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1666 Part XI: Malignant Lymphoid Diseases Chapter 101: Marginal Zone B-cell Lymphomas 1667

TABLE 101–2. Chemotherapy/Immunotherapy Experiences in Gastric Mucosa-Associated Lymphoid Tissue Lymphoma
Study Patients Early Stage Treatment Outcomes
Hammel 20 24 71% Cyclophosphamide or Chlorambucil 75% CR
Avilés 21 83 100% CHOP × 3 + CVP × 4 100% CR
Jäger 22 19 100% Cladribine 100% CR
Martinelli 23 27 86% Rituximab 46% CR; 31% PR
Raderer 24 7 57% R-CHOP/R-CNOP 100% CR
Conconi 25 13 100% Bortezomib 46% CR; 15% PR
Salar 26 21 64% Bendamustine + rituximab 94% CR; 6% PR

CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; CNOP, cyclophosphamide, mitoxantrone, vincristine, prednisone; CR, complete
response; CVP, cyclophosphamide, vincristine, prednisolone; PR, partial response; R, rituximab.

effective in the treatment of all stages of disease (Table 101–2). 20–26 It is In cases of SMZL associated with chronic HCV infection,
important to note that patients with the t(11;18) translocation are usu- longstanding antigenic stimulation of B-lymphocytes as a result of
ally unresponsive to alkylating drugs if administered as single agents. the interaction of the viral E2 glycoprotein with CD81 on B cells is
Fludarabine has important antitumor activity, especially when com- responsible for lymphocytes activation through the B-cell receptor
27
bined with rituximab, as has the combination of chlorambucil plus rit- (BCR), which ultimately leads to an increased rate of proliferation of
28
uximab. Radioimmunotherapy with Y-ibritumomab tiuxetan is also B cells. Antiviral treatments can induce remissions of SMZL, thus
90
29
effective for patients with MALT lymphoma. 30 proving the causative role of the infection in the pathogenetic process
of HCV-related SMZL. SMZL associated with chronic HCV infec-
34
COURSE AND PROGNOSIS tion is often associated with mixed cryoglobulinemia and the devel-
opment of cryoglobulinemic vasculitis.
MALT lymphoma usually has a favorable outcome, with a 5-year overall
survival greater than 85 percent in most series. The reported median
time-to-progression seems to be more favorable for gastrointestinal GENETIC ABERRATIONS AND MOLECULAR
MALT lymphomas than nongastrointestinal lymphomas; however, PATHOGENESIS
no significant differences in overall survival have been demonstrated
between the two disease subgroups. Approximately 30 to 50 percent of Cytogenetic abnormalities can be found in up to 80 percent of SMZL
patients with a H. pylori–positive gastric MALT lymphoma show per- patients, most frequently consisting of complete or partial 3q trisomy
sistent or progressive disease after H. pylori eradication with antibiotic (30 to 80 percent of cases) and gains of 12q (15 to 20 percent of patients).
therapy. Among complete responders, almost 15 percent relapse within However, the most significant karyotype aberrations, considered typi-
3 years, suggesting that additional therapies are required in a significant cal of SMZL, are deletions or translocations involving 7q32, which are
percentage of patients. Histologic transformation to diffuse large B-cell reported in nearly 40 percent of the cases. Other alterations involving
lymphoma has been reported in approximately 10 percent of the cases, chromosomes 8, 9p34, 12q23–24, 17p, and 18q, although not typical,
35
usually as a late event that occurs independently from dissemination. are helpful for the diagnosis of SMZL.
SMZL displays a characteristic transcriptional profile with a
molecular signature consisting of over-expression of genes involved in
SPLENIC MARGINAL ZONE LYMPHOMA the AKT1, BCR, and NF-κB signalling pathways. Mutations in signal-
ling pathways involved in marginal zone B-cell development are also
DEFINITION AND EPIDEMIOLOGY observed in nearly 60 percent of SMZL, with mutations of NOTCH2
36
SMZL is a mature B-cell neoplasm arising from postgerminal center being the most frequent, accounting for 20 percent of the cases. As
lymphocytes and involving the white pulp follicles of the spleen, the these mutations are restricted to SMZL, they represent a potential diag-
splenic hilar lymph nodes, the marrow and often the blood, showing nostic marker (and presumably a therapeutic target) for this lymphoma
characteristic neoplastic lymphoid elements referred to as “villous subtype.
lymphocytes.” It accounts for 1 to 2 percent of all lymphomas, with a
median age at diagnosis of nearly 65 years (range: 30 to 90 years) and a CLINICAL FEATURES
slight male predominance.
Isolated and generally asymptomatic splenomegaly and cytopenias
ETIOLOGY AND PATHOGENESIS are the most significant clinical characteristics of this lymphoma. The
majority of patients seek medical attention because of the presence of
The precise pathogenesis of SMZL is unknown: the cell of origin is a anemia and/or thrombocytopenia, mostly related to hypersplenism
marginal zone B cell, which is believed to be of postgerminal center rather than marrow insufficiency as a consequence of disease infiltra-
origin, as demonstrated by the presence of somatic hypermutations in tion. Lymphocytosis is always present, and basophilic villous cells in
IGHV genes 31,32 ; however, up to one-third of cases are nonmutated. Con- blood may also be found. Splenomegaly is detectable upon physical
versely, SMZL exhibits a low frequency of somatic mutations involving examination; dyspepsia and abdominal discomfort, due to the enlarged
oncogenes such as BCL-6, PAX5, and PIM1, which suggests a pathway (or sometimes markedly enlarged) spleen, are often reported. Massive
of differentiation that may not involve a transit through the germinal splenomegaly, frequently associated with small splenic hilar lymph
center. 33 nodes, is the typical feature of advanced cases.

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