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Page 2 of 19 Casadei et al. J Cancer Metastasis Treat 2022;8:21 https://dx.doi.org/10.20517/2394-4722.2022.05

INTRODUCTION
Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma, accounting for 70% of
[1]
[2]
cases in Western countries . Median age at presentation is 65 years old and the disease course is typically
made of remissions (even spontaneous ones in 5%-10% of cases ) but multiple relapses over time. Patients
[3]
typically present with painless lymphadenopathies, reported to have slowly enlarged over a few weeks or
months. Bone marrow involvement is present in about 70% of patients at diagnosis, whereas B symptoms
[1]
characterize only 20% of them . Sometimes the presentation is aggressive, because lymphadenopathies are
already bulky at diagnosis, determining consequences due to organ compression or infiltration in the chest
or the abdomen.

In this paper, we highlight the main features of FL heterogeneity and emphasize how this biological
heterogeneity could be connected to a different clinical behavior. If we start to look at FL in this way,
nothing will appear more obsolete than using the same treatment, without distinctions, in all the patients.

FOLLICULAR LYMPHOMA: A BIOLOGICALLY HETEROGENEOUS DISEASE
Despite the presence of a unique name, FL is an extremely heterogeneous disease, both clinically and
biologically. In fact, it is characterized by a wide range of clinical presentations, with a very well-known
[1]
possibility of transformation into diffuse large B-cell lymphoma (DLBCL) in 2% of cases/year . The basis of
FL heterogeneity lies in the different biological pathways which can be activated in this disease, and it is
partly, but not fully, captured by the histologic classification into Grades I-III, each associated with
increasing aggressiveness in the disease behavior [1,4,5] .

In the last years, significant improvements have been made in our understanding of FL biology. A multistep
pathogenesis and the crosstalk between FL cells and tumor microenvironment (TME) are emerging as
crucial steps of disease evolution. FL cells represent the malignant counterparts of normal
germinal center (GC) B cells: they are CD10 and BCL6+ and they show ongoing processes of class-switch
recombination and somatic hypermutation . The t(14;18) (q32;q21) translocation is considered the genetic
[6,7]
hallmark and founding lesion in FL, occurring in more than 85% of patients. It results in B-cell lymphoma 2
[8]
(BCL2) constitutive overexpression and therefore protection of lymphocytes from apoptosis . However, the
presence of t(14;18) alone is insufficient for lymphomagenesis. In fact, healthy adult individuals can display
mono- or oligo-clonal t(14;18)-positive B cells in peripheral blood, without having FL diagnosis . These
[9]
cells are thought to represent a pre-malignant pool of “FL-like cells” (FLLCs). Although it is not clearly
understood which cases subsequently progress into FL, it is postulated that FLLCs go through secondary
lymphoid tissue GCs repeatedly, acquiring additional genomic aberrations, while evading apoptosis, via
BCL2 constitutive expression .
[10]

Genetic profiles of FL tumors can evolve longitudinally over the disease course, explaining the dramatic
changes in disease clinical behavior, but also spatially, at different sites of involvement in the same moment.
Araf and colleagues demonstrated that, in a single patient, samples coming from different involved lymph
nodes could express different gene mutations . This heterogeneity increases as FL progresses from Grade
[11]
I-II to Grade 3 and more and more as it transforms into DLBCL [11-13] .

In this “heterogeneity context”, there are mutations other than Bcl-2 that occur early in FL history, such as
those affecting epigenetic regulation. Epigenetic mutations typically occur on histone post-translational
modifying genes, including cAMP response element-binding protein binding protein (CREBBP), histone-
lysine N-methyltransferase 2D (KMT2D), enhancer of zeste homologue 2 (EZH2), and E1A binding protein
P300 (EP300) [13-15] . KMT2D [16,17] and CREBBP are the most commonly mutated genes (70%-80% of
[18]