Received: 28 March 2023

DOI: 10.1002/hon.3152

REVIEW ARTICLE
- Accepted: 28 March 2023

Marginal zone lymphomas

Emanuele Zucca1,2,3 | Davide Rossi1,2,3 | Francesco Bertoni1,2,3

1
Oncology Institute of Southern Switzerland
(IOSI), Ente Ospedaliero Cantonale (EOC), Abstract
Bellinzona, Switzerland
The three main types of marginal zone lymphoma (MZL), recognized by the current
2
Institute of Oncology Research (IOR),
lymphoma classifications are the extranodal MZL of mucosa‐associated lymphoid
Bellinzona, Switzerland
3
Faculty of Biomedical Sciences, Università
tissue, the splenic MZL, and the nodal MZL. They share some karyotype lesions
della Svizzera Italiana (USI), Lugano, (trisomies of chromosomes 3 and 18, deletions at 6q23), and alterations of the nu-
Switzerland
clear factor kappa B (NFkB) pathway are also common in all of them. However, they
Correspondence differ in the presence of recurrent translocations, mutations affecting the Notch
Emanuele Zucca, Institute of Oncology signaling pathway (NOTCH2 and less commonly NOTCH1), the transcription factors
Research, IELSG, Via Francesco Chiesa 5,
Bellinzona 6500, Switzerland. Kruppel‐like factor 2 (KLF2) or the receptor‐type protein tyrosine phosphatase delta
Email: [email protected] (PTPRD). This review summarizes the most recent and significant advances in our
understanding of the epidemiology, genetics, and biology of MZLs and outlines the
current principles of the standard management of MZL at different anatomic sites.

KEYWORDS
extranodal MZL of MALT type, marginal zone lymphoma, nodal MZL, splenic MZL

1 | DEFINITION these cutaneous forms as primary cutaneous marginal zone “lym-

phoproliferative disorders” rather than “lymphomas,” and they
Marginal zone B‐cell‐derived lymphoproliferative diseases encom- typically do not require aggressive treatment. The ICC distin-
pass extranodal marginal zone lymphoma (MZL) of mucosa‐ guishes two subtypes of them based on expression of class‐
associated lymphoid tissue (MALT lymphoma), splenic MZL, and switched IgG or IgM.2
nodal MZL. Variants include pediatric subtype of nodal MZL and Marginal zone B‐cells, responding to both T‐cell‐dependent and
immunoproliferative small intestinal disease (IPSID), a form of MALT T‐cell‐independent antigens,4,5 are considered the normal counter-
lymphoma. Clonal B‐cell lymphocytosis of marginal‐zone origin may parts of the neoplastic cells in all subtypes of MZLs.6
1
precede the development of an overt MZL. These lymphomas infiltrate the marginal zone of reactive B‐cell
In 2022, two updated lymphoma classifications were proposed, follicles and spreads into the interfollicular region. In epithelial
the International Consensus Classification (ICC) and the 5th edi- tissues, the neoplastic cells commonly infiltrate the epithelium and
tion of the World Health Organization (WHO) classification, both form lymphoepithelial lesions. MZL B‐cells are morphologically
derived from the previous WHO classification.2,3 The ICC and the heterogeneous, including centrocyte‐like marginal zone B‐cells
5th edition of the WHO classification are largely superimposable monocytoid cells, small lymphocytes, and occasional large cells
for MZLs (see Table 1). The main difference from the prior tax- reminiscent of immunoblasts and centroblasts. The degree of
onomy relates to the distinction of marginal zone cutaneous plasma cell differentiation varies.7–9 MZLs represent distinct clini-
lymphomas as a distinct entity separate from other MALT lym- copathological entities with specific diagnostic criteria, genetic
phomas. Due to their indolent behavior, the ICC characterizes features, and clinical behaviors, although their differential diagnosis

-
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ZUCCA ET AL.
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TABLE 1 Marginal zone lymphoma entities across recent classifying proposals.

ICC, 2022 WHO‐5th, 2022 Revised WHO‐4th, 2016

Splenic MZL Splenic MZL Splenic MZL

Extranodal MZL of mucosa‐associated lymphoid Extranodal MZL of mucosa‐associated lymphoid Extranodal MZL of mucosa‐associated lymphoid
tissue, also known as MALT lymphoma tissue, also known as MALT lymphoma tissue, also known as MALT lymphoma

Primary cutaneous marginal zone Primary cutaneous marginal zone lymphoma Not considered as an entity
lymphoproliferative disorder (new distinct (new distinct entity)
entity)

Nodal MZL Nodal MZL Nodal MZL

Pediatric nodal MZL (provisional) Pediatric nodal MZL (distinct entity) Pediatric nodal MZL (provisional)

Abbreviations: ICC, International Consensus Classification; MZL, marginal zone lymphoma; WHO, World Health Organization Classification of Tumors
of the Haematopoietic and Lymphoid Tissues.

is challenging, particularly in cases with disseminated disease transformed blasts, prominent plasma cell differentiation, and a rich
involving lymph nodes, spleen, peripheral blood, bone marrow, or T‐cell non‐neoplastic component, suggest involvement in an immune
other extranodal sites.1 response. Extranodal MZL commonly arises in mucosal sites where
the presence of lymphocytes is acquired in response to chronic in-
fectious conditions or autoimmune processes. The tumor cells in
2 | EPIDEMIOLOGY AND RISK FACTORS MZLs show somatic hypermutation and intraclonal variation of the
variable region of the immunoglobulin heavy chain (IGHV) genes and
MZLs are a subtype of B‐cell non‐Hodgkin lymphomas (NHL) and are are driven by direct antigen stimulation. Antibodies expressed by
the third most common non‐Hodgkin lymphoma (after diffuse large MZL cells are often self‐directed, indicating cross‐reactivity between
B‐cell lymphoma and follicular lymphoma). In 2016, approx. 7500 exogenous and endogenous antigens. Over time, abnormal B‐cell
new cases of MZL were diagnosed in the United States, accounting clones with successive genetic abnormalities can replace the normal
for 7% of all mature NHLs. The age‐standardized incidence rate of B‐cell population of the inflammatory tissue, resulting in lymphoma.
MZL was 19.6 per 1,000,000 person‐years, as reported by the US Nuclear factor kappa B pathway activation (NF‐kB), trisomies of
10
SEER‐18 program from 2001 to 2017. chromosomes 3 and 18, and mutations in chromatin remodeling gene
Among MZL subtypes, 9% were splenic MZL, 30% nodal MZL, proteins are common in all MZLs. Extranodal MZLs have recurrent
and 61% extranodal MZL. The incidence of MZL has increased by chromosomal translocations, with t(11; 18)(q21; q21), t(14; 18)(q32;
1.0% annually from 2001 to 2017 in the United States, with q21), and t(1; 14)(p22; q32) being the most common. Deletions at
similar trends reported in other countries, likely due to improved 7q31–32 are a typical characteristic of splenic MZL. The Notch
diagnosis. The incidence of MZL subtypes appears to be changing pathway, which regulates normal B‐cell differentiation and homing, is
over time, with an increase in splenic MZL and a decrease in also activated by genetic events in MZLs. Mutations of NOTCH2
extranodal MZL.10–14 gene are recurrent in splenic and nodal MZLs, while mutations in
There are several recognized risk factors for MZL, including NOTCH1 are less common in splenic MZLs. Inactivation of protein
Helicobacter pylori infection, a family history of NHL, certain auto- tyrosine phosphatase delta (PRPRD) is almost exclusively detected in
immune diseases (such as Sjögren syndrome and systemic lupus er- nodal MZLs.6,18,19
ythematosus), and genetic loci in the human leukocyte antigen (HLA) A recent study identified two genetic clusters in splenic MZL:
region. There is also evidence linking MZL to a number of other NNK (comprising ~60% of SMZL and characterized by mutations of
factors, including Chlamydia psittaci, Borrelia burgdorferi, hepatitis C NF‐κB, NOTCH and KLF2) and DMT (~30% of cases, harboring mu-
virus (HCV), human immunodeficiency virus, and solid organ trans- tations affecting DNA damage response, MAPK and TLR). NNK‐
plantation.10,15–17 The decrease in gastric MZL observed in western SMZLs have inferior survival compared to DMT‐SMZLs. Mutations
countries is believed to be due to reduced H. pylori infection, wider in genes coding for epigenetic regulators, such as KMT2D and
indications for H. pylori‐eradication therapy, and increased over‐the‐ CREBBP, are common in all MZLs and highlight the deregulation of
counter use of proton pump inhibitors.1,6 the epigenome in these types of lymphomas.20

3 | MOLECULAR PATHOGENESIS 4 | TREATMENT

Chronic antigenic stimulation is a fundamental characteristic of MZL The course of MZLs is generally indolent, particularly in patients with
development. Histological features of extranodal MZL, such as the extranodal MZLs. Median survivals exceed 10 years, even though the
presence of tumor lymphocytes in non‐neoplastic follicles, scattered disease affects the patient's life expectancy. Active surveillance is
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90
- ZUCCA ET AL.

recommended for patients with advanced stage disease who are functions since older/frail adults receiving bendamustine‐rituximab
asymptomatic as the disease does not impair survival.21 H. pylori have shown higher rates of fatal toxicities. The need for rituximab
should be eradicated in all patients with gastric MZL and H. pylori maintenance is controversial in MZLs, with no evidence of survival
infection, irrespective of the stage. The anti‐H. pylori regimen should benefit.
be chosen based on the regional microbial patterns of antibiotic Historically splenectomy has been the recommended first
resistance. In localized, H. pylori‐positive gastric MZLs, the initial treatment for patients with splenic MZL, since it also allows for a
treatment should solely be H. pylori eradication, which induces lym- definitive pathologic diagnosis. Splenectomy can have however, se-
phoma regression and long‐term clinical disease control in three‐ vere complications (including infections, bleeding, thrombosis, and
quarters of patients. Post‐antibiotic follow‐up studies have shown a long‐term immune‐deficiency against capsuled bacteria) and in the
frequent persistence of monoclonal B‐cells after histological regres- last 2 decades, splenectomy has been progressively replaced by rit-
sion of the lymphoma as well as transient molecular or histological uximab (with or without chemotherapy) as the preferred initial
relapses without clinical or endoscopic evidence of disease; these therapy.21,22,25
patients can safely be managed with a watchful waiting strategy. The progression or relapse of the disease should be documented
Patients with concomitant chronic HCV infection should have the with a biopsy and a shift to an aggressive lymphoma should be
hepatitis treated and cured, because sustained MZL regression are considered in certain cases such as asymmetric growth and uptake in
observes in two thirds of patients after hepatitis treatment with PET scans, systemic symptoms, and elevated LDH. There are no
direct‐acting antivirals agents.22 specific phase 3 trials of relapsed MZL, but there are small phase 2
The efficacy of antibiotic therapy for non‐gastric extranodal trials and a few FDA‐approved treatments. The management is highly
MZLs is unproven. There is controversy regarding the use of antibi- individualized and depends on various factors such as the stage of the
otics directed against C. psittaci for treatment of ocular adnexa MZLs, disease, previous treatments, and patient age and health. Second‐line
as they have shown variable activities. Immunoproliferative small and subsequent treatments may include rituximab, lenalidomide plus
intestinal disease may respond to antibiotics against Campylobacter rituximab, ibrutinib, or copanlisib. Patients with MZL transformation
jejuni.23 to an aggressive lymphoma can be treated with anthracycline‐based
In H. pylori‐negative gastric MZLs, antibiotic treatment is likely chemoimmunotherapy, transplantation with autologous stem cells, or
ineffective, but it can still lead to occasional lymphoma responses, immunotherapy with CAR‐T cells.1
possibly due to false‐negative results of microbiological tests or
infection by other micro‐organisms. Involved‐site radiotherapy (24 Gy) A C KN O W L E D G EM E NT
is extremely efficacious in patients with localized H. pylori‐negative Open access funding provided by Universita della Svizzera italiana.
gastric MZL or in those without lymphoma regression following anti-
biotic therapy, as well as in localized, non‐gastric extranodal MZLs,
CO N F L I C T O F I N T E R E S T S T A TE M E N T
leading to long‐term local control in about 90% of patients. Long‐term
The authors have no conflicts of interest.
complications may include xerostomia after parotid irradiation, hy-
pothyroidism after thyroid irradiation, cataracts and dry eyes after
RE F E R E N CE S
orbital irradiation.24 Dose de‐escalation to 4 Gy reduces toxicities but
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