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1280 Part VII Hematologic Malignancies

TABLE Frequency of Common Genetic Aberrations in Extranodal Marginal Zone Lymphoma According to Primary Site of Disease
79.3
Genetic Abnormality 33,34,71
Genes Involved 77
t(11;18)(q21;q21) t(14;18)(q32;q21) t(1;14)(p22;q32) t(3;14)(p14.1;q32) +3 a +18 a
BIRC3/MALT1 IGH@/MALT1 IGH@/BCL10 IGH@/FOXP1 NFKBIZ, BCL6, FOXP1, … BCL2, NFATC1, …
Primary Site
Lung 36–53 6–10 2–7 0 13–20 7
Intestine (non-IPSID) 13–56 0 0–13 0 75 13–25
Stomach 6–26 1–5 0 0 11–18 6–29
Ocular adnexa 3–10 0–25 0 0–20 30–38 14–26
Salivary glands 0–5 0–16 0–2 0 8–55 8–19
Skin 0–4 0–14 0 0–10 20 4
Thyroid 0–17 0 0 0–50 11–17 0–22
All values expressed as percentages of cases.
a Mostly partial trisomies. Data summarized based on references noted.

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are also negative for BCL6, which may be helpful to exclude trans- heavy chain promoter. Although FOXP1 is overexpressed in these
formation to DLBCL. Except for IPSID, in which tumor cells express tumors, its exact significance in their biology is unknown.
a truncated alpha heavy chain without any light chain, most ENMZL Apart from the translocations described, all believed to be mutu-
are typically positive for IgM or, less commonly, IgA or IgG, with ally exclusive, ENMZL has also been associated with gains of genetic
light chain restriction. IgD expression is usually negative or very material, in particular partial trisomies of chromosomes 3 (including
weak. These immunoglobulins may be secreted, especially when there regions affecting FOXP1, NFKBIZ [NFκB inhibitor zeta], and
is significant plasmacytic differentiation, and can give rise to a BCL6) and 18 (affecting NFATC1 [nuclear factor of activated T
monoclonal band in the serum protein electrophoresis. The truncated cells, cytoplasmic, calcineurin-dependent 1], and BCL2). Gains at
heavy chains of IPSID usually do not appear as a monoclonal band 6p25 and losses at 6q (affecting TNFAIP3 [tumor necrosis factor,
because they comigrate with other serum proteins but can be detected α-induced protein 3]) 79,80 and 1p have also been reported. 77
with anti–alpha heavy chain antibodies on immunofixation. Consistent with a postgerminal center B-cell origin, ENMZL
have rearranged immunoglobulin genes that display somatic hyper-
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mutation of their variable regions. In the case of IPSID, there
Genetics are deletions of the alpha heavy chain gene in the VH and CH1
regions, which result in the production of an abnormal heavy chain
Specific chromosomal aberrations have been associated with ENMZL, that cannot bind light chains to form a complete immunoglobulin
the frequency of which depends strongly on the primary site of molecule. 82
disease (Table 79.3). 33,34,71 These abnormalities can be detected by
conventional cytogenetics in metaphase plates or through fluorescent
in situ hybridization (FISH) of interphase nuclei using specific Therapy for Early-Stage (I/II) Disease
probes. The most commonly observed abnormality is the t(11;18)
(q21;q21), which fuses the BIRC3 (baculoviral inhibitor of apoptosis Given its rarity, there are no randomized controlled trials defining
repeat containing 3, also known as API2, or apoptosis inhibitor-2 the optimal treatment for ENMZL. Most recommendations arise
protein) and MALT1 (MALT lymphoma translocation-1 protein) from consensus panels based on data from retrospective or uncon-
genes in chromosomes 11 and 18, respectively, leading to expression trolled prospective trials. The most extensive body of data has been
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of a BIRC3-MALT1 chimeric protein. The native MALT1 is part gathered on gastric ENMZL.
of a protein complex that includes the BCL10 protein (B-cell lym-
phoma protein 10) and that indirectly leads to nuclear factor kappa-B
(NFκB) activation, a process under strict control by several upstream Gastric Extranodal Marginal Zone Lymphoma
factors. Expression of the fusion protein leads to constitutive activa-
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tion of NFκB via canonic and noncanonic pathways, which in This form of ENMZL has a strong association with active H. pylori
turn leads to resistance to apoptosis and uncontrolled proliferation. infection. If histologic analysis of the gastric biopsies obtained during
The t(11;18) has a special prognostic significance in gastric ENMZL, staging endoscopy fails to demonstrate H. pylori, noninvasive
because its presence is associated with worse response to antibio- methods, such as breath tests, stool antigen test, or serology, should
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therapy, which is at least partly because of its higher prevalence in be used to exclude the infection. Although not necessarily a marker
H. pylori–negative gastric ENMZL. 76 of active infection, the presence of antibodies against H. pylori in an
Another, less frequently observed, abnormality is the t(14;18) individual not previously treated for this bacterium implicates it in
(q32;q21). This translocation is different from that observed in follicu- the pathogenesis of the lymphoma.
lar lymphoma, which involves the BCL2 gene, and instead brings the The focus of therapy for H. pylori–positive disease is on eradication
MALT1 gene under the influence of the immunoglobulin heavy chain of the infection with one of the currently recommended regimens for
gene promoter (IGH@), leading to overexpression of MALT1 and, this purpose. These commonly combine a PPI and clarithromycin
through mechanisms akin to those of t(11;18), constitutive activation with a second antibiotic, usually amoxicillin or metronidazole (triple
of NFκB. The t(1;14)(p22;q32) is seen even more rarely and causes therapy), but this is an issue in flux as resistance to clarithromycin
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overexpression of the BCL10 gene, which is placed under control of is increasing in several regions. Alternatively, quadruple therapy
the IGH@ promoter, and, in turn, activation of the same pathways with a PPI, bismuth, tetracycline, and metronidazole can be used.
affected by MALT1. A fourth translocation, t(3;14)(p14.1;q32), Most authors recommend 10–14 days of treatment because of
described mostly in ocular, cutaneous, and thyroid ENMZL, involves data suggesting better results than with 7-day courses. According
the FOXP1 (forkhead box protein P1) transcription factor and the to some authorities, eradication of H. pylori should be confirmed