2. findings and B-cell lineage it is somewhat ‘old fashioned’
compared with the definitions of some other entities in the
WHO classification in which molecular abnormalities are an
essential part of the definition.
The 2016 update, compared with the 2008 version of the
WHO classification, made relatively few changes to the
category of DLBCL (Table 1). The following modifications
were made:9
1. Cell-of-origin classification, i.e., germinal centre B-cell
(GCB) versus activated B-cell (ABC) or non-GCB type
should be included in the pathology report.
2. CD5 expression appears to have prognostic value and
should be assessed.
3. Emphasis is placed on expression of MYC and BCL2
(double expressor) as assessed by immunohistochemistry
as an adverse prognostic factor.
4. The provisional category ‘B cell lymphoma, unclassifi-
able, with features intermediate between DLBCL and
Burkitt lymphoma’ (BCLU) included in the 2008 WHO
classification is eliminated and replaced by two new
categories:
a. High-grade B-cell lymphoma, with MYC and BCL2
and/or BCL6 translocations (also known as double-hit
or triple-hit lymphoma);
b. High-grade B-cell lymphoma, not otherwise specified.
CLINICAL PRESENTATION
DLBCL is the most common type of non-Hodgkin lym-
phoma, worldwide and in the United States.10,11
The inci-
dence rate is 6.3% with an estimated 25,380 new cases in the
United States in 2016.11
DLBCL is more prevalent in elderly
patients with a median age in the 7th decade, although it also
occurs in young adults and rarely in children. There is a slight
male predominance. Clinically, most patients present with a
rapidly growing tumour mass involving one or more lymph
nodes and extranodal sites.8,12
Approximately 40% of pa-
tients present with extranodal disease. Virtually any tissue
organ can be the primary site of DLBCL, but gastrointestinal
tract is the most common site. About one-third of patients
with DLBCL present with B symptoms (fever, weight loss,
night sweats) and some patients present with symptoms
related to organ(s) involvement. Serum lactase dehydroge-
nase (LDH) and beta-2-microglobulin are often increased
above normal. Approximately half of patients present with
stage I-II disease whereas the other half present with stage
III–IV disease. The frequency of bone marrow involvement
is about 10–20%, dependent on the study, and involvement
includes two forms: concordant (bone marrow involved by
DLBCL) and discordant (bone marrow involved by low-
grade B cell lymphoma). Only concordant involvement pre-
dicts a worse overall survival.13,14
MORPHOLOGY
The name diffuse large B-cell lymphoma is self-explanatory.
The lymphoma cells are large and arranged in a diffuse
pattern that totally or partially effaces normal nodal or
extranodal architecture.15
Fine fibrosis may compartmen-
talise groups of lymphoma cells or the neoplasm may be
associated with sclerosis. Areas of geographic necrosis may
be present. Single cell apoptosis can be prominent and the
mitotic rate may be high. About 10% of cases of DLBCL are
associated with a starry sky pattern. This pattern is almost
always associated with a high proliferation rate. Variable
numbers of background reactive small T cells and histiocytes
are present in all cases of DLBCL.
The cytological findings in DLBCL are diverse. A number
of variants of DLBCL have been described but the centro-
blastic, immunoblastic, and anaplastic variants are most
common (Fig. 1).
Centroblastic variant
This is the most common morphological variant representing
approximately 80% of all DLBCL cases. Centroblasts are
large cells with a moderate amount of cytoplasm, round to
oval vesicular nuclei, vesicular chromatin, and 2–3 small
nucleoli often peripherally located adjacent to the nuclear
membrane. This variant can also show a spectrum, from
monomorphic tumours composed predominantly of centro-
blasts (>90%), to polymorphic tumours that consist of a
mixture of centroblasts (<90%), centrocytes, and
immunoblasts.
Immunoblastic variant
This variant represents 8–10% of cases of DLBCL. Tradi-
tionally, the immunoblastic variant has been defined by the
presence of at least 90% immunoblasts in the neoplasm.8
Immunoblasts are large lymphoid cells, each having
moderate-to-abundant basophilic cytoplasm and a prominent,
centrally located, trapezoid-shaped nucleolus, often with fine
strands of chromatin attached to the nuclear membrane
(‘spider legs’). In some cases, the immunoblasts can show
marked plasmacytic differentiation (and need to be distin-
guished from plasmablastic lymphoma and plasma cell
myeloma based on immunophenotypic and genetic findings).
More recently, Horn and colleagues16
have proposed
expanding the definition of the immunoblastic variant to
Table 1 2016 update of WHO classification of DLBCL: subtypes and
related entities
Diffuse large B-cell lymphoma, NOS
GCB versus ABC/non-GCB
MYC and BCL2 double expressor
CD5+
DLBCL subtypes
T-cell/histiocyte-rich large B-cell lymphoma
Primary DLBCL of the central nervous system
Primary cutaneous DLBCL, leg type
EBV positive DLBCL, NOS
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
HHV8+ DLBCL, NOS
Primary effusion lymphoma
Borderline cases
High-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6
translocations
High-grade B-cell lymphoma, NOS
B-cell lymphoma, unclassifiable, with features intermediate between
DLBCL and classical Hodgkin lymphoma
ABC, activated B-cell like; DLBCL, diffuse large B-cell lymphoma; GCB,
germinal centre B-cell like; HHV8, human herpesvirus 8; NOS, not
otherwise specified; WHO, World Health Organization.
2 LI et al. Pathology (2017), -(-), -
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3. include cases that contain less than 10% centroblasts, thereby
allowing inclusion of tumours in which immunoblasts and
plasmacytoid cells represent >90% of all cells, even though
the number of classical immunoblasts fails to reach the 90%
threshold.
Anaplastic variant
This variant is much less common, and represents about 3%
of all cases of DLBCL. The anaplastic variant is characterised
by large or very large lymphoma cells with pleomorphic or
bizarre nuclei. The lymphoma cells can mimic Hodgkin and
Reed–Sternberg cells or the cells of anaplastic large cell
lymphoma. The anaplastic variant often has a partial or
extensive sinusoidal pattern.
Rare variants
There are a number of other morphological variants of
DLBCL. The lymphoma cells can have multilobated or
cloverleaf-shaped nuclei. In our experience, these cases are
commonly extranodal (e.g., primary mediastinal B-cell lym-
phoma). In other cases the lymphoma cells are smaller than
typical large lymphoid cells (so-called small centroblastic). In
rare (<1%) cases the lymphoma cells have a signet ring
(mimicking gastric carcinoma) or spindle-cell (mimicking
sarcoma) appearance. Other cases can have cytoplasmic
granules, microvillous projections (‘sea anemone tumour’),
or intercellular junctions as observed by electron microscopy.
IMMUNOPHENOTYPE
Immunophenotypic evaluation is required to establish the
diagnosis of DLBCL and can be performed by either
immunohistochemistry or flow cytometry. The neoplastic
cells of DLBCL express pan B cell antigens such as CD19,
CD20, and CD22 as well as B-cell transcription factors
including PAX5, BOB.1 and OCT2 (Fig. 2).14,15
About
50–70% of cases of DLBCL express surface or cytoplasmic
immunoglobulin, most often IgM followed by IgG and IgA.17
However, at least a third of DLBCL cases are negative for Ig
and uncommonly cases lack one or more pan B-cell antigens.
Cases of DLBCL are negative for pan T-cell antigens
(Table 2).
In addition to establishing B-cell lineage in support of the
diagnosis, immunophenotyping plays an important role in
assessing for the presence of potential targets for therapy.
Expression of CD20 by the lymphoma cells is one indication
for using rituximab (anti-CD20) in addition to chemotherapy.
Monoclonal antibody therapies directed against CD19 and
CD22 are also available. About 10–15% of cases of DLBCL
are positive for CD3018
and there may be a role of anti-CD30
therapeutic agents, particularly in patients who fail standard
chemoimmunotherapy. About 20–25% of cases of DLBCL
are positive for PD-L1 and PD-L2; expression correlates with
PD-L1/L2 amplification at chromosome 9p24.1 and response
to PD1 inhibitors.19
A number of other targeted therapies are
in development for which immunophenotypic analysis may
be needed to showing the presence or absence of key markers
that predict treatment response.
Immunophenotypic analysis also has a role in predicting
prognosis in patients with DLBCL and these data can suggest
which patients may not respond to standard R-CHOP ther-
apy. This topic is discussed in detail later in this review.
CYTOGENETIC FINDINGS AND ANTIGEN
RECEPTOR GENE REARRANGEMENTS
Conventional cytogenetic analysis is helpful in the work-up of
cases of DLBCL as the results provide a global view of chro-
mosomal abnormalities. In general, complex karyotypes are
Fig. 1 Common morphological variants of DLBCL. (A) Centroblastic variant; (B) immunoblastic variant; (C,D) anaplastic variant with (C) haematoxylin and eosin
stain and (D) CD30 immunohistochemistry.
DIFFUSE LARGE B-CELL LYMPHOMA 3
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4. more common in tumours that are clinically aggressive or
resistant to therapy.Comparative genomic hybridization (CGH)
applied to the study of DLBCL has shown even greater
complexity with numerous gains and losses of chromosome loci
in a myriadofcombinations.20–22
Specific gains and losses have
been shown to correlate with cell-of-origin classification.22
There are three major translocations that occur in DLBCL
cases. The most common, in about 30% of cases, involves
BCL6 at the chromosome 3q27 locus.23,24
BCL6 is most often
juxtaposed with IGH on chromosome 14q32, but BCL6 is
promiscuous and there are many potential partner loci.
t(14;18)(q21;q32)/IGH-BCL2 is observed in 20–30% of
DLBCL cases.24
Translocations involving MYC at 8q24 also
occur in 10–15% of DLBCL cases and are often associated
with high-grade morphological features and a complex kar-
yotype.25
MYC can be juxtaposed with IGH, IGK, IGL or
non-immunoglobulin gene loci. Other uncommon trans-
locations have been reported in DLBCL (Table 3).
In routine practice, fresh tissue for conventional cytoge-
netics is often not available. In its place, fluorescence in situ
hybridisation (FISH) can be used to assess for rearrangements
of BCL6, BCL2, and MYC in fixed, paraffin embedded tissue
sections of cases of DLBCL. Either breakapart (BCL6, MYC)
or fusion probes (IGH-BCL2) are used most often. The
disadvantage of FISH in general is that these assays are
highly focused and the remainder of the cytogenetic profile
cannot be assessed. The prognostic importance of these
translocations is discussed in detail below.
The IGH genes are rearranged in virtually all cases of
DLBCL. IGK and/or IGL are rearranged in subsets of cases.
The T-cell receptor genes are usually in the germline
configuration. The immunoglobulin variable region genes
commonly undergo somatic hypermutation consistent with
passage through the germinal centre. Somatic mutations also
are detected in multiple other genes, such as MYC and PAX5,
and are observed in >50% of DLBCL cases.26
GENE EXPRESSION PROFILING
Alizadeh and colleagues27
were among the first to apply gene
expression profiling (GEP) methods to the study of DLBCL
and they divided cases into GCB (40–50%) and ABC
(50–60%) subtypes as well as a small (~10–15%) unclassi-
fiable group. In patients with DLBCL treated with CHOP
therapy, those with GCB neoplasms had a better survival than
those with ABC tumours. Subsequently, this observation was
confirmed in DLBCL patients treated with R-CHOP.28
Over
time, GCB versus ABC cell-of-origin classification has
Fig. 2 A case of DLBCL, centroblastic variant, with a starry sky pattern and MYC rearrangement. The lymphoma cells diffusely express CD20, P53, BCL2, and MYC
(~80%). Ki-67 demonstrated a high (~95%) proliferation rate.
Table 2 Markers commonly expressed in DLBCL
Markers Frequency Significance
CD19 Often Diagnosis, target
CD20 Often Diagnosis, target
CD22 Often Diagnosis, target
CD79a/CD79b Often Diagnosis
PAX5 Often Diagnosis
sIG or cytoIG 50–75%, IgM
more common
Diagnosis
CD5 5–10% Prognosis
CD30 Variably expressed,
more in anaplastic
Prognosis, target
CD10 30–60% All 3 markers (CD10,
BCL6, MUM1)
combined to define
GCB vs non-GCB
BCL6 60–90%
MUM1 35–65%
Ki67 Variably expressed
in every case,
usually >40%
Proliferative marker
MYC 20–40% Coexpression define
BCL2 Often Prognosis, target
P53 Variable depending
on cut-off
Prognosis
DLBCL, diffuse large B-cell lymphoma.
4 LI et al. Pathology (2017), -(-), -
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5. become widely used and best known. This model also has
biological correlates; for example, t(14;18)(q32;q21)/IGH-
BCL2 usually occur in the GCB subtype and NF-kB activa-
tion is more prominent in the ABC subtype. Nevertheless, the
GCB and ABC categories themselves are genetically
heterogeneous.
There are other models subdividing cases of DLBCL using
GEP data. Monti and colleagues29
subdivided cases of
DLBCL into three groups that were designated oxidative
phosphorylation, B-cell receptor/proliferation, and host
response. The oxidative phosphorylation group includes tu-
mours carrying t(14;18) as well as tumours with apoptotic
pathway defects. The B-cell receptor/proliferation group in-
cludes tumours that carry BCL6 translocations and likely
overlaps with the ABC subtype. The host response group has
a T-cell and dendritic cell signature and likely includes cases
of T-cell/histiocyte rich large B-cell lymphoma. Dybkaer and
colleagues30
sorted B cells from reactive tonsils and identi-
fied B-cell-associated gene signatures (BAGS) of which there
are five: naïve, centrocyte, centroblast, memory, and plas-
mablast B cells. These signatures are associated with mo-
lecular findings, for example, centroblastic tumours have a
large number of genetic alterations versus centrocytic tu-
mours, which have less genetic alterations but more often
carry TP53 mutations.30
TUMOUR MICROENVIRONMENT
The microenvironment of lymphoma cells, in other words,
their interaction with host inflammatory cells, is also impor-
tant in pathogenesis. Lenz and colleagues divided gene
expression signatures in DLBCL into three groups: germinal
centre B-cell, stromal-1 and stromal-2.31
The stromal-1
signature (prognostically favourable) is reflective of extra-
cellular matrix deposition and histiocyte infiltration. In
contrast, the stromal-2 signature (unfavourable) reflects
tumour blood vessel density. Specific gene mutations in cells
of the microenvironment likely affect the gene expression
profile or may more directly lead to increased signalling or
loss of key signals to lymphoma cells. It is also true that cells
in the microenvironment can stimulate tumour cell pathways
in the absence of genetic abnormalities. Epigenetic
modulation of tumour cells and microenvironmental cells
(e.g., methylation) is also likely important in DLBCL path-
ogenesis and has been linked to resistance to chemotherapy.32
Some investigators have used immunohistochemistry and
have combined tumour- and microenvironment-associated
characteristics to stratify cases of DLBCL. In one example,
Perry and colleagues33
used three variables: non-GCB
immunophenotype, expression of SPARC (secreted protein
acidic and rich in cysteine), and microvascular density in a
scoring system to stratify patients into favourable and
unfavourable groups.
NEXT GENERATION SEQUENCING
It has been known for a number of years, as shown by
using single gene assessment methods, that gene mutations
or deletions play a role in the pathogenesis of cases of
DLBCL. Next generation sequencing (NGS) approaches
have greatly enhanced our understanding of DLBCL cases
by enabling comprehensive identification of genetic alter-
ations in cases of DLBCL. An average of 75–90 mutations
per neoplasm (in some cases well over 100 mutations) has
been shown. Data suggest that DLBCL cells undergo
multiple rounds of clonal expansion and that gene muta-
tions can occur at any time point during this process.34
Gene mutations in DLBCL can be further divided into
driver versus passenger mutations. In general, driver mu-
tations tend to occur earlier in DLBCL pathogenesis and
impair key cellular processes involved in lymphomagenesis.
In contrast, passenger mutations are unlikely to have an
important role in pathogenesis and may be innocent
bystander events. Each individual case of DLBCL over time
also undergoes clonal selection of subclones that impart the
greatest survival advantage.
Gene mutations in DLBCL are involved in many cellular
processes and pathways including histone modification
(methylation and acetylation), cell growth, proliferation,
metabolism, differentiation, apoptosis, survival, homing/
migration, response to DNA damage, B-cell receptor
signalling, Toll-like receptor signalling, angiogenesis, and
immunoregulation.34–39
The presence of gene mutations is a
window into understanding disease pathogenesis as well as
being potential targets for therapeutic agents, either currently
available or in clinical trials.
The two cell-of-origin subtypes of DLBCL harbour
distinct repertoires of genetic aberrancies (Table 4). The GCB
subtype of DLBCL more often has mutations involved his-
tone methylation or acetylation (EZH2, EP300, CREBBP,
KMT2D), B-cell homing (GNA13, GNAI2, SIPR2), PI3K
pathway signalling, and the JAK-STAT pathway.22,34–39
In
contrast, genetic abnormalities that result in activation of B-
cell receptor signalling and the Toll-like receptor signalling
pathways, ultimately resulting in NF-kB pathway activation,
are more common in the ABC subtype [MYD88 (~20% of
cases), CD79A/B (~20%), CARD11 (~10%), MALT1, BCL10,
TNFAIP3, MYD88]. Specific types of large B-cell lymphoma
also have unique mutation profiles. For example, MYD88
L265P mutation is common (~60% of cases) in primary
DLBCL of the CNS.40
Mutations in immunosurveillance
genes (CD58, B2-microglobulin, TNFRSF14 and CIITA), the
NOTCH pathway, CDNK2A, and TP53 have been reported in
either type of DLBCL.22,41
Table 3 Chromosomal translocations and genes in DLBCLa
Translocation Genes Frequency
t(3;v)(q27;v) BCL6 and other partners;
IGH most common
30–40%
t(14;18)(q32;q21) IGH and BCL2 20–30%
t(8;v)(q24;v) MYC; IGH most common
partner; IGK or IGL ~10%;
also non-IG partners
~10%
inv(3q) TBL1XR1-TP63 ~5%
t(6;v)(p25.3;v) IRF4 with IG; usually IGH
but rarely IGK or IGL
4–5%
t(14;16)(q32;q24.1) IGH and IRF8 2–3%
t(5;14)(q33;q32) EBF1 and IGH 1–2%
t(14;17)(q32;p13.1) IGH and TNFRSF13 1–2%
t(9;14)(p13;q32) PAX5 and IGH 1%
DLBCL, diffuse large B-cell lymphoma; v, variable (a number of potential
gene partners occur).
a
Other rare translocations have been described in DLBCL but occur in
<1% of cases.
DIFFUSE LARGE B-CELL LYMPHOMA 5
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6. PROGNOSIS AND SPECIAL SUBGROUPS OF
DLBCL
As shown above, DLBCL is a highly heterogeneous group of
neoplasms and patients have a variable clinical course and
prognosis. Part of the task of the management of patients with
DLBCL is to distinguish patients who will do well being
treated with standard therapy versus patients who will not and
who may benefit from more aggressive therapy. A number of
tools have been developed to better stratify the risk of
DLBCL patients, and some prognostic factors have been
demonstrated in Fig. 3.
International prognostic index (IPI)
In 1994 the IPI was developed to stratify risk for patients with
DLBCL.42
The IPI includes five variables: age (cut-off, >60
years), Eastern Cooperative Oncology Group performance
status (0–1 versus 2–4), serum LDH level (cut-off, above
normal range), number of extranodal sites (0–1 versus 2 or
more), and stage (I–II versus III/IV) with each variable equal
to one point. The IPI score stratifies DLBCL patients into four
risk groups: low (score of 0 or 1); low-intermediate (score 2);
high-intermediate (score 3); and high (score 4–5) risk. The
IPI has been in widespread use for many years but it has some
limitations. Rituximab has greatly improved the outcome of
patients with DLBCL and as a result the IPI lost some of its
stratification power. For patients over 60 years of age, an age-
adjusted (aa)-IPI needs to be used. Others also have pointed
out that the IPI system over-simplifies the spectrum of some
patient abnormalities (as categorical variables) and therefore
other systems or revisions to the IPI have been suggested.
The National Cancer Center Network (NCCN) proposed an
enhanced IPI system which has a better ability to stratify risk
in DLBCL patients receiving chemoimmunotherapy.43
In the
NCCN-IPI, age and serum LDH level were further stratified
and the prognostic importance of specific extranodal sites
(bone marrow, lungs, brain, liver/gastrointestinal tract) was
recognised. This system has a maximum total score of 8
points and can stratify DLBCL patients into four distinct risk
groups: low (0–1 point); low-intermediate (2–3 points);
high-intermediate (4–5 points); and high (6 points)
(Table 5).
Morphology
The prognostic significance of morphological findings in
DLBCL is controversial. Some studies have reported that the
immunoblastic variant is associated with worse prognosis,
even in rituximab therapy era.16,44
The anaplastic variant of
DLBCL is another subset in which patients may do poorly.
These tumours are a heterogeneous group but a substantial
number of tumours carry TP53 mutations45
that are known to
be associated with a poorer prognosis.
Cell-of-origin classification
As was mentioned above, GEP has been used to divide cases
of DLBCL into GCB and ABC subtypes, with a small subset
of cases unclassifiable. Patients with DLBCL that had a GCB
profile had a better survival than those that had an ABC
profile.25,26
Overall, GEP is considered the ‘gold standard’
for cell-of-origin classification and is widely considered to
predict prognosis reliably. However, a recent review of the
literature has raised some doubts about the prognostic value
of cell-of-origin as generated by GEP.46
Traditional GEP methods were not practical for daily diag-
nostic practice for a variety of reasons including not being
suitable for formalin fixed, paraffin embedded tissue. As a
result, various immunohistochemical (IHC) algorithms were
developed as surrogates for GEP to predict cell-of-origin, and
at least six methods were developed.47–52
Of these, the Hans
algorithm was the first reported and is most commonly used.
This system employs CD10, BCL6 and MUM1/IRF4 and 30%
cut-offs for reactivity.47
GCB tumours are CD10+ or BCL6+/
CD10–/MUM1/IRF4–, and non-GCB tumours are CD10–/
MUM1/IRF4+ (BCL6 can be either positive or negative).
Originally, the Hans algorithm reported a 76% concordance
with cell-of-origin detected by GEP. Two other methods have
improved on the Hans system with 93% reported agreement
with the GEP profile: Choi et al.48
proposed a system with five
antibodies, GCET1, CD10, BCL6, MUM1/IRF4, and FOXP1;
and Visco et al.49
proposed a system with three antibodies,
CD10, FOXP1, and BCL6. Meyer et al.50
used a different
approach. Instead of looking at antibody results in a sequence,
the tally uses four antibodies each equal to a point: two GCB
markers (GCET1 and CD10) and two non-GCB markers
(FOXP1 and MUM1/IRF4). The results are tallied and if a tie,
LMO2 supporting GCB subtype is used as the tiebreaker.
In the era of the rituximab-CHOP regimen as standard
therapy for patients with DLBCL, many studies using sur-
rogate immunohistochemistry algorithms have shown that
patients with GCB versus non-GCB DLBCL have a better
overall and event-free survival, although the hazard ratios are
different. However, others have reported that these algo-
rithms are not reliable for predicting prognosis reviewed by
Schmidt-Hansen et al.46
The revised WHO classification
recommends assessing the cell-of-origin for all cases of
DLBCL. Despite the limitations of immunohistochemistry
algorithms, these are considered acceptable for cell-of-origin
classification if other methods are not available.
More recently, methods that can be applied to the analysis
of formalin fixed, paraffin embedded tissue have been
Table 4 Selected recurrently mutated genes in DLBCL and corresponding
targeted agents
Signalling
pathway/process
Gene mutated DLBCL
GCB ABC All
BCR/NF-kB CD79A Yes (20%)
CD79B Yes (20%)
CARD11 10%
MYD88 Yes (30%)
PI3K/mTOR/AKT FOXO1 9%
GNA13 20%
SGK1 20%
PTEN 40%
Epigenetic regulation EZH2 20%
MLL2 30%
MEF2B 20%
CREBBP 20%
EP300 Yes
Immune-regulation TNFRSF14 Yes
Apoptosis BCL2 Major Minor
P53 Yes
ABC, activated B-cell like; DLBCL, diffuse large B-cell lymphoma; GCB,
germinal centre B-cell like.
6 LI et al. Pathology (2017), -(-), -
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7. developed to determine cell-of-origin. The Lymph2X assay is
one of these methods and employs NanoString technology
and a 20-gene panel to determine cell-of-origin, with reported
95% concordance with traditional GEP results.53
Although
this approach is not standard-of-care yet, it seems likely that
this assay, or similarly developed assays that can be applied
to formalin fixed, paraffin embedded tissue will be used
increasingly in the future. However, it should be remembered
that GCB versus ABC subtyping provides only a general
perspective of the patient’s clinical outcome and direction for
which targeted agents may be helpful. These subtypes are still
heterogeneous and contain patient subgroups with different
prognoses and that likely will require vastly different thera-
peutic approaches.
MYC rearrangement and extra copy number
We have made significant progress in recent years in un-
derstanding the pathogenetic role and prognostic impact of
MYC in DLBCL. MYC, located at 8q24, is a transcription
factor which controls the expression of approximately 10% of
genes, either directly or indirectly, and is essential for many
cellular physiological functions.54,55
MYC translocations are
present in 5–15% of cases of DLBCL. Many (although not
Fig. 3 Poor prognostic factors in patients with DLBCL. (A) High International Prognostic Index (IPI); (B) MYC rearrangement; (C) double hit lymphoma; (D) double
expression lymphoma; (E) high p53 expression; (F) CD5 expression.
DIFFUSE LARGE B-CELL LYMPHOMA 7
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8. all) studies have shown that patients with DLBCL associated
with MYC rearrangement have a worse prognosis.25,56–60
A
possible explanation for the lack of total agreement on the
prognostic importance of MYC rearrangement in DLBCL is
that there are confounding variables that have not always
been accounted for in studies. One variable is the MYC
partner in various translocations. Others have reported that
patients with DLBCL associated with MYC translocations
that involve the immunoglobulin gene loci have a poorer
prognosis than non-immunoglobulin gene partners,61,62
although this finding has not been confirmed in other
studies.60,63
Another confounder is BCL2 or BCL6 rear-
rangements (or both) can be present simultaneously with
MYC rearrangement in cases of DLBCL and these additional
‘hits’ also influence prognosis. Coexistent TP53 abnormal-
ities also have not been accounted for in many studies and
this is another potential confounding variable.
In addition to rearrangement, extra copies of MYC can be
present in cases of DLBCL. In some cases, FISH studies may
show only 1–2 extra copies, but in other cases many extra
copies are present consistent with MYC amplification. The
prognostic impact of extra MYC copies is not consistent in
the literature, but recent studies have shown that extra MYC
copies have a negative impact on overall survival. The degree
of negative impact on prognosis appears to be less than that of
MYC rearrangement.63–65
BCL2 or BCL6 rearrangement
A number of investigators have assessed the prognostic
importance of BCL2 or BCL6 rearrangement in cases of
DLBCL. The studies have been contradictory, stating that
these rearrangements may or may not have prognostic impact
in patients with DLBCL. Overall, it seems fair to conclude
that these gene rearrangements are not powerful predictors of
prognosis when entire groups of cases of DLBCL are
assessed. However, there may be meaningful tumour subsets
where these data may be important. Visco and others66
showed that BCL2 rearrangements correlate with poorer
prognosis in patients with the GCB subtype of DLBCL, but
not in patients with non-GCB subtype (where the frequency
is very low) or in the overall DLBCL patient group. There are
also rare patients with DLBCL associated with BCL2 and
BCL6 rearrangements, but without MYC rearrangements or
extra copies. This patient subset is poorly analysed but one
study suggested that these patients have a poorer prognosis.67
Double hit lymphoma
Double hit lymphoma (DHL) was defined by Aukema and
colleagues68
as a B-cell lymphoma that carries MYC rear-
rangement and another oncogene rearrangement, usually
BCL2 but less often BCL6 and rarely BCL3 or CCND1 or
other known oncogenes. Cases with rearrangements of MYC,
BCL2, and BCL6 are known as triple hit lymphoma (THL)
and there are also very rare cases with four oncogene rear-
rangements (MYC, BCL2, BCL6, and CCND1). The revised
WHO classification has included DHL and triple hit lym-
phoma cases in a new category designated high-grade B-cell
lymphoma with MYC, BCL2, and/or BCL6 rearrangements.9
The revised WHO classification restricts cases with MYC and
CCND1 rearrangements to the category of mantle cell lym-
phoma and other very rare gene rearrangements with MYC
are not specified.9
Cases of DHL (and triple hit lymphoma)
represent about 10% of all cases that otherwise resemble
DLBCL.69–78
MYC rearrangement is thought to be a sec-
ondary event in most of these cases.
MYC/BCL2 DHL is the most common type of DHL,
representing about 65% of cases in one large study.71
MYC/
BCL2/BCL6 triple hit lymphomas occur in about 20% of
cases and MYC/BCL6 DHL in about 15% of all cases.71
The
clinical characteristics and prognosis of patients with MYC/
BCL2 DHL and MYC/BCL2/BCL6 THL are similar. Patients
with these lymphomas usually have an aggressive clinical
course characterised by advanced stage disease, extranodal
involvement (including bone marrow and the central nervous
system), high serum lactate dehydrogenase levels, and a high-
intermediate to high IPI score.69–78
Paradoxically, nearly all
cases of MYC/BCL2 DHL and MYC/BCL2/BCL6 THL have
a favourable GCB cell-of-origin.79
Conventional cytogenetic
analysis has shown that many cases of DHL/THL have a
complex karyotype suggesting that other genes may play a
role in the pathogenesis and resistance to therapy. TP53 is
commonly mutated in MYC/BCL2 DHL and MYC/BCL2/
BCL6 THL and may, in part, explain the high frequency of
complex karyotypes (see below).
A variety of therapeutic approaches have been proposed
for patients with DHL/THL, but overall survival of these
patients is poor. Although there is no consensus optimal
therapy, most investigators agree that standard R-CHOP
therapy is inadequate, more aggressive regimens are indi-
cated, and novel therapies are needed for patients with DHL/
THL. In a few studies, R-EPOCH appears to be more bene-
ficial than R-CHOP as a first line therapy for DHL/THL
patients.80–82
A clear role for stem cell transplantation is not
established.82
Patients with MYC/BCL6 DHL differ somewhat from other
DHL/THL cases. Patients with MYC/BCL6 DHL also usually
have a high IPI score, extranodal involvement, and an
aggressive clinical course in most, but not all studies. Cases
of MYC/BCL6 DHL may have a GCB or non-GCB cell-of-
origin.83–85
The GEP profile of MYC/BCL6 DHL substan-
tially differs from MYC/BCL2 DHL.86
Atypical MYC/BCL2 DHL
Some cases of DLBCL have abnormalities of MYC and
BCL2, but extra copies are present in lieu of rearrangement.
Li and colleagues87
reported three subsets: (1) MYC rear-
rangement with extra copies of BCL2; (2) extra copies of
MYC with BCL2 rearrangement; and (3) extra copies of MYC
Table 5 National Cancer Center Network International Prognostic
Index
Parameters Score
Age, years
40–60 1
60–75 2
75 3
LDH, normalised ratio
1–3 1
3 2
Ann Arbor stage III–IV 1
Extranodal disease (marrow, CNS,
lung, liver/GI tract)
1
Performance status 2 1
CNS, central nervous system; GI, gastrointestinal; LDH, lactase
dehydrogenase.
8 LI et al. Pathology (2017), -(-), -
Please cite this article in press as: Li S, et al., Diffuse large B-cell lymphoma, Pathology (2017), https://doi.org/10.1016/j.pathol.2017.09.006
9. and BCL2 without gene rearrangements. The authors reported
that patients with DLBCL associated with these abnormal-
ities also had a poorer prognosis and they suggested the
designation atypical double hit lymphoma. A recent large
series study including DLBCL cases with extra copies of both
MYC and BCL2 confirmed the negative prognostic effect of
such cases.65
In a recent study, Moore and colleagues63
confirmed an adverse prognostic impact of MYC rearrange-
ments with extra copies of BCL2 and vice versa, but did not
confirm any negative effect of extra copies of MYC with extra
copies of BCL2 in patients with DLBCL.
Double expressor lymphoma
Double expressor lymphoma (DEL), also known as double
positive lymphoma, is defined as a DLBCL in which MYC
and BCL2 are overexpressed as shown by immunohisto-
chemistry.88
Cut-offs for MYC of 40–50% and BCL2 of
50–70% have been used in the literature. In most studies, the
40% and 50%, respectively, have been used and these cut-
offs are recommended in the revised WHO classification.9
Cases of DLBCL that are also DEL includes cases of DHL
with MYC and BCL2 rearrangements as well as other cases
that lack these gene rearrangements. The former group be-
haves poorly as do cases of DHL discussed above. This
section is focused on cases that lack both gene
rearrangements.
DEL is far more common than DHL and represents
25–35% of all cases of DLBCL.88,89
Cases of DEL are also
far more common in the ABC/non-GCB group than in the
GCB group. Hu et al.89
suggested that overexpression of
MYC and BCL2 may explain the poorer prognosis of patients
with ABC subtype DLBCL. Other studies have confirmed the
adverse prognostic impact of MYC and BCL2 over-
expression, but have suggested that both cell-of-origin clas-
sification and DEL status have independent prognostic
importance. Overall, patients with DEL have a better prog-
nosis than patients with DHL. MYC translocation in DEL
predicts a poorer prognosis.90
Fig. 4 shows the relationships
between DLBCL with MYC or BCL2 rearrangement (DHL),
DEL, and the GCB/ABC subtypes of DLBCL.
TP53 mutations and p53 expression
TP53 is a tumour suppressor gene that is involved in many
cell functions including cell cycle arrest, DNA repair, and
apoptosis.91
These functions of p53 help to eliminate cells
that acquire deleterious mutations and therefore p53 is also
known as the ‘guardian of the genome’.
TP53 mutations are present in about 20% of cases of
DLBCL and have been shown to be an independent predictor
of poorer prognosis.22,41,92–94
Mutations in TP53 usually
result in loss-of-function and can occur in the DNA binding
domain or at other locations; DNA binding domain mutations
have greater adverse prognostic impact22,41,94
and some in-
vestigators have reported that non-DNA binding domain
mutations do not adversely affect prognosis.22
TP53 muta-
tions occur in both the GCB and ABC/non-GCB subtype of
DLBCL in approximately equal frequency. TP53 mutations
also occur in about one-third of MYC/BCL2 DHL cases, but
are uncommon in MYC/BCL6 DHL.95
Mutant p53 protein is known to have a longer half-life than
wild type p53 and therefore overexpression as detected by
immunohistochemistry can be used as a surrogate for TP53
mutation. In DLBCL, p53 expression in 50% of lymphoma
cells, especially if overexpression is intense, correlates
(imperfectly) with TP53 mutation and is associated with a
poorer prognosis in patients with DLBCL.96–98
p53 over-
expression (as well as mutation) also enhances the negative
prognostic effect of MYC rearrangement leading others to
suggest that the combination of MYC rearrangement and
TP53 mutation or prominent p53 overexpression may be
another form of double hit lymphoma.97,98
CD5+ DLBCL
CD5 is normally expressed in T-cells and a small CD5 pos-
itive B-cell population that is present in the blood and mantle
zones of lymphoid follicles. CD5 expression is characteristic
Fig. 4 Relationship between MYC and BCL2 rearrangements, double hit lymphoma (DHL), double expressor lymphoma (DEL), and GCB versus ABC/non-GCB in
patients with DLBCL.
DIFFUSE LARGE B-CELL LYMPHOMA 9
Please cite this article in press as: Li S, et al., Diffuse large B-cell lymphoma, Pathology (2017), https://doi.org/10.1016/j.pathol.2017.09.006
10. of two B-cell neoplasms, chronic lymphocytic leukaemia/
small lymphocytic lymphoma (CLL/SLL) and mantle cell
lymphoma, but can also occur in other B-cell lymphomas at a
low frequency. In DLBCL, CD5 is expressed by 5–10% of
cases.99,100
CD5 is thought to promote B-cell survival via
autocrine production of interleukin-10 and negative regula-
tion of B-cell receptor signalling by modifying intracellular
calcium mobilisation and modulation and activation of
various signalling pathways such as ERK1/2, PI3K, and
calcineurin.101,102
Patients with CD5+ DLBCL often have features associated
with aggressive clinical behaviour including older patient
age, extranodal sites of involvement, advanced clinical stage,
elevated serum LDH level, and higher IPI score.99,100
Cases
of CD5+ DLBCL often have a complex karyotype, usually
have an ABC/non-GCB cell-of-origin, and a distinctive gene
expression profile.99,100
Multiple studies have shown that
patients with CD5 positive DLBCL, treated with either
CHOP or R-CHOP therapy, have a poorer survival which is
not overcome by using aggressive chemotherapy regimens of
stem cell transplantation.100,103,104
For the above reasons the revised WHO classification rec-
ommends that CD5 expression be assessed in all newly
diagnosed cases of DLBCL.9
Importantly, CD5 positive
DLBCL must be distinguished from cases of CLL/SLL in
large cell transformation (so-called Richter syndrome) and
high-grade variants of mantle cell lymphoma, in particular the
pleomorphic variant. A history of CLL/SLL, overexpression
of CD23 and LEF1, and genetic abnormalities such as deletion
11q and trisomy 12 support CLL/SLL. Detection of strong
cyclin D1 overexpression and t(11;14)(q13;q32)/CCND1-IGH
support mantle cell lymphoma.
CD30 expression
CD30, also known as tumour necrosis factor receptor super
family 8 (TNFRSF8), is a type I transmembrane glycoprotein
that is involved in apoptosis and interacts with TNF receptor
associated factor (TRAF)2 and TRAF5 to activate the NF-kB
pathway.105
CD30 is normally expressed by a subset of
activated B- and T-lymphocytes, but not by non-activated
(resting) lymphocytes. CD30 expression was first detected
in Hodgkin–Reed–Sternberg cells of Hodgkin lymphoma
and subsequently in cases of anaplastic large cell lymphoma
and some non-lymphoid tumours such as embryonal carci-
noma of the testis.105
Uncommonly, CD30 can be expressed
by other lymphoma types including 10–15% of cases of
DLBCL.18,106
In most studies, CD30 expression by DLBCL has been
shown to correlate with a better prognosis than patients with
CD30 negative DLBCL. GEP analysis has shown that CD30
positive DLBCL have a signature characterised by down-
regulation of NF-kB, B-cell receptor signalling, and prolif-
eration.18
Another factor that may play a role explaining the
better prognosis of patients with CD30 positive DLBCL is
that CD30 expression and MYC rearrangement seem to be
almost mutually exclusive in the context of DLBCL.107,108
One exception to these comments is that DLBCL positive
for both CD30 and Epstein–Barr virus infection has an
aggressive clinical course.18
The revised WHO classification did not suggest that CD30
be assessed routinely in newly diagnosed cases of DLBCL.9
However, brentuximab vedotin is an agent targeted for
CD30 positive lymphomas that was approved by the United
States Food and Drug Administration recently.105
This agent
is an antibody drug conjugate in which CD30 antibody is
linked to a toxin (monomethyl auristatin E) that disrupts
mitotic microtubules. This agent has been shown to be
effective in many patients with classical Hodgkin lymphoma
or anaplastic large cell lymphoma who fail standard therapy.
There are less studies of the utility of this agent in patients with
DLBCL, but brentuximab vedotin may be shown to be of
benefit to patients with CD30 positive DLBCL, particularly
after relapse or if the disease is refractory to standard therapy.
TREATMENT
A detailed discussion of the treatment of patients with
DLBCL is beyond the scope of this review. The writers do
not have expertise in this field and it is assumed that most
readers of Pathology do not treat patients with DLBCL. Here
we attempt to review some of the overall concepts involved in
treating DLBCL patients.
The standard therapy for patients with DLBCL is ritux-
imab, cyclophosphamide, doxorubicin, vincristine, and
prednisone (R-CHOP). Using this regimen, approximately
60–70% of patients with DLBCL are cured of disease.
However, about 30–40% of patients will relapse or, in a
small patient’s subset, be refractory to R-CHOP therapy. The
current treatment options for these patients are not adequate.
Autologous stem cell transplantation is often recommended
for younger patients able to endure stem cell trans-
plantation.109
A subset of these patients can be salvaged,
however a substantial subset of patients are not cured by this
approach. The prognosis of these patients as well as that of
patients who cannot undergo transplantation (elderly patients
or who have comorbid diseases) is poor. Experimental agents
and clinical trials are indicated for this patient subgroup.
The direction of current clinical research for patients with
DLBCL is two-fold. For the subset of patients cured by using
R-CHOP therapy, research is directed at using less toxic
agents or lower doses of therapy that will still achieve cure
while causing fewer or ideally no side effects. For patients
who fail R-CHOP therapy, current research is focused on: (1)
risk stratification of DLBCL patients upfront to better predict
which patients will do well with R-CHOP versus patients
who may benefit from more aggressive treatment regimens,
such as dose-adjusted rituximab, etoposide, prednisone,
vincristine, cyclophosphamide, and doxorubicin (R-
EPOCH); and (2) development of novel agents that will be
more effective (and preferably also less toxic).
The great potential of our recent advances in understanding
the molecular findings in DLBCL is that this knowledge will
be translated into the development of novel, highly effective
therapies for patients with DLBCL. In other words, there is a
potentially prominent role for precision medicine in the
treatment of patients with DLBCL. In part, the potential of a
precision medicine approach is already being fulfilled. Many
targeted therapies that inhibit signalling pathways in DLBCL
cells are being actively explored and a number of novel
therapeutic agents are available or will be shortly.110–112
For
example ibrutinib, a Bruton tyrosine kinase (BTK) inhibitor,
has shown excellent preclinical activity and in patients with
ABC/non-GCB DLBCL when combined with R-CHOP.110
A number of novel targeted therapeutic agents are summar-
ised in Table 6.
10 LI et al. Pathology (2017), -(-), -
Please cite this article in press as: Li S, et al., Diffuse large B-cell lymphoma, Pathology (2017), https://doi.org/10.1016/j.pathol.2017.09.006
11. Another advance in the management of patients with
DLBCL, in our opinion likely to change current practice, is
the ‘liquid biopsy’, in other words, assessment of patient
blood (usually plasma) for DNA abnormalities that may be
used to guide treatment decisions. The liquid biopsy can be
used in at least two ways: (1) to assess for monoclonal VDJ
IGH rearrangements to detect the presence of residual disease
or detection of early relapse, before the disease is manifest by
traditional methods;113
and (2) to detect gene mutations
currently detected by tissue analysis.114
As this technology is
just now entering clinical use, time is needed to determine
what role and how big (or small) a role liquid biopsy will play
in the management of DLBCL patients.
DIAGNOSTIC WORK-UP
Cases of DLBCL require a complete work-up including
morphological assessment, immunophenotypic analysis,
cytogenetic analysis (conventional methods and FISH), and
molecular diagnostic assays to assess to various gene muta-
tions or copy number alterations (Fig. 5). Unless otherwise
specified, every test discussed in this section needs to be
performed.
Cell-of-origin classification can be performed using
immunohistochemical algorithms at this time, but may be
replaced in the future by GEP performed on fixed, paraffin
embedded tissue using recently developed small gene panels.
MYC and BCL2 immunohistochemistry are useful to identify
cases of double expressor lymphoma. Cut-offs of 40% and
50%, respectively, are suggested.9
Although we believe that
conventional karyotyping provides useful information for the
assessment of DLBCL, in cases without fresh tissue FISH is
adequate. MYC and BCL6 are most conveniently assessed
using breakapart probes. If MYC is rearranged, probes for
IGH, IGK, and IGL may be used to determine if the MYC
Table 6 Selected novel agents based on target-involved signalling pathways and DLBCL cell-of-origin classification
Signalling pathway Target Novel agent Benefited subtypes
Epigenetic regulation EZH2 GSK-126, EPZ-6438 GCB
BCR/NF-kB BTK Ibrutinib, ONO-4059 Non-GCB/ABC
SYK Entospletinib/GS-9973
NF-kB Bortezomib, carfilzomib, etc
JAK-STAT JAK1/2 Rulolitinib Non-GCB/ABC
STAT3 AZD9150 Non-GCB/ABC, MYC regulated DLBCL
Checkpoint inhibition PD-1 Nivolumab, atezolizuma, pembrolizumab GCB non-GCB
CTLA-4 Ipilumumab
PI3K/AKT/mTOR mTOR Tesirolimus GCB non-GCB
PI3K/mTOR VS-5584
Immunotherapy CD19 CAR-T, SGN-CD19A, blinatumomab GCB non-GCB
CD22 Inotumumab
Apoptosis BCL2 ABT-199 GCB non-GCB
Others CD30 Bentuximab GCB non-GCB
BET CPI-0610 MYC regulated
PIM kinase INCB053914 MYC/BCL2 regulated
ABC, activated B-cell like; DLBCL, diffuse large B-cell lymphoma; GCB, germinal centre B-cell like.
Fig. 5 An approach to the initial work-up of newly diagnosed cases of DLBCL.
DIFFUSE LARGE B-CELL LYMPHOMA 11
Please cite this article in press as: Li S, et al., Diffuse large B-cell lymphoma, Pathology (2017), https://doi.org/10.1016/j.pathol.2017.09.006
12. partner is an immunoglobulin gene. Although knowledge of
the MYC partner may prove to be essential, at this time its
value is not established and therefore this step can be omitted.
IGH-BCL2 can be assessed using dual colour dual fusion
probe sets. These tests can be performed in sequence to avoid
unnecessary FISH testing: MYC rearrangement first and then,
if rearranged, BCL2 and BCL6 rearrangements should be
done to identify cases of double hit lymphoma. Some pa-
thologists recommend MYC immunohistochemistry to
screen for cases that require MYC assessment by FISH. In our
experience, this approach has limitations. Using a 40% MYC
cut-off by immunohistochemistry, expression has a sensi-
tivity of 81% and a specificity of 61% to predict MYC
rearrangement.90
A number of gene mutations in DLBCL have value in
planning therapy using novel agents. A few of these genes
include MYD88, CXCR4, EZH2, CD79A, CD79B, and
CARD11. Other genes have powerful prognostic significance
and stratify patients into different groups (e.g., TP53).
Importantly, the work-up of DLBCL requires adequate tissue
to be obtained, to support traditional methods for pathological
diagnosis and to support molecular testing. It seems likely
that the work-up of DLBCL will expand over time as new
knowledge is acquired and more new therapeutic agents
become available, further emphasising the need for adequate
tissue. It is suggested that in the initial diagnosis of DLBCL
patients undergo an excisional tissue biopsy. If this is not
possible because of the location of disease, fine needle
aspiration with multiple core biopsy specimens should be
obtained. In some patients, the fine needle aspiration fluid
sample can be rich in lymphoma cells and can be used for
molecular studies. In other patients, particularly when the
DLBCL is associated with sclerosis, only the core biopsy
tissue may be representative and adequate for molecular
studies. It is also essential to visualise the specimens sent for
molecular studies to ensure that viable tumour is included in
the sample being analysed.
CONCLUSION
In the diagnosis of all lymphomas including DLBCL much
has changed since Pathology published its first issue in 1969.
Our knowledge of the clinical, morphological and immuno-
phenotypic spectrum of DLBCL and the molecular patho-
genesis of DLBCL have greatly expanded. This knowledge is
being translated into the design of novel treatment strategies
and the development of novel therapeutic agents.
The current standard therapy for patients with DLBCL is
the R-CHOP regimen and about 60–70% of patients are
cured. However, 30–40% of patients respond poorly to
standard therapy. Patients who fail standard therapy have had
few good treatment options until the last decade when many
advances have been made, including the development of a
number of novel targeted therapeutic agents made possible by
our more extensive knowledge. There is also great promise
for a precision medicine approach for the treatment of
DLBCL patients.
Cases of DLBCL require a complete diagnostic work-up.
In addition to the traditional role pathologists have had in
establishing the diagnosis, our role has expanded. It is
essential that we assess immunophenotypic and genetic
markers that are helpful for assessing prognosis (e.g., cell-of-
origin classification, double hit lymphoma). It is also essential
for pathologists to assess markers that are needed to justify
the use of experimental agents or currently available, often
expensive therapeutic agents (e.g., rituximab or ibrutinib) to
facilitate their optimal utility. Pathologists also must ensure
that adequate and viable tumour tissue is triaged for high-
throughput molecular analysis.
Conflicts of interest and sources of funding: The authors
state that there are no conflicts of interest to disclose.
Address for correspondence: L. Jeffrey Medeiros, MD, Department of
Hematopathology, MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit
72, Houston, TX 77030, USA. E-mail: ljmedeiros@mdanderson.org
References
1. Rappaport H. Tumors of the Hematopoeitic System. Washington DC:
Armed Forces Institute of Pathology, 1966.
2. Smith JL, Clein GP, Barker CR, Collins RD. Characterisation of ma-
lignant mediastinal lymphoid neoplasm (Sternberg sarcoma) as thymic
in origin. Lancet 1973; 1: 74–7.
3. Jaffe ES, Shevach EM, Frank MM, Berard CW, Green I. Nodular
lymphoma—evidence for origin from follicular B lymphocytes. N Engl
J Med 1974; 290: 813–9.
4. Lennert K, Stein H, Kaiserling E. Cytological and functional criteria for
the classification of malignant lymphomata. Br J Cancer Suppl 1975; 2:
29–43.
5. Lukes RJ, Collins RD. Immunologic characterization of human ma-
lignant lymphomas. Cancer 1974; (34 Suppl): 1488–503.
6. Taylor CR, Hartsock RJ. Classifications of lymphoma; reflections of
time and technology. Virchows Arch 2011; 458: 637–48.
7. Pizzi M, Gazzola A, Mannu C, et al. The role of molecular biology in the
diagnosis of lymphoid neoplasms. Front Biosci 2014; 19: 1088–104.
8. Swerdlow SH, Campo E, Harris NL, et al., editors. WHO Classification
of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon:
IARC, 2008.
9. Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the
World Health Organization classification of lymphoid neoplasms.
Blood 2016; 127: 2375–90.
10. Perry AM, Diebold J, Nathwani BN, et al. Non-Hodgkin lymphoma in
the developing world: review of 4539 cases from the international non-
Hodgkin lymphoma classification project. Haematologica 2016; 101:
1244–50.
11. Teras LR, DeSantis CE, Cerhan JR, Morton LM, Jemal A, Flowers CR.
2016 US lymphoid malignancy statistics by World Health Organization
subtypes. CA Cancer J Clin 2016; 66: 443–59.
12. Martelli M, Ferreri AJ, Agostinelli C, Di Rocco A, Pfreundschuh M,
Pileri SA. Diffuse large B-cell lymphoma. Crit Rev Oncol Hematol
2013; 87: 146–71.
13. Yao Z, Deng L, Xu-Monette ZY, et al. Concordant bone marrow
involvement of diffuse large B-cell lymphoma represents a distinct
clinical and biological entity in the era of immunotherapy. Leukemia
2017; Jul 12. https://doi.org/10.1038/leu.2017.222: (Epub ahead of
print).
14. Brudno J, Tadmor T, Pittaluga S, Nicolae A, Polliack A, Dunleavy K.
Discordant bone marrow involvement in non-Hodgkin lymphoma.
Blood 2016; 127: 965–70.
15. Korkolopoulou P, Vassilakopoulos T, Milionis V, Ioannou M. Recent
advances in aggressive large B-cell lymphomas: a comprehensive
review. Adv Anat Pathol 2016; 23: 202–43.
16. Horn H, Staiger AM, Vohringer M, et al. Diffuse large B-cell lym-
phomas of immunoblastic type are a major reservoir for MYC-IGH
translocations. Am J Surg Pathol 2015; 39: 61–6.
17. Loddenkemper C, Anagnostopoulos I, Hummel M, et al. Differential
Emu enhancer activity and expression of BOB.1/OBF.1, Oct2, PU.1,
and immunoglobulin in reactive B-cell populations, B-cell non-
Hodgkin lymphomas, and Hodgkin lymphomas. J Pathol 2004; 202:
60–9.
18. Hu S, Xu-Monette ZY, Balasubramanyam A, et al. CD30 expression
defines a novel subgroup of diffuse large B-cell lymphoma with
favorable prognosis and distinct gene expression signature: a report
from the International DLBCL Rituximab-CHOP Consortium Program
Study. Blood 2013; 121: 2715–24.
19. Georgiou K, Chen L, Berglund M, et al. Genetic basis of PD-L1
overexpression in diffuse large B-cell lymphomas. Blood 2016; 127:
3026–34.
12 LI et al. Pathology (2017), -(-), -
Please cite this article in press as: Li S, et al., Diffuse large B-cell lymphoma, Pathology (2017), https://doi.org/10.1016/j.pathol.2017.09.006
13. 20. Tagawa H, Suguro M, Tsuzuki S, et al. Comparison of genome profiles for
identification of distinct subgroups of diffuse large B-cell lymphoma.
Blood 2005; 106: 1770–7 (Erratum in: Blood 2006; 107: 3052).
21. Chen W, Houldsworth J, Olshen AB, et al. Array comparative genomic
hybridization reveals genomic copy number changes associated with
outcome in diffuse large B-cell lymphomas. Blood 2006; 107:
2477–85.
22. Karube K, Enjuanes A, Dlouhy I, et al. Integrating genomic alterations in
diffuse large B-cell lymphoma identifies new relevant pathways and po-
tential therapeutic targets. Leukemia 2017; Aug 14. https://doi.org/
10.1038/leu.2017.251: (Epub ahead of print).
23. Offit K, Lo Coco F, Louie DC, et al. Rearrangement of the bcl-6 gene
as a prognostic marker in diffuse large-cell lymphoma. N Engl J Med
1994; 331: 74–80.
24. Kramer MH, Hermans J, Wijburg E, et al. Clinical relevance of BCL2,
BCL6, and MYC rearrangements in diffuse large B-cell lymphoma.
Blood 1998; 92: 3152–62.
25. Barrans S, Crouch S, Smith A, et al. Rearrangement of MYC is associated
with poor prognosis in patients with diffuse large B-cell lymphoma treated
in the era of rituximab. J Clin Oncol 2010; 28: 3360–5.
26. Pasqualucci L, Trifonov V, Fabbri G, et al. Analysis of the coding
genome of diffuse large B-cell lymphoma. Nat Genet 2011; 43: 830–7.
27. Alizadeh AA, Eisen MB, Davis RE, et al. Distinct types of diffuse large
B-cell lymphoma identified by gene expression profiling. Nature 2000;
403: 503–11.
28. Rosenwald A, Wright G, Chan WC, et al. The use of molecular
profiling to predict survival after chemotherapy for diffuse large-B-cell
lymphoma. N Engl J Med 2002; 346: 1937–47.
29. Monti S, Savage KJ, Kutok JL, et al. Molecular profiling of diffuse
large B-cell lymphoma identifies robust subtypes including one
characterized by host inflammatory response. Blood 2005; 105:
1851–61.
30. Dybkær K, Bøgsted M, Falgreen S, et al. Diffuse large B-cell lym-
phoma classification system that associates normal B-cell subset phe-
notypes with prognosis. J Clin Oncol 2015; 33: 1379–88.
31. Lenz G, Wright G, Dave SS, et al. Stromal gene signatures in large-B-
cell lymphomas. N Engl J Med 2008; 359: 2313–23.
32. Clozel T, Yang S, Elstrom RL, et al. Mechanism-based epigenetic
chemosensitization therapy of diffuse large B-cell lymphoma. Cancer
Discov 2013; 3: 1002–19.
33. Perry AM, Cardesa-Salzmann TM, Meyer PN, et al. A new biologic
prognostic model based on immunohistochemistry predicts survival in
patients with diffuse large B-cell lymphoma. Blood 2012; 120: 2290–6.
34. Morin RD, Mungall K, Pleasance E, et al. Mutational and structural
analysis of diffuse large B-cell lymphoma using whole genome
sequencing. Blood 2013; 122: 1256–65.
35. Compagno M, Lim WK, Grunn A, et al. Mutations of multiple genes
cause deregulation of NF-kappaB in diffuse large B-cell lymphoma.
Nature 2009; 459: 717–21.
36. Davis RE, Ngo VN, Lenz G, et al. Chronic active B-cell-receptor
signalling in diffuse large B-cell lymphoma. Nature 2010; 463: 88–92.
37. Ngo VN, Young RM, Schmitz R, et al. Oncogenically active MYD88
mutations in human lymphoma. Nature 2011; 470: 115–9.
38. Pasqualucci L, Dominguez-Sola D, Chiarenza A, et al. Inactivating
mutations of acetyltransferase genes in B-cell lymphoma. Nature 2011;
471: 189–95.
39. Zhang J, Grubor V, Love CL, et al. Genetic heterogeneity of diffuse
large B-cell lymphoma. Proc Natl Acad Sci USA 2013; 110: 1398–403.
40. Lee JH, Jeong H, Choi WW, Oh H, Kim YS. Clinopathologic signif-
icance of MYD88 L265P mutation in diffuse large B-cell lymphoma: a
meta-analysis. Sci Rep 2017; 7: 1785.
41. Young KH, Weisenburger DD, Dave BJ, et al. Mutations in the DNA-
binding codons of TP53, which are associated with decreased expres-
sion of TRAILreceptor-2, predict for poor survival in diffuse large B-
cell lymphoma. Blood 2007; 110: 4396–405.
42. International Non-Hodgkin’s Lymphoma Prognostic Factors Project.
A predictive model for aggressive non-Hodgkin’s lymphoma. N Engl J
Med 1993; 329: 987–94.
43. Zhou Z, Sehn LH, Rademaker AW, et al. An enhanced International
Prognostic Index (NCCN-IPI) for patients with diffuse large B-cell
lymphoma treated in the rituximab era. Blood 2014; 12: 837–42.
44. Ott G, Ziepert M, Klapper W, et al. Immunoblastic morphology but not
the immunohistochemical GCB/nonGCB classifier predicts outcome in
diffuse large B-cell lymphoma in the RICOVER-60 trial of the
DSHNHL. Blood 2010; 116: 4916–25.
45. Li M, Liu Y, Wang Y, et al. Anaplastic variant of diffuse large B-cell
lymphoma displays intricate genetic alterations and distinct biological
features. Am J Surg Pathol 2017; 41: 1322–32.
46. Schmidt-Hansen M, Berendse S, Marafioti T, McNamara C. Does cell-of-
origin or MYC, BCL2 or PCL6 translocation status provide prognostic
information beyond the International Prognostic Index score in patients
with diffuse large B-cell lymphoma treated with rituximab and chemo-
therapy? A systematic review. Leuk Lymphoma 2017; 58: 2403–18.
47. Hans CP, Weisenburger DD, Greiner TC, et al. Confirmation of the
molecular classification of diffuse large B-cell lymphoma by immu-
nohistochemistry using a tissue microarray. Blood 2004; 103: 275–82.
48. Choi WW, Weisenburger DD, Greiner TC, et al. A new immunostain
algorithm classifies diffuse large B-cell lymphoma into molecular
subtypes with high accuracy. Clin Cancer Res 2009; 15: 5494–502.
49. Visco C, Li Y, Xu-Monette ZY, et al. Comprehensive gene expression
profiling and immunohistochemical studies support application of
immunophenotypic algorithm for molecular subtype classification in
diffuse large B-cell lymphoma: a report from the International DLBCL
Rituximab-CHOP Consortium Program Study. Leukemia 2012; 26:
2103–13.
50. Meyer PN, Fu K, Greiner TC, et al. Immunohistochemical methods for
predicting cell of origin and survival in patients with diffuse large B-
cell lymphoma treated with rituximab. J Clin Oncol 2011; 29: 200–7.
51. Muris JJ, Meijer CJ, Vos W, et al. Immunohistochemical profiling
based on Bcl-2, CD10 and MUM1 expression improves risk stratifi-
cation in patients with primary nodal diffuse large B cell lymphoma.
J Pathol 2006; 208: 714–23.
52. Nyman H, Adde M, Karjalainen-Lindsberg ML, et al. Prognostic
impact of immunohistochemically defined germinal center phenotype
in diffuse large B-cell lymphoma patients treated with immunoche-
motherapy. Blood 2007; 109: 4930–5.
53. Scott DW, Wright GW, Williams PM, et al. Determining cell-of-origin
subtypes of diffuse large B-cell lymphoma using gene expression in
formalin-fixed paraffin-embedded tissue. Blood 2014; 123: 1214–7.
54. Nie Z, Hu G, Wei G, et al. c-Myc is a universal amplifier of expressed
genes in lymphocytes and embryonic stem cells. Cell 2012; 151:
68–79.
55. Nguyen L, Papenhausen P, Shao H. The role of c-MYC in B-cell
lymphomas: diagnostic and molecular aspects. Genes (Basel) 2017; 8.
56. Horn H, Ziepert M, Becher C, et al. MYC status in concert with BCL2
and BCL6 expression predicts outcome in diffuse large B-cell lym-
phoma. Blood 2013; 121: 2253–63.
57. Lin P, Dickason TJ, Fayad LE, et al. Prognostic value of MYC rear-
rangement in cases of B-cell lymphoma, unclassifiable, with features
intermediate between diffuse large B-cell lymphoma and Burkitt lym-
phoma. Cancer 2012; 118: 1566–73.
58. Landsburg DJ, Falkiewicz MK, Petrich AM, et al. Sole rearrangement
but not amplification of MYC is associated with a poor prognosis in
patients with diffuse large B cell lymphoma and B cell lymphoma
unclassifiable. Br J Haematol 2016; 175: 631–40.
59. Li S, Weiss VL, Wang XJ, et al. High-grade B-cell lymphoma with
MYC rearrangement and without BCL2 and BCL6 rearrangements is
associated with high P53 expression and a poor prognosis. Am J Surg
Pathol 2016; 40: 253–61.
60. Epperla N, Maddocks KJ, Salhab M, et al. C-MYC-positive relapsed
and refractory, diffuse large B-cell lymphoma: impact of additional
“hits” and outcomes with subsequent therapy. Cancer 2017; 123:
4411–8.
61. Copie-Bergman C, Cuillière-Dartigues P, Baia M, et al. MYC-IG
rearrangements are negative predictors of survival in DLBCL patients
treated with immunochemotherapy: a GELA/LYSA study. Blood 2015;
126: 2466–74.
62. Pedersen MO, Gang AO, Poulsen TS, et al. MYC translocation partner
gene determines survival of patients with large B-cell lymphoma with
MYC- or double-hit MYC/BCL2 translocations. Eur J Haematol 2014;
92: 42–8.
63. Moore EM, Aggarwal N, Surti U, Swerdlow SH. Further exploration of
the complexities of large B-cell lymphomas with MYC abnormalities
and the importance of a blastoid morphology. Am J Surg Pathol 2017;
41: 1155–66.
64. Lu TX, Fan L, Wang L, et al. MYC or BCL2 copy number aberration
is a strong predictor of outcome in patients with diffuse large B-cell
lymphoma. Oncotarget 2015; 6: 18374–88.
65. Quesada AE, Medeiros LJ, Desai PA, et al. Increased MYC copy
number is an independent prognostic factor in patients with diffuse
large B-cell lymphoma. Mod Pathol 2017; Aug 4. https://doi.org/
10.1038/modpathol.2017.93: (Epub ahead of print).
66. Visco C, Tzankov A, Xu-Monette ZY, et al. Patients with diffuse large
B-cell lymphoma of germinal center origin with BCL2 translocations
have poor outcome,irrespective of MYC status: a report from an In-
ternational DLBCL rituximab-CHOP Consortium Program Study.
Haematologica 2013; 98: 255–63.
67. Naeini YB, Wu A, O’Malley DP. Aggressive B-cell lymphomas: fre-
quency, immunophenotype, and genetics in a reference laboratory
population. Ann Diagn Pathol 2016; 25: 7–14.
68. Aukema SM, Siebert R, Schuuring E, et al. Double-hit B-cell lym-
phomas. Blood 2011; 117: 2319–31.
DIFFUSE LARGE B-CELL LYMPHOMA 13
Please cite this article in press as: Li S, et al., Diffuse large B-cell lymphoma, Pathology (2017), https://doi.org/10.1016/j.pathol.2017.09.006
14. 69. Wang W, Hu S, Lu X, Young KH, Medeiros LJ. Triple-hit B-cell
lymphoma with MYC, BCL2, and BCL6 translocations/rearrange-
ments: clinicopathologic features of 11 cases. Am J Surg Pathol 2015;
39: 1132–9.
70. Li S, Saksena A, Desai P, et al. Prognostic impact of history of
follicular lymphoma, induction regimen and stem cell transplant in
patients with MYC/BCL2 double hit lymphoma. Oncotarget 2016; 7:
38122–32.
71. Landsburg DJ, Petrich AM, Abramson JS, et al. Impact of oncogene
rearrangement patterns on outcomes in patients with double-hit non-
Hodgkin lymphoma. Cancer 2016; 122: 559–64.
72. Kanungo A, Medeiros LJ, Abruzzo LV, Lin P. Lymphoid neoplasms
associated with concurrent t(14;18) and 8q24/c-MYC translocation
generally have a poor prognosis. Mod Pathol 2006; 19: 25–33.
73. Le Gouill S, Talmant P, Touzeau C, et al. The clinical presentation and
prognosis of diffuse large B-cell lymphoma with t(14;18) and 8q24/c-
MYC rearrangement. Haematologica 2007; 92: 1335–42.
74. Tomita N, Tokunaka M, Nakamura N, et al. Clinicopathological fea-
tures of lymphoma/leukemia patients carrying both BCL2 and MYC
translocations. Haematologica 2009; 94: 935–43.
75. Johnson NA, Savage KJ, Ludkovski O, et al. Lymphomas with con-
current BCL2 and MYC translocations: the critical factors associated
with survival. Blood 2009; 114: 2273–9.
76. Niitsu N, Okamoto M, Miura I, Hirano M. Clinical features and
prognosis of de novo diffuse large B-cell lymphoma with t(14;18) and
8q24/c-MYC translocations. Leukemia 2009; 23: 777–83.
77. Li S, Lin P, Fayad LE, et al. B-cell lymphomas with MYC/8q24
rearrangements and IGH@BCL2/t(14;18)(q32;q21): an aggressive
disease with heterogeneous histology, germinal center B-cell immu-
nophenotype and poor outcome. Mod Pathol 2012; 25: 145–56.
78. Pedersen MO, Gang AO, Poulsen TS, et al. Double-hit BCL2/MYC
translocations in a consecutive cohort of patients with large B-cell lym-
phoma – a single centre’s experience. Eur J Haematol 2012; 89: 63–71.
79. Lin P, Medeiros LJ. High-grade B-cell lymphoma/leukemia associated
with t(14;18) and 8q24/MYC rearrangement: a neoplasm of germinal
center immunophenotype with poor prognosis. Haematologica 2007;
92: 1297–301.
80. Oki Y, Noorani M, Lin P, et al. Double hit lymphoma: the MD
Anderson Cancer Center clinical experience. Br J Haematol 2014; 166:
891–901.
81. Landsburg DJ, Falkiewicz MK, Maly J, et al. Outcomes of patients
with double-hit lymphoma who achieve first complete remission. J Clin
Oncol 2017; 35: 2260–7.
82. Petrich AM, Gandhi M, Jovanovic B, et al. Impact of induction
regimen and stem cell transplantation on outcomes in double-hit lym-
phoma: a multicenter retrospective analysis. Blood 2014; 124:
2354–61.
83. Pillai RK, Sathanoori M, Van Oss SB, Swerdlow SH. Double-hit B-cell
lymphomas with BCL6 and MYC translocations are aggressive,
frequently extranodal lymphomas distinct from BCL2 double-hit B-cell
lymphomas. Am J Surg Pathol 2013; 37: 323–32.
84. Turakhia SK, Hill BT, Dufresne SD, Nakashima MO, Cotta CV.
Aggressive B-cell lymphomas with translocations involving BCL6 and
MYC have distinct clinical-pathologic characteristics. Am J Clin Pathol
2014; 142: 339–46.
85. Li S, Desai P, Lin P, et al. MYC/BCL6 double-hit lymphoma (DHL): a
tumour associated with an aggressive clinical course and poor prog-
nosis. Histopathology 2016; 68: 1090–8.
86. Aukema SM, Kreuz M, Kohler CW, et al. Biological characterization
of adult MYC-translocation-positive mature B-cell lymphomas other
than molecular Burkitt lymphoma. Haematologica 2014; 99: 726–35.
87. Li S, Seegmiller AC, Lin P, et al. B-cell lymphomas with concurrent
MYC and BCL2 abnormalities other than translocations behave simi-
larly to MYC/BCL2 double-hit lymphomas. Mod Pathol 2015; 28:
208–17.
88. Johnson NA, Slack GW, Savage KJ, et al. Concurrent expression of
MYC and BCL2 in diffuse large B-cell lymphoma treated with ritux-
imab plus cyclophosphamide, doxorubicin, vincristine, and prednisone.
J Clin Oncol 2012; 30: 3452–9.
89. Hu S, Xu-Monette ZY, Tzankov A, et al. MYC/BCL2 protein coex-
pression contributes to the inferior survival of activated B-cell subtype
of diffuse large B-cell lymphoma and demonstrates high-risk gene
expression signatures: a report from the International DLBCL
Rituximab-CHOP Consortium Program. Blood 2013; 121: 4021–31.
90. Wang XJ, Medeiros LJ, Lin P, et al. MYC cytogenetic status correlates
with expression and has prognostic significance in patients with MYC/
BCL2 protein double-positive diffuse large B-cell lymphoma. Am J
Surg Pathol 2015; 39: 1250–8.
91. Xu-Monette ZY, Medeiros LJ, Li Y, et al. Dysfunction of the TP53
tumor suppressor gene in lymphoid malignancies. Blood 2012; 119:
3668–83.
92. Ichikawa A, Kinoshita T, Watanabe T, et al. Mutations of the p53 gene
as a prognostic factor in aggressive B-cell lymphoma. N Engl J Med
1997; 337: 529–34.
93. Kerbauy FR, Colleoni GW, Saad ST, et al. Detection and possible
prognostic relevance of p53 gene mutations in diffuse large B-cell
lymphoma. An analysis of 51 cases and review of the literature. Leuk
Lymphoma 2004; 45: 2071–8.
94. Xu-Monette ZY, Wu L, Visco C, et al. Mutational profile and prog-
nostic significance of TP53 in diffuse large B-cell lymphoma patients
treated with R-CHOP: report from an International DLBCL Rituximab-
CHOP Consortium Program Study. Blood 2012; 120: 3986–96.
95. Gebauer N, Bernard V, Gebauer W, Thorns C, Feller AC, Merz H.
TP53 mutations are frequent events in double-hit B-cell lymphomas
with MYC and BCL2 but not MYC and BCL6 translocations. Leuk
Lymphoma 2015; 56: 179–85.
96. Xie Y, Bulbul MA, Ji L, et al. p53 expression is a strong marker of
inferior survival in de novo diffuse large B-cell lymphoma and may
have enhanced negative effect with MYC coexpression: a single
institutional clinicopathologic study. Am J Clin Pathol 2014; 141:
593–604.
97. Wang XJ, Medeiros LJ, Bueso-Ramos CE, et al. P53 expression cor-
relates with poorer survival and augments the negative prognostic
effect of MYC rearrangement, expression or concurrent MYC/BCL2
expression in diffuse large B-cell lymphoma. Mod Pathol 2017; 30:
194–203.
98. Clipson A, Barrans S, Zeng N, et al. The prognosis of MYC trans-
location positive diffuse large B-cell lymphoma depends on the second
hit. J Pathol Clin Res 2015; 1: 125–33.
99. Yamaguchi M, Seto M, Okamoto M, et al. De novo CD5+ diffuse large
B-cell lymphoma: a clinicopathologic study of 109 patients. Blood
2002; 99: 815–21.
100. Xu-Monette ZY, Tu M, Jabbar KJ, et al. Clinical and biological sig-
nificance of de novo CD5+ diffuse large B-cell lymphoma in Western
countries. Oncotarget 2015; 6: 5615–33.
101. Gary-Gouy H, Harriague J, Bismuth G, Platzer C, Schmitt C,
Dalloul AH. Human CD5 promotes B-cell survival through stimulation
of autocrine IL-10 production. Blood 2002; 100: 4537–43.
102. Gary-Gouy H, Harriague J, Dalloul A, Donnadieu E, Bismuth G. CD5-
negative regulation of B cell receptor signaling pathways originates
from tyrosine residue Y429 outside an immunoreceptor tyrosine-based
inhibitory motif. J Immunol 2002; 168: 232–9.
103. Alinari L, Gru A, Quinion C, et al. De novo CD5+ diffuse large B-cell
lymphoma: adverse outcomes with and without stem cell trans-
plantation in a large, multicenter, rituximab treated cohort. Am J
Hematol 2016; 91: 395–9.
104. Thakral B, Medeiros LJ, Desai P, et al. Prognostic impact of CD5
expression in diffuse large B-cell lymphoma in patients treated with
rituximab-EPOCH. Eur J Haematol 2017; 98: 415–21.
105. Bhatt G, Maddocks K, Christian B. CD30 and CD30-targeted therapies
in Hodgkin lymphoma and other B cell lymphomas. Curr Hematol
Malig Rep 2016; 11: 480–91.
106. Slack GW, Steidl C, Sehn LH, Gascoyne RD. CD30 expression in de
novo diffuse large B-cell lymphoma: a population-based study from
British Columbia. Br J Haematol 2014; 167: 608–17.
107. Wang XJ, Seegmiller AC, Reddy NM, Li S. CD30 expression and its
correlation with MYC rearrangement in de novo diffuse large B-cell
lymphoma. Eur J Haematol 2016; 97: 39–47.
108. Xu J, Oki Y, Saksena A, et al. CD30 expression and prognostic sig-
nificance in R-EPOCH-treated patients with diffuse large B-cell lym-
phoma. Hum Pathol 2017; 60: 160–6.
109. Epperla N, Hamadani M. Hematopoietic cell transplantation for diffuse
large B-cell and follicular lymphoma: current controversies and ad-
vances. Hematol Oncol Stem Cell Ther 2017; Jun 13. https://doi.org/
10.1016/j.hemonc.2017.05.004: (Epub ahead of print).
110. Wiestner A. Targeting B-Cell receptor signaling for anticancer therapy:
the Bruton’s tyrosine kinase inhibitor ibrutinib induces impressive re-
sponses in B-cell malignancies. J Clin Oncol 2013; 31: 128–30.
111. Bohers E, Mareschal S, Bertrand P, et al. Activating somatic mutations
in diffuse large B-cell lymphomas: lessons from next generation
sequencing and key elements in the precision medicine era. Leuk
Lymphoma 2015; 56: 1213–22.
112. Karmali R, Gordon LI. Molecular subtyping in diffuse large B cell
lymphoma: closer to approach of precision therapy. Curr Treat Options
Oncol 2017; 18: 11.
113. Herrera AF, Kim HT, Kong KA, et al. Next-generation sequencing-
based detection of circulating tumour DNA after allogeneic stem cell
transplantation for lymphoma. Br J Haematol 2016; 175: 841–50.
114. Rossi D, Diop F, Spaccarotella E, et al. Diffuse large B-cell lymphoma
genotyping on the liquid biopsy. Blood 2017; 129: 1947–57.
14 LI et al. Pathology (2017), -(-), -
Please cite this article in press as: Li S, et al., Diffuse large B-cell lymphoma, Pathology (2017), https://doi.org/10.1016/j.pathol.2017.09.006
