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Page 90 Oquendo et al. J Transl Genet Genom 2021;5:89-111 https://dx.doi.org/10.20517/jtgg.2021.04

patients with improved management and treatment choices.

Keywords: Splenic marginal zone lymphoma, pathogenesis, genetics, epigenetics, clinical

INTRODUCTION
The World Health Organization classification of tumours of the hematopoietic and lymphoid tissues defines
three marginal zone (MZ) lymphoma entities, splenic marginal zone lymphoma (SMZL), nodal MZL
(NMZL) and extranodal MZL . In addition, a number of provisional entities are emerging; these include
[1]
splenic diffuse red pulp lymphoma (SDRPL), hairy cell leukaemia-variant (HCL-v) and clonal B-cell
lymphocytosis of marginal zone origin (CBL-MZ), the latter of which is clonally related to SMZL in a
[2-5]
proportion of cases . SMZL comprises less than 2% of lymphoid neoplasms, typically involving the spleen,
bone marrow and peripheral blood, although a minority of patients have low volume extra hilar intra-
abdominal lymphadenopathy detectable on CT scanning. Patients most commonly present with abdominal
discomfort due to massive splenomegaly, anaemia secondary to hypersplenism or auto-immune haemolysis,
or incidentally due to either clinical or radiological detection of asymptomatic splenomegaly or an abnormal
[6,7]
blood count. The median age of diagnosis is 65 and patients exhibit a 10-year median survival time . The
diagnosis is most secure in patients who undergo splenectomy, now performed almost always for
therapeutic reasons, but it increasingly relies on a combination of clinical features together with an
assessment of lymphocyte morphology and immunophenotype, bone marrow histology and
[7]
immunohistochemistry . In the absence of splenic histology, the differential diagnosis from common low-
grade B-cell disorders such as chronic lymphocytic leukaemia (CLL), follicular lymphoma (FL), and mantle
cell lymphoma (MCL) is usually straightforward but SMZL lacks a disease-specific immunophenotype and
the distinction between SMZL and some cases of HCL-v, SDRPL and lymphoplasmacytic lymphoma (LPL)
may be more difficult. Approximately 70% of patients have a progressive disease requiring treatment.
Standard treatment options include splenectomy, Rituximab or Rituximab and bendamustine, all of which
achieve high response rates with prolonged progression-free survival . However, up to 30% of patients
[8,9]
relapse and are intolerant of, or resistant to, standard therapies or transform to diffuse large B-cell
[10]
lymphoma (DLBCL) with dismal survival . Therefore, there is an unmet need for well tolerated, preferably
oral, novel therapies.

Whilst SMZL is still a relatively under-studied malignancy, several works published over the last decade or
so have begun to unravel the intrinsic molecular defects present in the SMZL B-cell, and extrinsic cellular
mechanisms that reflect micro-environmental and antigenic interactions [Figure 1]. This review will focus
on providing a summary of the (epi)genetic and immunogenetic landscape of the disease, the associated
clinico-biological implications of these aberrations, as well as supplying an overview of key unanswered
questions that might direct future research in this area.

ANALYSIS OF THE IMMUNOGLOBULIN GENES
The most important molecule expressed on the cell surface of SMZL B-cells is the B-cell receptor (BCR),
which allows interaction with antigens and antigenic elements within the tumour microenvironment.
Seminal sequencing studies of the immunoglobulin (IG) have been performed on the myriad of mature B-
cell neoplasms, including SMZL, where they have identified key features of the B-cell receptor
immunoglobulin repertoire indicating that clonal B-cell selection by antigen/superantigens is an important
feature of SMZL pathophysiology. Investigation of large SMZL cohorts has demonstrated remarkably biased
usage of immunoglobulin heavy chain (IGHV) genes, namely enrichment of the IGHV1-02 (30%), IGHV4-
34 (11%) and IGHV3-23 (9%) genes, which collectively represent almost half of SMZL cases [20,21] . What is