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

Autoimmune phenomena can be associated with this lymphoma, COURSE AND PROGNOSIS
a result of the production of autoantibodies sustained by the neoplastic The median overall survival for patients with SMZL is 5 to 10 years,
clone. Hemolytic autoimmune anemia or immune thrombocytopenia although a median survival time of less than 4 years has been docu-
are present in 10 to 15 percent of patients. In up to 40 percent, a serum mented in a subset of patients presenting with advanced or aggressive
monoclonal paraprotein can be detected.
disease (25 to 30 percent of cases). In 10 to 20 percent of cases, histo-
logic transformation into a diffuse large B-cell lymphoma occurs.
MORPHOLOGY A prognostic model has been recently developed and validated in
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A micronodular lymphoid infiltrate of small lymphocytes typically sur- a cohort of more than 300 patients based on three variables: hemo-
globin concentration (<120 g/L), LDH (if elevated at diagnosis), and
rounds and replaces the splenic white pulp germinal centers in SMZL, albumin levels (<35 g/L). This model, although lacking therapeutic
with involvement of the red pulp also consistently observed. The malig- implications, allows stratification of patients into three risk-groups,
nant cells resemble those of marginal zone MALT lymphoma; although including a low-risk group (no risk factors) with an 88 percent 5-year
some are larger and resemble centroblasts or immunoblasts. Plasma- cause-specific survival rate, an intermediate-risk group (one risk fac-
cytic differentiation is usually appreciated within germinal centers. tor) with a 73 percent 5-year cause-specific survival rate, and a high
Neoplastic lymphocytes are typically CD20+, CD23−, CD38−, CD5−, risk group (at least two risk factors) with a 50 percent cause-specific
CD10−, cyclin D1−, IgD+. Intertrabecular lymphoid nodules in the survival rate.
marrow mimic the morphology of tumor nodules in the spleen, with
occasional reactive germinal centers surrounded by neoplastic cells.
Neoplastic lymphocytes can usually be recognized in the blood, with NODAL MARGINAL ZONE LYMPHOMA
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the classic villous morphology, characterized by the presence of polar
small cytoplasmic projections (seen in only a subset of cells). DEFINITION AND EPIDEMIOLOGY
Nodal MZL is a mature, postgerminal center B-cell lymphoma, shar-
DIFFERENTIAL DIAGNOSIS ing many morphologic and immunohistochemical characteristics with
SMZL can be distinguished from other indolent lymphomas associ- EMZL and SMZL, although it is considered a distinct clinicopathologic
ated with splenomegaly by the integration of clinical, morphologic, subtype by the current WHO classification. It is a rare disease, account-
immunohistochemical and genetic data. Both follicular lymphoma and ing for less than 2 percent of all lymphomas, with a median age at onset
mantle cell lymphoma may show a micronodular pattern of splenic of between 50 and 60 years. The association with autoimmune phenom-
involvement: however, the expression of both CD5 and cyclin D1 by ena is weak for this lymphoma, in contrast to other MZLs.
mantle cell lymphoma and of CD10 by follicular lymphoma represent
clear diagnostic clues differentiating these subtypes. A more challeng- GENETIC ABERRATIONS AND MOLECULAR
ing distinction is with lymphoplasmacytic lymphoma because plas- PATHOGENESIS
macytic differentiation is seen in 28 percent of cases of SMZL. The
presence of a very large IgM paraprotein spike (>10 g/L) favors the No typical cytogenetic aberrations have been demonstrated for NMZL:
diagnosis of lymphoplasmacytic lymphoma (LPL) rather than SMZL, among the reported abnormalities are gains of chromosomes 3, 7, 12, and
though small IgM paraprotein spikes may also been seen in SMZL (<10 18, and structural rearrangements of chromosome 1, with breakpoints in
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g/L usually). 1q21 or 1p34. Gain of several regions of chromosome 3 constitute a
common marker of NMZL, occurring in 20 to 25 percent of patients, and
are shared with patients presenting with EMZL. More than three-quar-
THERAPY ters of patients harbor somatic IGHV gene mutations, and show a biased
Treatment is required only in symptomatic SMZL patients with mas- use of IGHV segments 3 and 4. These mutations are equally seen in both
sive splenomegaly causing pain, early satiety or cytopenias, defined as HCV-positive and HCV-negative patients; however, IGHV gene segment
hemoglobin less than 100 g/L, platelets less than 80,000/μL, or neu- 1–69 seems to be preferentially used in HCV-related cases, suggesting
trophils less than 1000/μL. Asymptomatic patients may be followed differential antigenic stimulation driving lymphoma B-cell precursor
clinically without intervention for many years, since treatment does not selection, and the possible pathogenic role of HCV itself. 45
influence survival. 15
When treatment is indicated because of the occurrence of clinical CLINICAL FEATURES
symptoms, the recommended frontline therapy is splenectomy, which The majority of patients affected by NMZL present with disseminated
allows a rapid correction of anemia, thrombocytopenia and neutropenia—if peripheral and abdominal nodal involvement. Marrow infiltration is
present—and the removal of the dominant focus of the disease, even seen in less than half of the patients, and blood involvement is rare.
though such management does not influence marrow infiltration or Extranodal disease is absent, by definition and the presence of sple-
blood lymphocytosis. Postsplenectomy partial remissions are generally nomegaly should suggest a diagnosis of SMZL. Performance status is
stably maintained for years, and patients can remain asymptomatic, generally good with lymphoma-related symptoms reported in 10 to 40
with a median time to next treatment of 8 years. 38 percent of the cases. A serum monoclonal component is detected in
Systemic therapy is required when major contraindications to only 10 percent of patients.
surgery exist, in elderly patients, in those who relapse or progress after
splenectomy and in case of advanced disseminated nodal disease or
high-grade transformation. Rituximab, used both as a single agent or MORPHOLOGY
combined with chemotherapy, is highly effective in this subgroup of Neoplastic elements within lymph nodes have a marginal zone pattern
patients 41,42 and is preferred to splenectomy by some authorities. Che- of infiltration, with residual follicles being well-preserved or expanded
motherapy regimens are based on alkylating agents (such as chlorambu- in some cases (“MALT-type” NMZL), diminished in other cases
cil or cyclophosphamide), fludarabine or bendamustine. 39,40 (“splenic-type” NMZL), or sometimes colonized by the lymphoma cells,

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