Best Practice & Research Clinical Haematology 31 (2018) 2e14

Contents lists available at ScienceDirect

Best Practice & Research Clinical Haematology

journal homepage: www.elsevier.com/locate/beha

Pathogenesis of follicular lymphoma

Tracy Lackraj, Rashmi Goswami, Robert Kridel*
Princess Margaret Cancer Centre e UHN, Toronto, ON, Canada

a b s t r a c t

Keywords: Follicular lymphoma (FL) is presented as a germinal centre B cell lymphoma that is
Follicular lymphoma characterized by an indolent clinical course, but remains e paradoxically e largely
Pathogenesis incurable to date. The last years have seen significant progress in our understanding of FL
Mutations
lymphomagenesis, which is a multi-step process beginning in the bone marrow with the
Epigenetic
hallmark t(14;18)(q32;q21) translocation. The pathobiology of FL is complex and combines
Microenvironment
broad somatic changes at the level of both the genome and the epigenome, the latter
evidenced by highly recurrent mutations in chromatin-modifying genes such as KMT2D
and CREBBP. While the importance of the FL microenvironment has since long been well
understood, it has become evident that somatic lesions within tumour cells re-educate
normal immune and stromal cells to their advantage. Enhanced understanding of FL
pathogenesis is currently leading to refined therapeutic targeting of perturbed biology,
paving the way for precision medicine in this lymphoma subtype.
© 2017 Elsevier Ltd. All rights reserved.

1. Introduction

Follicular lymphoma (FL) is the second most common non-Hodgkin lymphoma, with an estimated 5 new cases per
100,000 persons per year and a median age of presentation of 60 years [1,2]. The disease is characterized by the clonal
proliferation of neoplastic lymphoid cells that share morphological, immunophenotypic and molecular genetic attributes of
germinal centre B cells [3,4]. These tumours contain a mixture of neoplastic centrocytes and centroblasts along with various
non-neoplastic cells including T cells, follicular dendritic cells, and macrophages, and mirroring the formation of secondary
lymphoid follicles [5]. FL can be designated as low grade (1 and 2) or higher grade (3A and 3B) disease, depending on the
number of centroblasts per high-power field [6].
Although FL is considered to be incurable, it is characterized as an indolent lymphoma and is therefore subject to slow
progression and high response rates to therapy [4,7]. In the present chemoimmunotherapy era, the median survival for newly
diagnosed patients has significantly increased and is now approaching 20 years [8,9]. The disease course is typically punc-
tuated by multiple relapses and increasing chemotherapy resistance, leading to progression and/or transformation of the
disease into an aggressive subtype which is associated with poor outcome [10e12]. Clinical outcomes are highly variable, with
a minority of treated patients experiencing poor outcome despite treatment, and others on expectant management
remaining free of progression [7,13]. Relating the diversity of clinical trajectories to inter-patient molecular heterogeneity has
been a major research effort over the last decades.

* Corresponding author. Princess Margaret Cancer Centre, Division of Medical Oncology and Hematology, 610 University Ave, OPG 6th floor, Suite 6-714,
Toronto, ON M5G 2M9, Canada.
E-mail address: [email protected] (R. Kridel).

https://doi.org/10.1016/j.beha.2017.10.006
1521-6926/© 2017 Elsevier Ltd. All rights reserved.
 T. Lackraj et al. / Best Practice & Research Clinical Haematology 31 (2018) 2e14 3

In this review, we aim to provide an update on the pathogenesis of FL, given that substantial progress has been made in our
understanding of the mechanistic underpinnings of lymphomagenesis in the last five years [3]. Recent advances in
sequencing technology have provided unprecedented insight into genetic aberrations, shedding light on how perturbed
biological networks lead to lymphomagenesis. Moreover, while the role of normal infiltrating immune cells has long been
recognized, tumour-intrinsic properties that re-educate the microenvironment towards a tumour-supporting milieu have
only recently become better understood. We will also review current knowledge on early steps of FL development, as well as
on clonal evolution over the course of progression and transformation. Other topics with ties to biology, including risk models
and novel therapeutic agents, are reviewed elsewhere in this issue.

2. Early steps of FL pathogenesis (Fig. 1)

The classical model of FL pathogenesis is characterized by the reciprocal translocation t(14;18)(q32;q21), which is present
in 85e90% of cases [14,15]. This somatic rearrangement, which is thought to constitute the first step of lymphomagenesis, is
initiated within the bone marrow during B-cell lymphopoiesis and appears to result from erroneous immunoglobulin heavy
chain gene (IGH) rearrangement [16,17]. The t(14;18) translocation leads to placement of the B cell lymphoma 2 (BCL2) gene
under the inductive influence of transcriptional enhancers associated with IGH, resulting in overexpression of anti-apoptotic
BCL2 leading to increased cell survival and uncontrolled cell proliferation in germinal centres [18e20]. BCL2, along with other
anti-apoptotic proteins, inhibits apoptosis by binding and neutralizing activated pro-apoptotic proteins including the
mitochondrial outer membrane permeabilizers BAX and BAK, as well as the intracellular stress sensors BIM and PUMA which
activate BAX and BAK [21e23].
The t(14;18) translocation is also seen at low frequency (0.1e10 cells/million) in the peripheral blood of >50% of healthy
individuals, suggesting that the rearrangement itself is insufficient for malignant transformation and therefore secondary
genetic alterations are required for cellular transformation to FL [24e27]. In individuals harbouring the translocation in their
peripheral blood cells, typically just one or two clonal events can be identified and are specifically enriched in IgDþ/
CD27þ memory B cells, suggesting that these cells have undergone the germinal centre reaction [27,28]. It was recently
shown in a mouse model that such t(14;18) positive memory B cells repeatedly re-enter germinal centres where they are
exposed to the mutator activity of activation-induced cytidine deaminase (AID) [20]. This protracted process is in keeping
with the observation that long-lived FL precursors may give rise to overt clinical disease years after accidental transfer via
allogeneic transplantation [29,30]. Circulating t(14;18) positive cells have aptly been named FL-like B cells and their abun-
dance has been linked with development of FL [31], with a 23-fold risk reported for a frequency > 1 cell/10,000 [32]. BCL2-
expressing B cells can also be incidentally found in germinal centres from otherwise normal appearing lymph nodes, a sit-
uation referred to as in situ follicular neoplasia (ISFN), an additional precursor lesion that is described in more detail below.

Fig. 1. Early steps of follicular lymphoma pathogenesis. Initiation of classical FL lymphomagenesis begins in the bone marrow with the t(14;18) translocation,
followed by migration into the germinal centre where the accumulation of secondary genetic events may occur and lead to progression of disease. Alterations of
KMT2D and CREBBP constitute early genetic lesions in FL. Non-malignant t(14;18)þ B cells, otherwise known as “FL-like cells” may re-enter the germinal centre
and potentially lead to ISFN or progress into asymptomatic or overt FL.
4 T. Lackraj et al. / Best Practice & Research Clinical Haematology 31 (2018) 2e14

Recently, the notion that the t(14;18) is the first, or the only genetic event initiating FL has been challenged by the dis-
covery of KMT2D and CREBBP alterations as early genetic events [33,34]. In a mouse model, deletion of KMT2D led to an
increase in germinal centre B cells only when the ablation occurred during early B cell development, as opposed to during the
germinal centre reaction [35]. Similarly, excision of CREBBP in the hematopoietic stem and progenitor cell compartment
(HSPC) was recently shown to lead to lymphoproliferation and lymphoma [36]. In the latter study, the presence of a CREBBP
mutation in the HSPC was documented in one lymphoma patient, demonstrating that such mutations may represent pre-
malignant events, akin to the t(14;18). The characterization of the sequence of genetic hits involved in the earliest steps of
lymphomagenesis is currently an area of intense investigation.

3. Broad genomic and epigenomic alterations

3.1. Genome-wide alterations

Comparatively low-resolution characterization of FL cancer genomes has been utilized since the 1980s to describe sec-
ondary cytogenetic abnormalities and, over the years, increasing resolution of comparative genomic hybridization and single
nucleotide polymorphism arrays led to identification of recurrent chromosomal abnormalities such as non-random losses of
chromosomes 1p36 and 6q, and gains of 7, 18, and X [37e39]. Moreover, careful screening of genes contained within
recurrently deleted regions has led to identification of critical tumour suppressors such as EPHA7 and TNFRSF14 [40,41]. With
the advent of massively parallel sequencing technology, we now have a near complete picture of the landscape of alterations
across the FL genome, with typical samples harbouring 4,000e10,000 single nucleotide variants, 200e800 small insertions or
deletions, and 5e50 structural rearrangements such as larger deletions or insertions, duplications or translocations [42]. In
addition, a substantial fraction of typical FL genomes is affected by copy number alterations including homozygous and
heterozygous deletions, low- and high-level amplifications, or loss of heterozygosity [42]. While many of these somatic events
may represent passenger rather than driver alterations, the complexity of genomic findings nonetheless suggests that FL
pathogenesis is the result of multiple biological disruptions. Whole-genome interrogation of individual biopsies using next-
generation sequencing is limited by sequencing depth that can be achieved at reasonable cost, and confounded by spatial
heterogeneity, suggesting that current studies actually underestimate the true extent of somatic changes. These aspects are
important as they need to be taken into consideration for the successful implementation of precision medicine. A summary of
recurrent gene mutations is shown in Fig. 2.

3.2. Epigenomic alterations

Epigenetic modifications involve the addition or removal of chemical groups to DNA or histones, and are characterized by
families of enzymes known as writers or erasers of the genetic code [43e45]. B-cell lymphomas were among the first cancers
in which recurrent alterations in chromatin modifiers were identified. FL in particular has emerged as a prototype of a cancer
that depends on deregulated epigenetic control of gene expression, given that mutations in chromatin-modifying genes occur
with high frequency, affecting histone methyltransferases, histone acetyltransferases or histone linker proteins, with several
epigenetic modifiers often mutated in individual cases, suggesting that these mutations act in concert, rather than inde-
pendently, to promote lymphomagenesis (Fig. 3A) [33,34,46e49].
Characteristically for FL, alterations of epigenetic modifiers exert broad transcriptional changes and favor the maintenance
of a germinal centre B cell state, as opposed to B cell activation and/or plasma cell differentiation. Truncating and missense
mutations affecting KMT2D are observed in 60e70% of FL cases and loss of KMT2D results in decreased global H3K4
methylation levels and down-regulation of key sets of genes involved in immune signaling and B cell differentiation [35,50].

Fig. 2. Mutation frequencies in 246 previously reported follicular lymphoma samples [42]. Mutations shown include single nucleotide nonsense or missense
variants, as well as frameshift or non-frameshift inducing small insertions and deletions.
 T. Lackraj et al. / Best Practice & Research Clinical Haematology 31 (2018) 2e14 5

B. BCL6
CREBBP
Genetic Alterations: transcriptional
MEF2B activation
EZH2 KMT2D EP300
activating
deactivating
methylation
t(14;18)
acetylation BCL6 BCL2

PRDM1

NOTCH2 apoptosis

transcriptional transcriptional transcriptional

repression repression repression
CDKN2A CD40 BCL6
CDKN1A/P21 JAK-STAT TP53
BLIMP1 TLR, BCR FOXO1 DNA damage
PRDM1 TNFAIP3 MHC class II genes differentiation
FOXP1 SOCS3
response
TNFRSF14

Glucose,
C. mTOR amino acid D. TNFRSF14 E. JAK-STAT
ttumour
Growth suppression
DNA
factors BTLA
damage
IL-4
HVEM Normal B-cell (T cells)
LAMTOR
PI3K
TP53 VATP-ase

SESTRIN1
cytoplasm
AKT RAGC IL-4 P P
IL-21 STAT6 JAK JAK STAT6

AMPK FL B-cell P P SOCS1

STAT6 STAT6
mTORC1 p70S6K
BCR
activation

P
tumour-supportive
T cell

STAT6
STAT6
microenvironment

4E-BP1/2 LTa

P
LTb
TNFa

mRNA cell growth / cellular proliferation

translation proliferation CXCL13 survival
FDC CCL19 differentiation

Fig. 3. Molecular pathways in follicular lymphoma. The complexity of the FL genetic landscape is characterized by (A) alterations in epigenetic modifiers such as
EZH2, KMT2D, CREBBP, and EP300, along with alterations of a number of key cellular pathways including (B) BCL6, (C) mTOR, (D) TNFRSF14, and (E) JAK-STAT.
Activating and deactivating genetic alterations are shown for each of these key pathways along with their respective outcomes.

Inactivating mutations of the acetyltransferase CREBBP are seen at a similar frequency and also exert pleiotropic effects on
gene expression, potentially in part mediated by defective acetylation of BCL6 and TP53 [36,48,51,52]. Gain-of-function
mutations of EZH2 increase gene repression via enhanced H3K27 trimethylation and result in repression of plasma cell
differentiation signatures [53]. In individual studies, alterations of each of these three genes were shown to cooperate with
BCL2 overexpression to promote lymphomagenesis in the VavP-BCL2 mouse model [35,50e53].
In addition to histone modifications, perturbation of DNA methylation is common in cancer. DNA from FL tumours is
broadly hypomethylated in comparison to normal germinal centre B cells, resulting in decreased expression of dark zone-
related genes [54]. This is in keeping with a prior observation that FL shares a transcriptional program with light zone
rather than dark zone B cells [55]. Specific programs that have been reported to be suppressed by DNA methylation include
cell cycle and DNA repair [54]. An integrative analysis of epigenetic marks in primary FL samples recently refined the notion
that FL has a light zone (or “centrocytic”) origin, with recognition of distinct subtypes, one more closely related to centrocytic
epigenetic circuits, whereas the other subtype resembled activated B cells [56]. Future studies are warranted to shed light on
how such observations relate to treatment response and patient outcomes, given that subtyping in diffuse large B-cell
lymphoma (DLBCL), the most common aggressive B cell lymphoma, is holding great promise for personalizing therapeutic
approaches in that disease.

4. Perturbation of key molecular pathways

Catalogs of recurrently altered genes have been reported in several studies [34,42,49,57e59]. Herein, we aim to sum-
marize recent genetic and functional studies that illustrate the relevance of particular, discrete pathway alterations in FL
(Fig. 3BeE).

4.1. Role of BCL6 expression

B cell lymphoma 6 (BCL6) is a transcriptional repressor that plays a key role for formation and maintenance of germinal
centres and is commonly expressed in FL (>95% of cases) [60]. BCL6 is recurrently altered by chromosomal translocations or
6 T. Lackraj et al. / Best Practice & Research Clinical Haematology 31 (2018) 2e14

somatic mutations [61e65] and translocations were reported to increase the risk of subsequent higher-grade transformation
[61]. Ying et al. identified MEF2B, which is subjected to recurrent genetic alterations in FL, as a transcriptional activator of BCL6
in normal germinal centre B cells that is required for DLBCL proliferation [66]. The findings of this study showed that mu-
tations of MEF2B resulted in enhanced transcriptional activity of MEF2B, likely through disruption of its interaction with the
corepressor CABIN1, and deregulated expression of BCL6. Since BCL6 plays a key role in modulating cell cycle, plasma-cell
differentiation, responses to DNA damage, and antiapoptotic molecules, somatic mutations of MEF2B may contribute to
lymphomagenesis through deregulation of BCL6 expression. In addition, Valls et al. recently demonstrated that the BCL6
protein binds and represses expression of NOTCH2 and Notch pathway genes in FL, leading to an inverse correlation between
BCL6 and NOTCH2 pathway gene expression [67]. It was also shown that inducible expression of NOTCH2 inhibited GC for-
mation in mice and led to an increase in FL cell death, suggesting that BCL6 repression of NOTCH2 is a vital function in FL and
GC B-cells, and that established FLs may be dependent on BCL6 for its role in suppression of NOTCH2 [67].

4.2. Activation of mTOR signalling

A combination of exome and extended targeted sequencing by Okosun et al. revealed recurrent somatic non-silent mu-
tations in the gene RRAGC, which encodes a Ras-related GTP-binding protein (RAGC) [68]. These mutations were uniquely
enriched in FL (18%) and uncommon in other B cell malignancies. Interestingly, more than half of the identified mutations
preferentially co-occurred with ATP6V1B2 and ATP6AP1 mutations, components of the vacuolar Hþ-adenosine triphosphate
ATPase (v-ATPase) which has previously been known as an important component for amino acid-induced mTORC1 activation
[68]. In this model, RAGC mutants display increased raptor binding, making mTORC1 signalling resistant to amino acid
deprivation. Additionally, recent findings of a focused genetic screen by Oricchio et al. identified SESTRIN1 as a relevant target
of the 6q deletion in FL [69]. SESTRIN1 is a known regulator of mTORC1 and mediates cell growth inhibition in response to
TP53 activation upon DNA damage. The findings of this study established SESTRIN1 as a tumour suppressor in lymphoma and
demonstrated that in addition to chromosomal loss, SESTRIN1 is epigenetically silenced by the lymphoma-specific mutant
EZH2Y641X, resulting in mTORC1 activation. The results of this study also suggest that SESTRIN1 deletions may predict reduced
efficacy of EZH2 inhibitor treatment. It is important to note that mutations in EZH2 and RRAGC and loss of SESTRIN1 show a
mutually exclusive relationship, suggesting that they provide alternative pathways to maintain mTORC1 activity under
conditions that would typically shut down cell growth [69].

4.3. Disruption of TNFRSF14-BTLA binding

Mutations in TNFRSF14 (also known as HVEM, for Herpes Virus Entry Mediator) were first recognized in a study that
systematically aimed to detect genetic mutations within a minimally deleted region in the 1p36 locus, lost in 34% of FL [40]. It
is now known that TNFRSF14 mutations occur in 28e40% of cases, a significant proportion of these being truncating mutations
(35%) [57,70,71]. Together, genomic losses and mutations are thought to account for frequent loss of TNFRSF14 expression in
human FL, disrupting binding to its ligand BTLA. Boice et al. recently reported that loss of TNFRSF14 results in enhanced B cell
receptor-related mitogenic signals and activation of tumour-supporting stromal elements such as follicular dendritic and
fibroblast reticular cells [70]. In addition, an increase in CCL19 and CXCL13-mediated recruitment of follicular T helper cells
was evident, which in turn led to support of B cell growth through the production of IL-4, IL-21, and CD40L.

4.4. Role of JAK-STAT signalling

The role of somatic alterations affecting TNFRSF14 is additional to recognized genetic lesions affecting members of the JAK-
STAT signalling pathway. Whole-exome sequencing performed by Yildiz et al. reported recurrent mutations in STAT6 in 11% of
FLs and identified the amino acid residue 419 as a novel STAT6 mutation hotspot [59]. The findings of this study also support
the conclusion that FL-associated STAT6 mutations are activating, and strengthen the recognition of the IL-4/JAK/STAT6 axis as
a driver of FL pathogenesis. It has also been shown that inactivating mutations in SOCS1, an inhibitor of JAK/STAT signalling,
are found in 10e25% of FLs and are preferentially targeted to somatic hypermutation hotspot motifs [57,72]. It was suggested
that SOCS1 mutations contribute to deregulated STAT activity [73], further supporting the importance of JAK-STAT signalling
in FL pathogenesis.

4.5. Proliferation as a hallmark of adverse biology

Regulation of the cell cycle and cell proliferation is a key target in a variety of human malignancies, and increased prolif-
eration has been linked with higher grade tumours and potentially with inferior outcomes in FL [74,75]. A study by Pruneri
et al. assessed the prevalence of CCND3 abnormalities in FLs and found increased immunoreactivity of CCND3 from grade I to
grade III FL [76]. More recently, a study conducted by Oricchio et al. identified a pattern of genomic alterations that impair the
retinoblastoma pathway in nearly 50% of FLs [77]. Among these lesions are homozygous and heterozygous deletions of the p16/
CDKN2A/B and RB1 loci seen in 7 and 12% of FLs respectively, along with more frequent gains of chromosome 12 that include
CDK4 seen in 29% of FLs. Of interest is the finding that these genomic alterations are associated with high-risk disease and play a
role in FL pathogenesis, likely due to alterations of the cell cycle checkpoint leading to growth of the germinal centre B cells.
 T. Lackraj et al. / Best Practice & Research Clinical Haematology 31 (2018) 2e14 7

5. Re-education of the tumour microenvironment

Previous studies demonstrated that malignant FL cells fail to thrive in vitro in the absence of cell extrinsic stimuli, sug-
gesting a crucial role for the tumour microenvironment in their expansion and survival [78e80]. These findings are supported
by results of gene expression studies, which revealed that gene signatures derived from non-malignant tumour-infiltrating
cells influence patient outcomes [81,82]. It was proposed that FL tumour cells, in early stages of pathogenesis, colonize
reactive germinal centres that support their proliferation and survival [83]. FL is, however, not a passive colonizer of pre-
existing secondary lymphoid structures, but rather “re-educates” the tumour microenvironment to its advantage, while
simultaneously escaping immune surveillance [83].
In this regard, a defining feature of non-malignant cells in FL samples is the skewing of normal T cell function. The
expression program of both CD4þ and CD8þ tumour infiltrating lymphocytes was shown to differ from their normal
counterparts in healthy individuals [84]. Follicular T helper cells are significantly enriched in FL tumours, stimulate CD40
signalling and secrete abundant IL4 that results in activation of STAT6-mediated signalling by paracrine stimulation of tumour
cells [85,86]. As mentioned above, the importance of this interaction is illustrated by strong selective pressure for genetic
alterations that enhance this interaction, namely TNFRSF14 and STAT6 mutations [59,70]. Additional cellular elements sup-
porting tumour growth are recruited, including for example mesenchymal stromal cells and tumour-promoting macro-
phages, with the CCL2 cytokine playing a key role in the recruitment of monocytes by stromal elements [87]. Stromal cells
cooperate with follicular T helper cells as follicular T helper cell-derived IL4 upregulates CXCL12 secretion by stromal cells,
which in turn increases FL tumour cell migration, adhesion and migration [88]. The relevance of stromal cells is further
exemplified by the recent observation that loss of surface TNFRSF14 results in lymphoid stroma activation via increased
production of TNF-a, LTa and LTb [70]. FL tumour cells not only benefit from tumour-promoting properties of recruited, and
re-educated non-malignant cellular elements, but also mange to escape immune surveillance. When FL cells are incubated in
the presence of autologous T cells, defects of T-cell synapse formation are observed [89]. Furthermore, CREBBP mutations have
been associated with reduced expression of MHC class II [34], whereas B2M mutations, resulting in loss of MHC class I, are
more typical of transformed FL [42,90]. Taken together, these observations suggest that FL actively perturbs the composition
of the microenvironment to its advantage while effectively evading control by normal immune cells, with at least some of
these effects mediated by frequent genetic mutations.
The observation that the vast majority of FLs express surface immunoglobulin (sIg) despite ongoing somatic hyper-
mutation implies positive selection for sIg expression [91,92]. Unlike other B-cell malignancies, the usage of IGHV genes is not
stereotyped, suggesting that antigen selection may not play a major role in the expansion of FL cells. While self-antigen
recognition was documented to occur in FL [92,93], a more common explanation underlying continuing sIg expression
may reside in frequent N-glycosylation motifs that are introduced during somatic hypermutation and are characteristic of FL,
being present in 80% of cases, while being uncommon in other B cell malignancies and in normal B cells [94]. Such motifs are
relevant because they allow for the addition of unusual, high-mannose terminated glycans in V regions whereas constant
regions are fully glycosylated [95]. Mannosylated sIg binds C-type lectins such as DC-SIGN or the mannose receptor [96],
resulting in activation of intra-cellular signalling pathways [97]. Lectins are expressed, for example, by tumour-associated
macrophages that can be found in the tumour microenvironment to varying extents [98]. In summary, high mannose in
sIg represents an additional, and likely key mechanism, by which FL cells thrive in a tumour-supportive milieu.

6. Pathological variants

Careful characterization of the diversity of clinical and biological properties seen in subgroups of FL has led to the
recognition that certain clinico-genetic constellations define discrete variations of FL, some of which are recognized as
variants or even entities in the revised 2016 WHO classification [99].

6.1. In situ follicular neoplasia (ISFN)

Occasionally, immunohistochemical assessment of an otherwise architecturally normal appearing lymph node reveals
increased expression of BCL2 within germinal centre B cells, which is not seen under normal physiological conditions
[100,101]. These are typically incidental findings on lymph node excisions performed for reasons unrelated to suspected
lymphoma, and need to be distinguished from partial involvement by FL. ISFN, previously named in situ FL, may be associated
with progression to overt FL, although the risk is typically considered to be low [102]. Conversely, and in retrospect, ISFN is
commonly observed in those patients that eventually develop clinical FL [103]. Consistently, secondary genetic alterations
that are characteristic of FL (e.g. mutations in EZH2, TNFRSF14, KMT2D or deletions of 1p36) have been reported in ISFN, albeit
at a lower frequency than in manifest FL, suggesting that ISFN is, indeed, a pre-malignant condition [104,105].

6.2. t(14;18)-negative FL

Although the majority of FL cases are characterized by the t(14;18) translocation, there is a small subset of 10e15% of cases
which do not harbour the characteristic t(14;18) translocation or other BCL2 rearrangements and are described as t(14;18)-
negative FL [106]. While such patients have similar outcomes to patients whose samples harbour the translocation, the
8 T. Lackraj et al. / Best Practice & Research Clinical Haematology 31 (2018) 2e14

absence of the t(14;18) is associated with distinct molecular features that include absence of CD10 expression, presence of
IRF4 expression, BCL6 alterations including translocations, and enrichment of activated B cell-like, NF-kB and proliferation
signatures [107e111].

6.3. Pediatric-type FL

Pediatric follicular lymphoma was a recognized variant in the 2008 WHO classification and has become, under the term
“pediatric-type FL” (PTFL), a definitive entity in the 2016 revision [99]. The change in terminology was motivated by the fact
that similar clinico-pathological presentations can occur in adults. Clinically, PTFL is distinct from classical FL in the sense that
PTFL is most often localized and that patients typically do not experience relapse after excision, which is distinct from the
natural evolution of classical FL [112]. Pathologically, PTFL is characterized by high proliferation and lack of t(14;18) rear-
rangement [113]. Alterations involving TNFRSF14 and IRF4 are common but, overall, genomic complexity is low [114,115].
Recently, genomic studies have underscored that PFTL is a biologically distinct lymphoma that, unlike classical FL, typically
does not harbour mutations in epigenetic modifiers, but is rather characterized by low genetic complexity and by mutations
in the MEK/ERK pathway (MAP2K1 mutations reported in 43%) [116,117].

6.4. Duodenal-type FL

Duodenal-type FL, a distinct subtype from other gastro-intestinal FLs is typically presented as solitary or multiple polypoid
lesions which are confined to the mucosa and submucosa of the second part of the duodenum and contains features that
overlap with ISFN [118]. Lesions associated with duodenal-type FL are histologically low grade, express CD20, CD10 and BCL2
with variable expression of BCL6, and have a low proliferative index [118,119]. This subtype of FL presents with an indolent
course and rarely progresses into overt FL (risk <10%), and may even spontaneously regress, leading to excellent patient
outcomes [99,118]. Biologically, duodenal-type FLs appear to have a gene expression program that is distinct from nodal FL
and more closely related to MALT lymphoma, justifying their recognition as a distinct variant of FL [6,120].

7. Transformation and progression as evolutionary inflection points

FL is mostly considered to be incurable and, consequently, progression is the norm following observation or treatment.
Studies of tumour evolution are typically of relatively small scale, given challenges associated with accruing larger numbers of
serial specimens reflecting defined clinical scenarios. There is, however, a clear signal that evolution occurs in a branching
rather than linear pattern, as demonstrated by studies focusing on cytogenetic alterations [38,121,122], sequencing of IGH
variable regions [29,123e125] or sequencing of whole exomes or genomes [33,34,42,90]. The corollary of such a diverging
mode of tumour evolution is the existence of spatial intra-tumour diversity documented to exist in FL [42,126,127]. Herein, we
will describe transformation and progression from an evolutionary perspective.

7.1. Transformation

Given that histological transformation to more aggressive lymphoma is a key contributor to FL-related mortality, many
studies have attempted to uncover mechanisms underlying transformation, which occurs in 2e3% of patients
[11,12,128e132]. Histology at the time of transformation is most often in keeping with DLBCL (80%) and more rarely with
composite lymphomas (14%) or lymphomas resembling morphologically high-grade B cell lymphomas (6%) [133]. As the vast
majority of FL cases harbour the t(14;18), and as MYC translocation is a common event driving transformation to aggressive
lymphoma, a significant proportion of transformed FLs (TFLs) are de facto double-hit lymphomas and, by the revised 2016
WHO classification, are classified as high-grade B cell lymphoma, with MYC and BCL2 and/or BCL6 translocations [99]. It
remains to be definitively demonstrated whether double-hit TFL possesses similar poor prognostic implications compared to
double-hit de novo DLBCL [134].
The process of transformation to more aggressive lymphoma occurs through activation of known or putative oncogenes
(MYC and CCND3) and inactivation of known or putative tumour suppressor genes (TP53, CDKN2A/B, B2M, S1PR2, GNA13)
[42,49,90,135e141]. It follows then that increased proliferation resulting from cell cycle deregulation, defective DNA damage
response, altered B cell migration and escape from immune surveillance are crucial driving factors for histological trans-
formation of FL to a more aggressive lymphoma. Beyond individual gene alterations, TFL is differentiated from preceding
indolent FL by an overall increase in single nucleotide mutations, small insertions and deletions, copy number changes, and
structural rearrangements [42], suggesting that transformation is a complex process that may result from multiple biological
perturbations. Recently, we demonstrated that transformation is associated with dramatic clonal expansions during which
subclones that typically evade detection at the time of FL diagnosis come to dominance under strong selective pressure, the
nature of which still needs to be elucidated as this pattern of evolution was independent of treatment [42]. Sequencing of
circulating tumour DNA (ctDNA) has emerged as a novel approach for monitoring tumour evolution and holds promise for
early detection of transformation [126].
Cell of origin subtyping has shown to be useful in de novo DLBCL where molecular classification into germinal centre B cell
(GCB) or activated B cell (ABC) subtypes predicts outcome following immunochemotherapy and predicts response to novel
 T. Lackraj et al. / Best Practice & Research Clinical Haematology 31 (2018) 2e14 9

agents such as B cell receptor inhibitors (e.g. ibrutinib) or immune modulators (e.g. lenalidomide) [142e144]. As TFL is the
result of clonal outgrowth from underlying FL with an immunophenotype resembling normal germinal centre B cells, it is not
surprising that the majority of TFL are similarly subtyped as GCB [65,140,145]. However, 16% of TFLs have an ABC phenotype
and, similar to ABC-DLBCL, harbour recurrent genetic alterations in the B cell signalling and NF-kB pathways, including
mutations in CD79B, BCL10 and MYD88, for example [65]. Importantly, ABC-TFL has a comparatively low incidence of t(14;18)
and frequently results from underlying t(14;18)-negative FL [65], whereas ABC-related genes were shown to be enriched in
t(14;18)-negative FL [111]. Taken together, these findings suggest that key molecular phenotypes may be maintained during
tumour evolution in FL. Future studies are warranted to elucidate how best to use novel biological insight in circumventing
treatment resistance that is frequently observed in TFL.

7.2. Progression in the absence of transformation

Several reports have shown that clonal evolution occurs in FL, even in the absence of transformation [33,34,42]. There is,
however, considerable heterogeneity in the extent and patterns of clonal divergence between individual patients, with some
cases showing low divergence between sampled time points, and others showing more drastic changes. Some of these ob-
servations may be sampling artifacts as spatial heterogeneity may confound temporal analyses. Recently, early onset of
disease progression and relapse has been established as a significant predictor of disease outcome and survival in FL, with
only 34e50% of patients who experience progression within 24 months of initial treatment being alive at 5 years
[13,42,146,147]. With the limitation that many of these studies include transformation as an early progression event, it ap-
pears that patients who are destined to progress early may harbour disease that has distinct biological attributes. We showed
that early progression occurs with comparatively small degrees of clonal divergence [42]. Although subclones increased in
prevalence over time, these changes were consistent with drift, rather than with positive selection, suggesting that
resistance-conferring properties are largely present prior to treatment in those patients ultimately experiencing early pro-
gression. This leaves the opportunity to retrospectively study such patients to identify predictors of early progression. While
we were able to identify a small number of genes that appeared to be preferentially mutated in early versus late progressors,
additional studies are needed to fully elucidate genomic properties that confer treatment resistance, to improve therapeutic
approaches for such patients.

8. Summary

FL is the most common indolent lymphoma and remains incurable despite recent therapeutic advances. Our under-
standing of the molecular basis underlying FL pathogenesis has considerably increased over the last decade, with novel gene
mutations shedding light on perturbed biology underpinning lymphomagenesis. It is now appreciated that FL is a disease of
both the genome and epigenome, with highly recurrent mutations affecting epigenetic modifiers such as KTM2D, CREBBP and
EZH2. Such mutations exert broad effects on transcription, effectively locking down the malignant FL phenotype. While the
relevance of normal, tumour-infiltrating, immune and stromal cells has since long been recognized, there is now increasing
evidence that FL tumour cells re-educate the tumour microenvironment to their advantage. This is best illustrated by
TNFRSF14 mutations that have intrinsic effects on the tumour cell and induce a tumour-promoting microenvironment.
Granular insight into disease biology also allows for the identification of molecular contrasts that predict patient outcomes, or
define discrete pathological variants such as pediatric FL, the latter lacking otherwise typical mutations in chromatin-
modifying genes, but harbouring frequent MEK/ERK pathway mutations. Going forward, we expect that continuing insight
into the intricate links between disrupted biology and inter-patient heterogeneity will lead to novel therapeutic approaches
and will allow for more precise tailoring of treatment to underlying tumour biology.

Practice points

 Given inter-patient heterogeneity, large-scale translational research studies, along with well annotated clinical
data, are required to comprehensively determine ties between disease biology and patient outcomes.
 Prediction of poor outcome, and especially of transformation, remains a major challenge. It is possible that
granular monitoring of circulating tumor DNA might prove clinically useful.
 Recent insights into the biology of FL are already leading to novel, targeted therapies but the best drug combi-
nations remain to be defined.
 As the role of the microenvironment in FL pathogenesis is undisputed, it is expected that immune-directed
therapies will continue to be an area of active investigation over the next years.
10 T. Lackraj et al. / Best Practice & Research Clinical Haematology 31 (2018) 2e14

Research agenda

 Deep, longitudinal characterization of those “healthy” individuals who eventually develop FL may increase our
understanding of the sequence of genetic events leading to FL.
 Accrual of high quality primary patient specimens, as part of clinical trials or as part of routine biobanking, is
important to further our understanding of mechanisms underlying pathogenesis, especially as available cell line
models are reflective of aggressive lymphoma, rather than indolent FL.
 While the mechanistic role played by mutations affecting the most frequently altered genes is currently being
elucidated, the distribution of genetic alterations is such that many patients harbour mutations in genes whose
pathogenetic role is unclear.
 Epistatic interactions between genetic alterations need to be elucidated as they may shed light on rational ther-
apeutic approaches.

Conflicts of interest

The authors declare no conflicts of interest.

Acknowledgments

The authors wish to thank the Princess Margaret Cancer Centre and the Leukemia & Lymphoma Society of Canada (grant
513421) for ongoing research support.

References

[1] Dreyling M, Ghielmini M, Rule S, Salles G, Vitolo U, Ladetto M, et al. Newly diagnosed and relapsed follicular lymphoma: ESMO Clinical Practice
Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2016;27:v83e90. https://doi.org/10.1093/annonc/mdw400.
[2] Siegel R, Miller K, Jemal A. Cancer statistics, 2017. CA Cancer J Clin 2017;67:7e30. https://doi.org/10.3322/caac.21254.
[3] Kridel R, Sehn LH, Gascoyne RD. Pathogenesis of follicular lymphoma. J Clin Investig 2012;122:3424e31. https://doi.org/10.1172/JCI63186.
[4] Kahl BS, Yang D. Follicular lymphoma: evolving therapeutic strategies. Blood 2016;127:2055e64. https://doi.org/10.1182/blood-2015-11-624288.
[5] de Jong D, Fest T. The microenvironment in follicular lymphoma. Best Pract Res Clin Haematol 2011;24:135e46. https://doi.org/10.1016/j.beha.2011.
02.007.
[6] Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al. WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon,
France: IARC; 2008.
[7] Horning SJ, Rosenberg SA. The natural history of initially untreated low-grade non-Hodgkin’s lymphomas. N Engl J Med 1984;311:1471e5. https://doi.
org/10.1056/NEJM198412063112303.
[8] Tan D, Horning SJ, Hoppe RT, Levy R, Rosenberg S a, Sigal BM, et al. Improvements in observed and relative survival in follicular grade 1-2 lymphoma
during 4 decades: the Stanford University experience. Blood 2013;122:981e7. https://doi.org/10.1182/blood-2013-03-491514.
[9] Junlen HR, Peterson S, Kimby E, Lockmer S, Linden O, Nilsson-Ehle H, et al. Follicular lymphoma in Sweden: nationwide improved survival in the
rituximab era, particularly in elderly women - a Swedish Lymphoma Registry study. Leukemia 2014;29:668e76. https://doi.org/10.1038/leu.2014.251.
[10] Johnson PW, Rohatiner AZ, Whelan JS, Price CG, Love S, Lim J, et al. Patterns of survival in patients with recurrent follicular lymphoma: a 20-year
study from a single center. J Clin Oncol 1995;13:140e7. https://doi.org/10.1200/JCO.1995.13.1.140.
[11] Al-Tourah AJ, Gill KK, Chhanabhai M, Hoskins PJ, Klasa RJ, Savage KJ, et al. Population-based analysis of incidence and outcome of transformed non-
Hodgkin’s lymphoma. J Clin Oncol 2008;26:5165e9. https://doi.org/10.1200/JCO.2008.16.0283.
[12] Wagner-Johnston ND, Link BK, Byrtek M, Dawson KL, Hainsworth J, Flowers CR, et al. Outcomes of transformed follicular lymphoma in the modern
era: a report from the National LymphoCare Study (NLCS). Blood 2015;126:851e8. https://doi.org/10.1182/blood-2015-01-621375.
[13] Casulo C, Byrtek M, Dawson KL, Zhou X, Farber CM, Flowers CR, et al. Early relapse of follicular lymphoma after rituximab plus cyclophosphamide,
doxorubicin, vincristine, and prednisone defines patients at high risk for death: an analysis from the national LymphoCare study. J Clin Oncol 2015;
33:2516e22. https://doi.org/10.1200/JCO.2014.59.7534.
[14] Tsujimoto Y, Finger LR, Yunis J, Nowell PC, Croce CM. Cloning of the chromosome breakpoint of neoplastic B cells with the t(14;18) chromosome
translocation. Science 1984;226:1097e9.
[15] Tsujimoto Y, Cossman J, Jaffe E, Croce CM. Involvement of the bcl-2 gene in human follicular lymphoma. Science 1985;228:1440e3.
[16] Tsujimoto Y, Gorham J, Cossman J, Jaffe E, Croce CM. The t(14;18) chromosome translocations involved in B-cell neoplasms result from mistakes in
VDJ joining. Science 1985;229:1390e3.
[17] Roulland S, Faroudi M, Mamessier E, Sungalee S, Salles G, Nadel B. Early steps of follicular lymphoma pathogenesis. Adv Immunol 2011;111:1e46.
Elsevier.
[18] McDonnell TJ, Deane N, Platt FM, Nunez G, Jaeger U, McKearn JP, et al. bcl-2-immunoglobulin transgenic mice demonstrate extended B cell survival
and follicular lymphoproliferation. Cell 1989;57:79e88.
[19] McDonnell TJ, Korsmeyer SJ. Progression from lymphoid hyperplasia to high-grade malignant lymphoma in mice transgenic for the t(14; 18). Nature
1991;349:254e6. https://doi.org/10.1038/349254a0.
[20] Sungalee S, Mamessier E, Morgado E, Gre
goire E, Brohawn PZ, Morehouse CA, et al. Germinal center reentries of BCL2-overexpressing B cells drive
follicular lymphoma progression. J Clin Investig 2014:1e4. https://doi.org/10.1172/JCI72415.
[21] Strasser A, Cory S, Adams JM. Deciphering the rules of programmed cell death to improve therapy of cancer and other diseases: deciphering cell
death to improve cancer therapy. EMBO J 2011;30:3667e83. https://doi.org/10.1038/emboj.2011.307.
[22] Brunelle JK, Letai A. Control of mitochondrial apoptosis by the Bcl-2 family. J Cell Sci 2009;122:437e41. https://doi.org/10.1242/jcs.031682.
[23] Llambi F, Moldoveanu T, Tait SWG, Bouchier-Hayes L, Temirov J, McCormick LL, et al. A unified model of mammalian BCL-2 protein family interactions
at the mitochondria. Mol Cell 2011;44:517e31. https://doi.org/10.1016/j.molcel.2011.10.001.
[24] Limpens J, Stad R, Vos C, de Vlaam C, de Jong D, van Ommen GJ, et al. Lymphoma-associated translocation t(14;18) in blood B cells of normal in-
dividuals. Blood 1995;85:2528e36.
 T. Lackraj et al. / Best Practice & Research Clinical Haematology 31 (2018) 2e14 11

[25] Do€lken G, Illerhaus G, Hirt C, Mertelsmann R. BCL-2/JH rearrangements in circulating B cells of healthy blood donors and patients with nonmalignant
diseases. J Clin Oncol 1996;14:1333e44.
[26] Schüler F, Do€lken L, Hirt C, Kiefer T, Berg T, Fusch G, et al. Prevalence and frequency of circulating t(14;18)-MBR translocation carrying cells in healthy
individuals. Int J Cancer 2009;124:958e63. https://doi.org/10.1002/ijc.23958.
[27] Roulland S, Navarro J-M, Grenot P, Milili M, Agopian J, Montpellier B, et al. Follicular lymphoma-like B cells in healthy individuals: a novel inter-
mediate step in early lymphomagenesis. J Exp Med 2006;203:2425e31. https://doi.org/10.1084/jem.20061292.
[28] Hirt C, Do€lken G, Janz S, Rabkin CS. Distribution of t(14;18)-positive, putative lymphoma precursor cells among B-cell subsets in healthy individuals1.
Br J Haematol 2007;138:349e53. https://doi.org/10.1111/j.1365-2141.2007.06671.x.
[29] Carlotti E, Wrench D, Matthews J, Iqbal S, Davies A, Norton A, et al. Transformation of follicular lymphoma to diffuse large B-cell lymphoma may
occur by divergent evolution from a common progenitor cell or by direct evolution from the follicular lymphoma clone. Blood 2009;113:3553e7.
https://doi.org/10.1182/blood-2008-08-174839.
[30] Weigert O, Kopp N, Lane AA, Yoda A, Dahlberg SE, Neuberg D, et al. Molecular ontogeny of donor-derived follicular lymphomas occurring after
hematopoietic cell transplantation. Cancer Discov 2012;2:47e55. https://doi.org/10.1158/2159-8290.CD-11-0208.
[31] Hirt C, Camargo MC, Yu KJ, Hewitt SM, Do €lken G, Rabkin CS. Risk of follicular lymphoma associated with BCL2 translocations in peripheral blood. Leuk
Lymphoma 2014:1e15. https://doi.org/10.3109/10428194.2014.999324.
[32] Roulland S, Kelly RS, Morgado E, Sungalee S, Solal-Celigny P, Colombat P, et al. t(14;18) translocation: a predictive blood biomarker for follicular
lymphoma. J Clin Oncol 2014;32. https://doi.org/10.1200/JCO.2013.52.8190.
[33] Green MR, Gentles AJ, Nair RV, Irish JM, Kihira S, Liu CL, et al. Hierarchy in somatic mutations arising during genomic evolution and progression of
follicular lymphoma. Blood 2013;121:1604e11. https://doi.org/10.1182/blood-2012-09-457283.
[34] Green MR, Kihira S, Liu CL, Nair RV, Salari R, Gentles AJ, et al. Mutations in early follicular lymphoma progenitors are associated with suppressed
antigen presentation. Proc Natl Acad Sci 2015;112:E1116e25. https://doi.org/10.1073/pnas.1501199112.
[35] Zhang J, Dominguez-Sola D, Hussein S, Lee J-E, Holmes AB, Bansal M, et al. Disruption of KMT2D perturbs germinal center B cell development and
promotes lymphomagenesis. Nat Med 2015:1e13. https://doi.org/10.1038/nm.3940.
[36] Horton SJ, Giotopoulos G, Yun H, Vohra S, Sheppard O, Bashford-Rogers R, et al. Early loss of Crebbp confers malignant stem cell properties on
lymphoid progenitors. Nat Cell Biol 2017. https://doi.org/10.1038/ncb3597.
[37] Schwaenen C, Viardot A, Berger H, Barth TFE, Bentink S, Do €hner H, et al. Microarray-based genomic profiling reveals novel genomic aberrations in
follicular lymphoma which associate with patient survival and gene expression status. Genes, Chromosom Cancer 2009;48:39e54. https://doi.org/10.
1002/gcc.20617.
[38] Johnson NA, Al-Tourah A, Brown CJ, Connors JM, Gascoyne RD, Horsman DE. Prognostic significance of secondary cytogenetic alterations in follicular
lymphomas. Genes, Chromosom Cancer 2008;47:1038e48. https://doi.org/10.1002/gcc.20606.
[39] Cheung K-JJ, Shah SP, Steidl C, Johnson N, Relander T, Telenius A, et al. Genome-wide profiling of follicular lymphoma by array comparative genomic
hybridization reveals prognostically significant DNA copy number imbalances. Blood 2009;113:137e48. https://doi.org/10.1182/blood-2008-02-
140616.
[40] Cheung K-JJ, Johnson NA, Affleck JG, Severson T, Steidl C, Ben-Neriah S, et al. Acquired TNFRSF14 mutations in follicular lymphoma are associated with
worse prognosis. Cancer Res 2010;70:9166e74. https://doi.org/10.1158/0008-5472.CAN-10-2460.
[41] Oricchio E, Nanjangud G, Wolfe AL, Schatz JH, Mavrakis KJ, Jiang M, et al. The Eph-receptor A7 is a soluble tumor suppressor for follicular lymphoma.
Cell 2011;147:554e64. https://doi.org/10.1016/j.cell.2011.09.035.The.
[42] Kridel R, Chan FC, Mottok A, Boyle M, Farinha P, Tan K, et al. Histological transformation and progression in follicular lymphoma: a clonal evolution
study. PLOS Med 2016;13, e1002197. https://doi.org/10.1371/journal.pmed.1002197.
[43] Shen H, Laird PW. Interplay between the cancer genome and epigenome. Cell 2013;153:38e55. https://doi.org/10.1016/j.cell.2013.03.008.
[44] Plass C, Pfister SM, Lindroth AM, Bogatyrova O, Claus R, Lichter P. Mutations in regulators of the epigenome and their connections to global chromatin
patterns in cancer. Nat Rev Genet 2013;14:765e80. https://doi.org/10.1038/nrg3554.
[45] Bannister AJ, Kouzarides T. Regulation of chromatin by histone modifications. Cell Res 2011;21:381e95. https://doi.org/10.1038/cr.2011.22.
[46] Morin RD, Johnson NA, Severson TM, Mungall AJ, An J, Goya R, et al. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell
lymphomas of germinal-center origin. Nat Genet 2010;42:181e5. https://doi.org/10.1038/ng.518.
[47] Morin RD, Mendez-Lago M, Mungall AJ, Goya R, Mungall KL, Corbett RD, et al. Frequent mutation of histone-modifying genes in non-Hodgkin
lymphoma. Nature 2011;476:298e303. https://doi.org/10.1038/nature10351.
[48] Pasqualucci L, Dominguez-Sola D, Chiarenza A, Fabbri G, Grunn A, Trifonov V, et al. Inactivating mutations of acetyltransferase genes in B-cell
lymphoma. Nature 2011;471:189e95. https://doi.org/10.1038/nature09730.
[49] Okosun J, Bo €do€r C, Wang J, Araf S, Yang C-Y, Pan C, et al. Integrated genomic analysis identifies recurrent mutations and evolution patterns driving the
initiation and progression of follicular lymphoma. Nat Genet 2013;46:176e81. https://doi.org/10.1038/ng.2856.
[50] Ortega-Molina A, Boss IW, Canela A, Pan H, Jiang Y, Zhao C, et al. The histone lysine methyltransferase KMT2D sustains a gene expression program
that represses B cell lymphoma development. Nat Med 2015:1e15. https://doi.org/10.1038/nm.3943.
[51] García-Ramírez I, Tadros S, Gonza
lez-Herrero I, Martín-Lorenzo A, Rodríguez-Hern
andez G, Moore D, et al. Crebbp loss cooperates with Bcl2 over-
expression to promote lymphoma in mice. Blood 2017;129:2645e56. https://doi.org/10.1182/blood-2016-08-733469.
[52] Zhang J, Vlasevska S, Wells VA, Nataraj S, Holmes AB, Duval R, et al. The crebbp acetyltransferase is a haploinsufficient tumor Suppressor in B Cell
lymphoma. Cancer Discov 2017. https://doi.org/10.1158/2159-8290.CD-16-1417.
[53] Be
guelin W, Popovic R, Teater M, Jiang Y, Bunting KL, Rosen M, et al. EZH2 is required for germinal center formation and somatic EZH2 mutations
promote lymphoid transformation. Cancer Cell 2013;23:677e92. https://doi.org/10.1016/j.ccr.2013.04.011.
[54] Kretzmer H, Bernhart SH, Wang W, Haake A, Weniger MA, Bergmann AK, et al. DNA methylome analysis in Burkitt and follicular lymphomas
identifies differentially methylated regions linked to somatic mutation and transcriptional control. Nat Genet 2015;47:1316e25. https://doi.org/10.
1038/ng.3413.
[55] Victora GD, Dominguez-Sola D, Holmes AB, Deroubaix S, Dalla-Favera R, Nussenzweig MC. Identification of human germinal center light and dark
zone cells and their relationship to human B-cell lymphomas. Blood 2012;120:2240e8. https://doi.org/10.1182/blood-2012-03-415380.
[56] Koues OI, Kowalewski R a, Chang L-W, Pyfrom SC, Schmidt J a, Luo H, et al. Enhancer sequence variants and transcription-factor deregulation
synergize to construct pathogenic regulatory circuits in B-Cell lymphoma. Immunity 2015;42:186e98. https://doi.org/10.1016/j.immuni.2014.12.021.
[57] Pastore A, Jurinovic V, Kridel R, Hoster E, Staiger AM, Szczepanowski M, et al. Integration of gene mutations in risk prognostication for patients
receiving first-line immunochemotherapy for follicular lymphoma: a retrospective analysis of a prospective clinical trial and validation in a
population-based registry. Lancet Oncol 2015;2045:1e12. https://doi.org/10.1016/S1470-2045(15)00169-2.
[58] Krysiak K, Gomez F, White BS, Matlock M, Miller CA, Trani L, et al. Recurrent somatic mutations affecting B-cell receptor signaling pathway genes in
follicular lymphoma. Blood 2017;129:473e83. https://doi.org/10.1182/blood-2016-07-729954.
[59] Yildiz M, Li H, Bernard D, Amin NA, Ouillette P, Jones S, et al. Activating STAT6 mutations in follicular lymphoma. Blood 2015;125:668e79. https://doi.
org/10.1182/blood-2014-06-582650.
[60] Basso K, Dalla-Favera R. Roles of BCL6 in normal and transformed germinal center B cells. Immunol Rev 2012;247:172e83. https://doi.org/10.1111/j.
1600-065X.2012.01112.x.
[61] Akasaka T. BCL6 gene translocation in follicular lymphoma: a harbinger of eventual transformation to diffuse aggressive lymphoma. Blood 2003;102:
1443e8. https://doi.org/10.1182/blood-2002-08-2482.
[62] Lo Coco F, Ye BH, Lista F, Corradini P, Offit K, Knowles DM, et al. Rearrangements of the BCL6 gene in diffuse large cell non-Hodgkin’s lymphoma.
Blood 1994;83:1757e9.
12 T. Lackraj et al. / Best Practice & Research Clinical Haematology 31 (2018) 2e14

[63] Bastard C, Deweindt C, Kerckaert JP, Lenormand B, Rossi A, Pezzella F, et al. LAZ3 rearrangements in non-Hodgkin’s lymphoma: correlation with
histology, immunophenotype, karyotype, and clinical outcome in 217 patients. Blood 1994;83:2423e7.
[64] Otsuki T, Yano T, Clark HM, Bastard C, Kerckaert JP, Jaffe ES, et al. Analysis of LAZ3 (BCL-6) status in B-cell non-Hodgkin’s lymphomas: results of
rearrangement and gene expression studies and a mutational analysis of coding region sequences. Blood 1995;85:2877e84.
[65] Kridel R, Mottok A, Farinha P, Ben-Neriah S, Ennishi D, Zheng Y, et al. Cell of origin of transformed follicular lymphoma. Blood 2015;126:2118e27.
https://doi.org/10.1182/blood-2015-06-649905.
[66] Ying CY, Dominguez-Sola D, Fabi M, Lorenz IC, Hussein S, Bansal M, et al. MEF2B mutations lead to deregulated expression of the oncogene BCL6 in
diffuse large B cell lymphoma. Nat Immunol 2013;14:1084e92. https://doi.org/10.1038/ni.2688.
[67] Valls E, Lobry C, Geng H, Wang L, Cardenas M, Rivas M, et al. BCL6 antagonizes NOTCH2 to maintain survival of human follicular lymphoma cells.
Cancer Discov 2017;7:506e21. https://doi.org/10.1158/2159-8290.CD-16-1189.
[68] Okosun J, Wolfson RL, Wang J, Araf S, Wilkins L, Castellano BM, et al. Recurrent mTORC1-activating RRAGC mutations in follicular lymphoma. Nat
Genet 2015;48:183e8. https://doi.org/10.1038/ng.3473.
[69] Oricchio E, Katanayeva N, Donaldson MC, Sungalee S, Joyce PP, Be
guelin W, et al. Genetic and epigenetic inactivation of <em>SESTRIN1</em>
controls mTORC1 and response to EZH2 inhibition in follicular lymphoma. Sci Transl Med 2017;9:1e11. https://doi.org/10.1126/scitranslmed.aak9969.
[70] Boice M, Salloum D, Mourcin F, Sanghvi V, Amin R, Oricchio E, et al. Loss of the HVEM tumor suppressor in lymphoma and restoration by modified
CAR-t cells. Cell 2016;167:405e18. https://doi.org/10.1016/j.cell.2016.08.032. e13.
[71] Launay E, Pangault C, Bertrand P, Jardin F, Lamy T, Tilly H, et al. High rate of TNFRSF14 gene alterations related to 1p36 region in de novo follicular
lymphoma and impact on prognosis. Leukemia 2012;26:559e62. https://doi.org/10.1038/leu.2011.266.
[72] Mottok A, Renne
C, Seifert M, Oppermann E, Bechstein W, Hansmann M-L, et al. Inactivating SOCS1 mutations are caused by aberrant somatic
hypermutation and restricted to a subset of B-cell lymphoma entities. Blood 2009;114:4503e6. https://doi.org/10.1182/blood-2009-06-225839.
[73] Melzner I, Bucur AJ, Brüderlein S, Dorsch K, Hasel C, Barth TFE, et al. Biallelic mutation SOCS-1 impairs JAK2 degradation and sustains phospho-JAK2
action in the MedB-1 mediastinal lymphoma line. Blood 2005;105:2535e42. https://doi.org/10.1182/blood-2004-09-3701.
[74] Xerri L, Bachy E, Fabiani B, Canioni D, Chassagne-Cle
ment C, Dartigues-Cuille
res P, et al. Identification of MUM1 as a prognostic immunohistochemical
marker in follicular lymphoma using computerized image analysis. Hum Pathol 2014;45:2085e93. https://doi.org/10.1016/j.humpath.2014.06.019.
[75] Martin AR, Weisenburger DD, Chan WC, Ruby EI, Anderson JR, Vose JM, et al. Prognostic value of cellular proliferation and histologic grade in
follicular lymphoma. Blood 1995;85:3671e8.
[76] Pruneri G, Valentini S, Fabris S, Del Curto B, Laszlo D, Bertolini F, et al. Cyclin D3 immunoreactivity in follicular lymphoma is independent of the t(6;
14)(p21.1;q32.3) translocation or cyclin D3 gene amplification and is correlated with histologic grade and Ki-67 labeling index. Int J Cancer 2004;112:
71e7. https://doi.org/10.1002/ijc.20354.
[77] Oricchio E, Ciriello G, Jiang M, Boice MH, Schatz JH, Heguy A, et al. Frequent disruption of the RB pathway in indolent follicular lymphoma suggests a
new combination therapy. J Exp Med 2014;211:1379e91. https://doi.org/10.1084/jem.20132120.
[78] Buske C, Twiling A, Gogowski G, Schreiber K, Feuring-Buske M, Wulf GG, et al. In vitro activation of low-grade non-Hodgkin’s lymphoma by murine
fibroblasts, IL-4, anti-CD40 antibodies and the soluble CD40 ligand. Leukemia 1997;11:1862e7.
[79] Johnson PW, Watt SM, Betts DR, Davies D, Jordan S, Norton AJ, et al. Isolated follicular lymphoma cells are resistant to apoptosis and can be grown
in vitro in the CD40/stromal cell system. Blood 1993;82:1848e57.
[80] Umetsu DT, Esserman L, Donlon TA, DeKruyff RH, Levy R. Induction of proliferation of human follicular (B type) lymphoma cells by cognate inter-
action with CD4þ T cell clones. J Immunol 1990;144:2550e7.
[81] Dave SS, Wright G, Tan B, Rosenwald A, Gascoyne RD, Chan WC, et al. Prediction of survival in follicular lymphoma based on molecular features of
tumor-infiltrating immune cells. N Engl J Med 2004;351:2159e69. https://doi.org/10.1056/NEJMoa041869.
[82] Harjunp€ a€
a A, Taskinen M, Nykter M, Karjalainen-Lindsberg M-L, Nyman H, Monni O, et al. Differential gene expression in non-malignant tumour
microenvironment is associated with outcome in follicular lymphoma patients treated with rituximab and CHOP. Br J Haematol 2006;135:33e42.
https://doi.org/10.1111/j.1365-2141.2006.06255.x.
[83] Scott DW, Gascoyne RD. The tumour microenvironment in B cell lymphomas. Nat Rev Cancer 2014;14:517e34. https://doi.org/10.1038/nrc3774.
[84] Kiaii S, Clear AJ, Ramsay AG, Davies D, Sangaralingam A, Lee A, et al. Follicular lymphoma cells induce changes in T-cell gene expression and function:
potential impact on survival and risk of transformation. J Clin Oncol 2013;31:2654e61. https://doi.org/10.1200/JCO.2012.44.2137.
[85] Pangault C, Ame
-Thomas P, Ruminy P, Rossille D, Caron G, Baia M, et al. Follicular lymphoma cell niche: identification of a preeminent IL-4-dependent
T(FH)-B cell axis. Leukemia 2010;24:2080e9. https://doi.org/10.1038/leu.2010.223.
[86] Ame
-Thomas P, Le Priol J, Yssel H, Caron G, Pangault C, Jean R, et al. Characterization of intratumoral follicular helper T cells in follicular lymphoma:
role in the survival of malignant B cells. Leukemia 2012;26:1053e63. https://doi.org/10.1038/leu.2011.301.
[87] Guilloton F, Caron G, Me
nard C, Pangault C, Ame
-Thomas P, Dulong J, et al. Mesenchymal stromal cells orchestrate follicular lymphoma cell niche
through the CCL2-dependent recruitment and polarization of monocytes. Blood 2012;119:2556e67. https://doi.org/10.1182/blood-2011-08-370908.
[88] Pandey S, Mourcin FEE, Marchand T, Nayar S, Guirriec M, Pangault C, et al. IL-4/CXCL12 loop is a key regulator of lymphoid stroma function in
follicular lymphoma. Blood 2017;129:2507e18. https://doi.org/10.1182/blood-2016-08.
[89] Ramsay AG, Clear AJ, Kelly G, Fatah R, Matthews J, Macdougall F, et al. Follicular lymphoma cells induce T-cell immunologic synapse dysfunction that
can be repaired with lenalidomide: implications for the tumor microenvironment and immunotherapy. Blood 2009;114:4713e20. https://doi.org/10.
1182/blood-2009-04-217687.
[90] Pasqualucci L, Khiabanian H, Fangazio M, Vasishtha M, Messina M, Holmes AB, et al. Genetics of follicular lymphoma transformation. Cell Rep 2014;6:
130e40. https://doi.org/10.1016/j.celrep.2013.12.027.
[91] Bahler DW, Levy R. Clonal evolution of a follicular lymphoma: evidence for antigen selection. Proc Natl Acad Sci U. S. A 1992;89:6770e4.
[92] Cha S, Qin H, Kannan S, Rawal S, Watkins LS, Baio FE, et al. Nonstereotyped lymphoma B cell receptors recognize vimentin as a shared autoantigen.
J Immunol 2013;190:4887e98. https://doi.org/10.4049/jimmunol.1300179.
[93] Sachen KL, Strohman MJ, Singletary J, Alizadeh A a, Kattah NH, Lossos C, et al. Self-antigen recognition by follicular lymphoma B-cell receptors. Blood
2012;120:4182e90. https://doi.org/10.1182/blood-2012-05-427534.
[94] Zhu D, McCarthy H, Ottensmeier CH, Johnson P, Hamblin TJ, Stevenson FK. Acquisition of potential N-glycosylation sites in the immunoglobulin
variable region by somatic mutation is a distinctive feature of follicular lymphoma. Blood 2002;99:2562e8. https://doi.org/10.1182/blood.V99.7.2562.
[95] Radcliffe CM, Arnold JN, Suter DM, Wormald MR, Harvey DJ, Royle L, et al. Human follicular lymphoma cells contain oligomannose glycans in the
antigen-binding site of the B-cell receptor. J Biol Chem 2007;282:7405e15. https://doi.org/10.1074/jbc.M602690200.
[96] Coelho V, Krysov S, Ghaemmaghami AM, Emara M, Potter KN, Johnson P, et al. Glycosylation of surface Ig creates a functional bridge between human
follicular lymphoma and microenvironmental lectins. Proc Natl Acad Sci U. S. A 2010;107:18587e92. https://doi.org/10.1073/pnas.1009388107.
[97] Linley A, Krysov S, Ponzoni M, Johnson PW, Packham G, Stevenson FK. Lectin binding to surface Ig variable regions provides a universal persistent
activating signal for follicular lymphoma cells. Blood 2015;126:1902e10. https://doi.org/10.1182/blood-2015-04-640805.
[98] Kridel R, Xerri L, Gelas-Dore B, Tan K, Feugier P, Vawda A, et al. The prognostic impact of CD163-positive macrophages in follicular lymphoma: a study
from the BC cancer agency and the lymphoma study association. Clin Cancer Res 2015;21:3428e35. https://doi.org/10.1158/1078-0432.CCR-14-3253.
[99] Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, et al. The 2016 revision of the World Health Organization classification of lymphoid
neoplasms. Blood 2016;127:2375e90. https://doi.org/10.1182/blood-2016-01-643569.
[100] Cong P, Raffeld M, Teruya-Feldstein J, Sorbara L, Pittaluga S, Jaffe ES. In situ localization of follicular lymphoma: description and analysis by laser
capture microdissection. Blood 2002;99:3376e82. https://doi.org/10.1182/blood.V99.9.3376.
[101] Jegalian AG, Eberle FC, Pack SD, Mirvis M, Raffeld M, Pittaluga S, et al. Follicular lymphoma in situ: clinical implications and comparisons with partial
involvement by follicular lymphoma. Blood 2011;118:2976e84. https://doi.org/10.1182/blood-2011-05-355255.
 T. Lackraj et al. / Best Practice & Research Clinical Haematology 31 (2018) 2e14 13

[102] Jegalian AG, Eberle FC, Pack SD, Mirvis M, Raffeld M, Pittaluga S, et al. Follicular lymphoma in situ: clinical implications and comparisons with partial
involvement by follicular lymphoma. Blood 2011;118:2976e84. https://doi.org/10.1182/blood-2011-05-355255.
[103] Morita K, Nakamine H, Nakai T, Takano M, Takeda M, Enomoto Y, et al. A retrospective study of patients with follicular lymphoma (FL): identification
of in situ FL or FL-like B cells of uncertain significance in lymph nodes resected at the time of previous surgery for carcinomas. J Clin Pathol 2015;68:
541e6. https://doi.org/10.1136/jclinpath-2015-202933.
[104] Schmidt J, Salaverria I, Haake a, Bonzheim I, Adam P, Montes-Moreno S, et al. Increasing genomic and epigenomic complexity in the clonal evolution
from in situ to manifest t(14;18)-positive follicular lymphoma. Leukemia 2013;28:1103e12. https://doi.org/10.1038/leu.2013.307.
[105] Mamessier E, Song JY, Eberle FC, Pack S, Drevet C, Chetaille B, et al. Early lesions of follicular lymphoma: a genetic perspective. Haematologica 2014;
99:481e8. https://doi.org/10.3324/haematol.2013.094474.
[106] Swerdlow SH, Campo E, Harris N, Jaffe ES, Pileri SA, Stein H, et al. WHO classification of tumours of haematopoeitic and lymphoid tissues. 4th ed.
IARC; 2008.
[107] Karube K, Guo Y, Suzumiya J, Sugita Y, Nomura Y, Yamamoto K, et al. CD10-MUM1þ follicular lymphoma lacks BCL2 gene translocation and shows
characteristic biologic and clinical features. Blood 2007;109:3076e9. https://doi.org/10.1182/blood-2006-09-045989.
[108] Karube K, Ying G, Tagawa H, Niino D, Aoki R, Kimura Y, et al. BCL6 gene amplification/3q27 gain is associated with unique clinicopathological
characteristics among follicular lymphoma without BCL2 gene translocation. Mod Pathol 2008;21:973e8. https://doi.org/10.1038/modpathol.2008.
75.
[109] Horsman DE, Okamoto I, Ludkovski O, Le N, Harder L, Gesk S, et al. Follicular lymphoma lacking the t(14;18)(q32;q21): identification of two disease
subtypes. Br J Haematol 2003;120:424e33.
[110] Gu K, Fu K, Jain S, Liu Z, Iqbal J, Li M, et al. t(14;18)-negative follicular lymphomas are associated with a high frequency of BCL6 rearrangement at the
alternative breakpoint region. Mod Pathol 2009;22:1251e7. https://doi.org/10.1038/modpathol.2009.81.
[111] Leich E, Salaverria I, Bea S, Zettl A, Wright G, Moreno V, et al. Follicular lymphomas with and without translocation t(14;18) differ in gene expression
profiles and genetic alterations. Blood 2009;114:826e34. https://doi.org/10.1182/blood-2009-01-198580.
[112] Louissaint A, Ackerman AM, Dias-Santagata D, Ferry JA, Hochberg EP, Huang MS, et al. Pediatric-type nodal follicular lymphoma: an indolent clonal
proliferation in children and adults with high proliferation index and no BCL2 rearrangement. Blood 2012;120:2395e404. https://doi.org/10.1182/
blood-2012-05-429514.
[113] Liu Q, Salaverria I, Pittaluga S, Jegalian AG, Xi L, Siebert R, et al. Follicular lymphomas in children and young adults: a comparison of the pediatric
variant with usual follicular lymphoma. Am J Surg Pathol 2013;37:333e43. https://doi.org/10.1097/PAS.0b013e31826b9b57.
[114] Martin-Guerrero I, Salaverria I, Burkhardt B, Szczepanowski M, Baudis M, Bens S, et al. Recurrent loss of heterozygosity in 1p36 associated with
TNFRSF14 mutations in IRF4 translocation negative pediatric follicular lymphomas. Haematologica 2013;98:1237e41. https://doi.org/10.3324/hae-
matol.2012.073916.
[115] Schmidt J, Gong S, Marafioti T, Mankel B, Gonzalez-Farre B, Balague
O, et al. Genome-wide analysis of pediatric-type follicular lymphoma reveals low
genetic complexity and recurrent alterations of TNFRSF14 gene. Blood 2016;128:1101e11. https://doi.org/10.1182/blood-2016-03-703819.
[116] Ozawa MG, Bhaduri A, Chisholm KM, Baker SA, Ma L, Zehnder JL, et al. A study of the mutational landscape of pediatric-type follicular lymphoma and
pediatric nodal marginal zone lymphoma. Mod Pathol 2016;29:1212e20. https://doi.org/10.1038/modpathol.2016.102.
[117] Louissaint A, Schafernak KT, Geyer JT, Kovach AE, Ghandi M, Gratzinger D, et al. Pediatric-type nodal follicular lymphoma: a biologically distinct
lymphoma with frequent MAPK pathway mutations. Blood 2016;128:1093e100. https://doi.org/10.1182/blood-2015-12-682591.
[118] Schmatz A-I, Streubel B, Kretschmer-Chott E, Püspo € k A, Ja
€ger U, Mannhalter C, et al. Primary follicular lymphoma of the duodenum is a distinct
mucosal/submucosal variant of follicular lymphoma: a retrospective study of 63 cases. J Clin Oncol 2011;29:1445e51. https://doi.org/10.1200/JCO.
2010.32.9193.
[119] Takata K, Sato Y, Nakamura N, Tokunaka M, Miki Y, Yukie Kikuti Y, et al. Duodenal follicular lymphoma lacks AID but expresses BACH2 and has
memory B-cell characteristics. Mod Pathol 2013;26:22e31. https://doi.org/10.1038/modpathol.2012.127.
[120] Takata K, Tanino M, Ennishi D, Tari A, Sato Y, Okada H, et al. Duodenal follicular lymphoma: comprehensive gene expression analysis with insights
into pathogenesis. Cancer Sci 2014:1e8. https://doi.org/10.1111/cas.12392.
[121] Ho € glund M, Sehn L, Connors JM, Gascoyne RD, Siebert R, Sa €ll T, et al. Identification of cytogenetic subgroups and karyotypic pathways of clonal
evolution in follicular lymphomas. Genes Chromosom Cancer 2004;39:195e204. https://doi.org/10.1002/gcc.10314.
[122] d'Amore F, Chan E, Iqbal J, Geng H, Young K, Xiao L, et al. Clonal evolution in t(14;18)-positive follicular lymphoma, evidence for multiple common
pathways, and frequent parallel clonal evolution. Clin Cancer Res 2008;14:7180e7. https://doi.org/10.1158/1078-0432.CCR-08-0752.
[123] Ottensmeier CH, Thompsett AR, Zhu D, Wilkins BS, Sweetenham JW, Stevenson FK. Analysis of VH genes in follicular and diffuse lymphoma shows
ongoing somatic mutation and multiple isotype transcripts in early disease with changes during disease progression. Blood 1998;91:4292e9.
[124] Loeffler M, Kreuz M, Haake A, Hasenclever D, Trautmann H, Arnold C, et al. Genomic and epigenomic co-evolution in follicular lymphomas. Leukemia
2014:456e63. https://doi.org/10.1038/leu.2014.209.
[125] Carlotti E, Wrench D, Rosignoli G, Marzec J, Sangaralingam A, Hazanov L, et al. High throughput sequencing analysis of the immunoglobulin heavy
chain gene from flow-sorted B cell sub-populations define the dynamics of follicular lymphoma clonal evolution. PLoS One 2015;10, e0134833.
https://doi.org/10.1371/journal.pone.0134833.
[126] Scherer F, Kurtz DM, Newman AM, Stehr H, Craig AFM, Esfahani MS, et al. Distinct biological subtypes and patterns of genome evolution in lymphoma
revealed by circulating tumor DNA. Sci Transl Med 2016;8, 364ra155. https://doi.org/10.1126/scitranslmed.aai8545.
[127] Wartenberg M, Vasil P, zum Bueschenfelde CM, Ott G, Rosenwald A, Fend F, et al. Somatic hypermutation analysis in follicular lymphoma provides
evidence suggesting bidirectional cell migration between lymph node and bone marrow during disease progression and relapse. Haematologica
2013;98:1433e41. https://doi.org/10.3324/haematol.2012.074252.
[128] Montoto S, Davies AJ, Matthews J, Calaminici M, Norton AJ, Amess J, et al. Risk and clinical implications of transformation of follicular lymphoma to
diffuse large B-Cell lymphoma. J Clin Oncol 2007;25:2426e33. https://doi.org/10.1200/JCO.2006.09.3260.
[129] Bastion Y, Sebban C, Berger F, Felman P, Salles G, Dumontet C, et al. Incidence, predictive factors, and outcome of lymphoma transformation in
follicular lymphoma patients. J Clin Oncol 1997;15:1587e94. https://doi.org/10.1200/JCO.1997.15.4.1587.
[130] Kridel R, Sehn LH, Gascoyne RD. Can histologic transformation of follicular lymphoma be predicted and prevented? Blood 2017;130:258e66. https://
doi.org/10.1182/blood-2017-03-691345.
[131] Link BK, Maurer MJ, Nowakowski GS, Ansell SM, Macon WR, Syrbu SI, et al. Rates and outcomes of follicular lymphoma transformation in the
immunochemotherapy era: a report from the university of Iowa/Mayo clinic specialized program of research excellence molecular epidemiology
resource. J Clin Oncol 2013;31:3272e8. https://doi.org/10.1200/JCO.2012.48.3990.
[132] Sarkozy C, Trneny M, Xerri L, Wickham N, Feugier P, Leppa S, et al. Risk factors and outcomes for patients with follicular lymphoma who had
histologic transformation after response to first-line immunochemotherapy in the PRIMA trial. J Clin Oncol 2016;34:2575e82. https://doi.org/10.
1200/JCO.2015.65.7163.
[133] Lossos IS, Gascoyne RD. Transformation of follicular lymphoma. Best Pract Res Clin Haematol 2011;24:147e63. https://doi.org/10.1016/j.beha.2011.02.
006.
[134] Johnson NA, Savage KJ, Ludkovski O, Ben-Neriah S, Woods R, Steidl C, et al. Lymphomas with concurrent BCL2 and MYC translocations: the critical
factors associated with survival. Blood 2009;114:2273e9. https://doi.org/10.1182/blood-2009-03-212191.
[135] Lo Coco F, Gaidano G, Louie DC, Offit K, Chaganti RS, Dalla-Favera R. p53 mutations are associated with histologic transformation of follicular
lymphoma. Blood 1993;82:2289e95.
[136] Sander CA, Yano T, Clark HM, Harris C, Longo DL, Jaffe ES, et al. p53 mutation is associated with progression in follicular lymphomas. Blood 1993;82:
1994e2004.
14 T. Lackraj et al. / Best Practice & Research Clinical Haematology 31 (2018) 2e14

[137] Yano T, Jaffe ES, Longo DL, Raffeld M. MYC rearrangements in histologically progressed follicular lymphomas. Blood 1992;80:758e67.
[138] Fitzgibbon J, Iqbal S, Davies A, O'Shea D, Carlotti E, Chaplin T, et al. Genome-wide detection of recurring sites of uniparental disomy in follicular and
transformed follicular lymphoma. Leukemia 2007;21:1514e20. https://doi.org/10.1038/sj.leu.2404696.
[139] Lossos IS, Alizadeh AA, Diehn M, Warnke R, Thorstenson Y, Oefner PJ, et al. Transformation of follicular lymphoma to diffuse large-cell lymphoma:
alternative patterns with increased or decreased expression of c-myc and its regulated genes. Proc Natl Acad Sci 2002;99:8886e91. https://doi.org/
10.1073/pnas.132253599.
[140] Bouska A, McKeithan TW, Deffenbacher KE, Lachel C, Wright GW, Iqbal J, et al. Genome-wide copy-number analyses reveal genomic abnormalities
involved in transformation of follicular lymphoma. Blood 2014;123:1681e90. https://doi.org/10.1182/blood-2013-05-500595.
[141] Bouska A, Zhang W, Gong Q, Iqbal J, Scuto A, Vose J, et al. Combined copy number and mutation analysis identifies oncogenic pathways associated
with transformation of follicular lymphoma, vol. 8; 2016. p. 1e9. https://doi.org/10.1038/leu.2016.175.
[142] Lenz G, Wright G, Dave SS, Xiao W, Powell J, Zhao H, et al. Stromal gene signatures in large-B-cell lymphomas. N Engl J Med 2008;359:2313e23.
https://doi.org/10.1056/NEJMoa0802885.
[143] Nowakowski GS, LaPlant B, Macon WR, Reeder CB, Foran JM, Nelson GD, et al. Lenalidomide combined with R-CHOP overcomes negative prognostic
impact of non-germinal center B-cell phenotype in newly diagnosed diffuse large B-cell lymphoma: a phase II study. J Clin Oncol 2015;33:251e7.
https://doi.org/10.1200/JCO.2014.55.5714.
[144] Wilson WH, Young RM, Schmitz R, Yang Y, Pittaluga S, Wright G, et al. Targeting B cell receptor signaling with ibrutinib in diffuse large B cell
lymphoma. Nat Med 2015;21:1e6. https://doi.org/10.1038/nm.3884.
[145] Davies AJ, Rosenwald A, Wright G, Lee A, Last KW, Weisenburger DD, et al. Transformation of follicular lymphoma to diffuse large B-cell lymphoma
proceeds by distinct oncogenic mechanisms. Br J Haematol 2007;136:286e93. https://doi.org/10.1111/j.1365-2141.2006.06439.x.Transformation.
[146] Mozessohn L, Cheung MC, Crump M, Buckstein R, Berinstein N, Imrie K, et al. Chemoimmunotherapy resistant follicular lymphoma: predictors of
resistance, association with transformation and prognosis. Leuk Lymphoma 2014;55:2502e7. https://doi.org/10.3109/10428194.2014.885513.
[147] Maurer MJ, Bachy E, Ghesquie res H, Ansell SM, Nowakowski GS, Thompson CA, et al. Early event status informs subsequent outcome in newly
diagnosed follicular lymphoma. Am J Hematol 2016;91:1096e101. https://doi.org/10.1002/ajh.24492.