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CHAPTER 101 addition, two provisional entities are recognized by the 2008 WHO clas-
sification: splenic diffuse red pulp lymphoma and hairy-cell leukemia
MARGINAL ZONE B-CELL variant, which represent two subtypes of splenic lymphomas with fea-
tures overlapping with those of MZL.
In adults, MZLs account for 5 to 17 percent of all non-Hodgkin
LYMPHOMAS lymphomas (NHLs); MALT lymphoma is the most frequent overall,
being the third most frequent NHL and representing 7 to 8 percent of all
B-cell neoplasms. It mostly affects middle-aged adults, at a median age
Pier Luigi Zinzani and Alessandro Broccoli of 60 years, with a slight female preponderance and often in association
with chronic antigenic stimulation, either as a consequence of a chronic
infection or an autoimmune disease. Gastric MALT lymphoma is by far
the most common clinical entity, displaying considerable geographic
SUMMARY variability with a higher incidence in areas associated with a high inci-
dence of Helicobacter pylori infection. SMZL and NMZL represent
Indolent B-cell lymphomas deriving from the marginal zone include three 20 percent and 10 percent of MZLs, respectively, accounting for less
specific entities: extranodal marginal zone (or mucosa-associated lymphoid than 2 percent of all NHLs. The median age at disease onset is 65 years
tissue) lymphoma (EMZL), splenic marginal zone lymphoma (SMZL), and for SMZL, and between 50 and 60 years for NMZL. 2,3
nodal marginal zone lymphoma (NMZL). The clinical and molecular charac- Each lymphoma subtype is presented and discussed separately in
teristics are distinctive for each of these entities, although some phenotypic terms of epidemiology, etiology and pathogenesis, clinical presentation
and genetic features are overlapping. EMZL is the most common entity, arising and treatment strategies.
at virtually any extranodal site, commonly associated with chronic antigenic
stimulation either as a result of an external infection (e.g., Helicobacter pylori EXTRANODAL MARGINAL ZONE
in the stomach) or an autoimmune disease (as Sjögren syndrome or Hashi-
moto thyroiditis). SMZL accounts for approximately 20 percent of all mar- LYMPHOMA
ginal zone lymphomas, with patients typically presenting with an enlarged
spleen and involvement of marrow and splenic hilar lymph nodes. NMZL is the DEFINITION
least-common entity, representing approximately 10 percent of all marginal EMZL or MALT lymphoma is an extranodal lymphoma that arises both
zone lymphomas and typically presenting with lymph node-based disease in organs with an anatomically well-defined MALT, such as the gut,
without splenic or extranodal site involvement. the nasopharynx and the lung (in which MALT represents an acquired
and specialized immunologic barrier associated with highly permeable
mucosal sites in close contact with the external environment), and in
sites which normally lack lymphoid tissue, but have accumulated B cells
INTRODUCTION AND CLASSIFICATION in response to a chronic infection or an autoimmune process, such as
the salivary glands, the ocular adnexa (orbits, conjunctiva and lacrimal
Marginal zone lymphomas (MZLs) represent a heterogeneous group glands), the skin, the thyroid, the genitourinary tract (bladder, prostate,
of indolent lymphoproliferative disorders originating from memory kidney, uterus), and the breasts.
B-lymphocytes, which are normally present in the marginal zone—that
is, the outer part of the mantle zone—of the secondary lymphoid folli- EPIDEMIOLOGY
cles. The spleen and the mucosa-associated lymphoid tissues (MALT) MALT lymphoma accounts for at least 50 percent of primary gastric
are the most frequently involved anatomic compartments; lymph nodes
may also been involved, albeit rarely. The 2008 World Health Organiza- lymphomas, typically presenting in middle-aged adults, with a female
tion (WHO) Classification of Tumours of Haematopoietic and Lymphoid predominance. Gastric MALT lymphoma is particularly common in
Tissue identifies three distinct subtypes of MZL based on the involved the north-eastern part of Italy, which is an area of high prevalence of
site, the clinical presentation and course of the disease, as well as the H. pylori infection. In contrast, a specific subtype of small intestinal
molecular profiles, namely, extranodal MZL of MALT type (also termed MALT lymphoma (termed immunoproliferative small intestinal disease
extranodal marginal zone lymphoma [EMZL]); splenic marginal zone [IPSID]) tends to be more frequent in the Middle East, on the Indian
subcontinent, and in the Cape Region of South Africa.
1
lymphoma (SMZL); and nodal marginal zone lymphoma (NMZL). In
ETIOLOGY AND PATHOGENESIS
Sustained antigenic stimulation, triggered either by a chronic infection
Acronyms and Abbreviations: AKT1, protein kinase Bα; BCL6, B-cell CLL/ or by an autoimmune process, induces an initially polyclonal B-cell
lymphoma 6 gene; BCL10, B-cell CLL/lymphoma 10 gene; BCR, B-cell receptor; CD, proliferation, as well as the development of an inflammatory response,
cluster of differentiation; EMZL, extranodal marginal zone lymphoma; HCV, hepati- with the attraction of neutrophils, which release reactive oxygen spe-
tis C virus; Ig, immunoglobulin; IGHV, immunoglobulin heavy-chain variable region cies (ROS). ROS are genotoxic, and may induce a wide range of genetic
gene; IPSID, immunoproliferative small intestinal disease; LDH, lactate dehydro- abnormalities. Moreover, the prolonged proliferation of B-lymphocytes
genase; LPL, lymphoplasmacytic lymphoma; MALT, mucosa-associated lymphoid induced by a chronic lymphoproliferative stimulus may increase the
tissue; MZL, marginal zone lymphoma; NF-κB, nuclear factor-kappa B; NMZL, nodal risk of DNA damage (double-strand breaks and translocations), as a
marginal zone lymphoma; PAX5, paired box gene 5; PIM1, protooncogene proteins consequence of the genetic instability of B cells during somatic hyper-
pim; ROS, reactive oxygen species; SMZL, splenic marginal zone lymphoma; WHO, mutation and class-switch recombination. Genetic abnormalities tend
World Health Organization. to involve those genes related to the activation of nuclear factor-kappa B
(NF-κB), a key transcription factor regulating the expression of several

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