value
FDR
Geom mean
of
intensities
in EBV+
Geom mean Foldof
change
intensities
in EBV-
BLNK
0.0003381
0.0159
592.5
1214.82
0.49
NFKBIA
0.0025516
0.06
BLNK
1887.96
1.35
BCL6
0.0248577
0.273
575.13
927.76
0.62
LRMP
0.0250088
0.273
653.37
1091.59
0.6
CDC7
0.0346789
0.273
273.26
212.11
1.29
SCYA3
0.0349144
0.273
265.89
166.43
1.6
EBV+
EBV-
Bi R, et al. Unpublished data from FUSCC
Thank you