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8/3/2019 The Oncologist 2006 Cohen 1100 17
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Lymphoma
The Oncologist 2006;11:11001117 www.TheOncologist.com
Non-Hodgkins Lymphoma of Mucosa-Associated Lymphoid Tissue
Seth M. Cohen,, Magdalena Petryk,, Mala Varma,, Peter S. Kozuch,
Elizabeth D. Ames, Michael L. Grossbard
aSt. Lukes-Roosevelt Hospital Center, New York, USA; bBeth Israel Medical Center, New York, USA;cContinuum Cancer Centers of New York, New York, USA
K W. Mucosa-associated lymphoid tissue Non-Hodgkins lymphoma Helicobacter pylori
Correspondence: Michael L. Grossbard, M.D., Division of Hematology/Oncology, St. Lukes-Roosevelt Hospital Center, Suite 11G, 100010th Avenue, New York, NY 10019, USA. Telephone: 212-523-5419; Fax: 212-523-2004; e-mail: [email protected] Received March17, 2006; accepted for publication August 24, 2006. AlphaMed Press 1083-7519/2006/$20.00/0 doi:10.1634/theoncologist.11-10-1100
AbstractT -
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20 MALT
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.The Oncologist 2006;11:11001117
Introduction
The concept of mucosa-associated lymphoid tissue (MALT)
lymphomas was introduced by Isaacson and Wright in
1983. They described two cases of gastrointestinal (GI)
lymphoma with histology resembling that of mucosa-asso-
ciated lymphoid tissue rather than lymph nodes [1]. A year
later, lymphomas of similar histology were identified in
extraintestinal sites in these same patients [2].After more
than 20 years of clinical research, MALT lymphomas are
now recognized as a distinct subtype of non-Hodgkins
lymphoma (NHL) with unique pathogenic, histological,
and clinical features. Although this subtype of NHL occurs
frequently, optimal management remains elusive. This
manuscript reviews features of the diagnosis, pathology,
and management of MALT lymphoma.
Definition and Classification
MALT lymphomas constitute a group of low-grade extra-
nodal B-cell neoplasms that share similar clinical, patho-
logic, immunologic, and molecular features and arise in the
Learning Objectives
After completing this course, the reader will be able to:
1. Outline the definition and classification of MALT lymphoma.
2. Summarize the current understanding of the pathogenesis of MALT lymphoma.
3. Articulate treatment options for patients with MALT lymphoma.
Access and take the CME test online and receive 1AMA PRA Category 1 Credit at CME.TheOncologist.comCMECME
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context of pre-existing prolonged lymphoid proliferation
in mucosal sites. In the past, this disease was often misin-
terpreted as pseudolymphoma, but in recent years, it has
been classified as a specific subtype of NHL.
The Revised European-American Lymphoma (REAL)
classification first recognized MALT lymphoma as adiscrete entity in 1994. MALT NHL was classified as a
peripheral B-cell neoplasm, in the group of marginal zone
B-cell lymphomas (MZLs) [3], with a marginal zone B
cell being its normal counterpar t. In the more recent World
Health Organization (WHO) classification system, MZLs
comprise three subtypes: nodal, extranodal (MALT type),
and splenic.
The distinction between nodal and extranodal MZLs
is clinically important. Despite overlapping morphologic
features, they demonstrate distinct clinical behavior. Nodal
MZL behaves as a conventional indolent and incurable
low-grade lymphoma, often widely disseminated early inthe disease course. Extranodal MALT lymphoma remains
localized for an extended duration, lacks poor prognostic
features, and has a superior 5-year overall survival rate
(81% versus 56%) and failure-free survival rate (65% ver-
sus 28%) compared with its nodal counterpart [4].
The lymphoid tissue in which MALT lymphomas arise
normally may be present at the site of origin (e.g., Waldey-
ers ring or intestinal Peyers patches) or may be acquired
in the setting of chronic infection or autoimmune disorder.
MALT lymphomas occur most commonly in the GI tract
but have been described in a variety of extranodal sites
including the ocular adnexa, salivary gland, thyroid, lung,
thymus, and breast.
Histologic features of low-grade MALT lymphomas are
similar regardless of the site of origin. This tumor is charac-
terized by an infiltrate of centrocyte-like cells (small- to
medium-sized lymphocytes with abundant cytoplasm and
irregularly shaped nuclei), but scattered transformed blasts
(large cells) also are present. Nonmalignant reactive fol-
licles are observed frequently. A pivotal feature is the pres-
ence of lymphoepithelial lesions, with invasion and partial
destruction of mucosal glands and crypts by aggregates
of tumor cells. The immunophenotype of a MALT lym-
phoma cell recapitulates that of the marginal zone B-cell.
Typically, tumors express pan-B antigens (CD19, CD20,
CD22, CD79a), but they lack CD5, CD10, CD23, and Bcl-1
expression. In rare cases, MALT lymphomas exhibit aber-
rant CD5 expression, which may be associated with a more
aggressive clinical course [5]. Table 1 summar izes the
immunophenotypic and genetic features of common small
lymphocytic B-cell neoplasms included in the differential
diagnosis of MALT lymphomas. Surface immunoglobu-
lins that demonstrate light chain restriction are present on
MALT lymphoma cells. In a prospective study by Wohrer
and colleagues, 19 of 52 (36%) patients with newly diag-
nosed MALT lymphoma also were found to have a serum
monoclonal gammopathy [6]. Plasmacytic differentiation
is associated with the production of a paraprotein, correlat-
ing in turn with advanced disease, including involvement oflymph nodes and bone marrow [6, 7].
Molecular Characteristics
Subtypes of NHL have characteristic chromosomal altera-
tions. Unique to MALT lymphomas are at least three recip-
rocal translocations: t(11;18)(q21;q21), t(1;14)(p22;q32),
and t(14;18)(q32;q21). The translocation t(11;18)(q21;q21)
is found in 18%53% of cases in all anatomic MALT lym-
phoma sites [8, 9]. The translocation t(1;14)(p22;q32) is
much less common, but more specific, and is found in gas-
tric and pulmonary MALT lymphomas. The translocation
t(14;18)(q32;q21), cytogenetically identical to the transloca-tion involvingBCL-2 in follicular lymphoma but affecting
malt lymphoma translocation 1 gene (MALT1) in this case,
has been described in approximately 20% of MALT lym-
phomas and involves rearrangement of the immunoglobu-
lin heavy-chain locus (IGH) to theMALT1 gene [10]. It is
more commonly found in lymphomas of the ocular adnexa,
liver, and skin than of the GI tract or lung, and is frequently
associated with other genetic abnormalities including tri-
somy 3 and 18. Trisomy 3 occurs in60% of MALT lympho-
mas, but is not specific for this type of lymphoma [11].
Recent work on the products of these seemingly unre-
lated translocations has enhanced our understanding
of the biology of MALT lymphomas. The translocation
t(11;18)(q21;q21) results in a fusion of the apoptosis inhibi-
tor 2 (API2) gene on chromosome 11q21 with theMALT1
gene on chromosome 18q21 [1214]. The product of the
translocation, a novel fusion protein API2-MALT1, mark-
edly increases nuclear activation of nuclear factor (NF) -
T 1. Immunophenotypic and cytogenetic features ofsmall lymphocytic B-cell neoplasms
L CD5 CD10 CD23 CD43
C
Marginalzone/MALTlymphoma
/+ t(11;18)t(1;14)t(14;18)(q32;q21)t(3;14) Tri-somy 3, 18
SLL + + + Del 13q14Trisomy 12
Follicular +/ /+ t(14;18)
Mantle + /+ + t(11;14)
Abbreviations: MALT, mucosa-associated lymphoid tissue;SLL, small lymphocytic lymphoma.
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B, which induces the transcription of a number of genes
involved in immunity, inf lammation, and apoptosis. Trans-
location t(1;14) results in the juxtaposition of the coding
region ofBCL-10 to chromosome 14 with resulting over-
expression of the Bcl-10 protein. The overexpressed Bcl-10
increases nuclear NF-B, thus affecting the same apoptoticsignaling pathway as the API2-MALT1 protein. The net
result of these translocations is inhibition of apoptosis, con-
ferring a survival advantage on affected cells.
Recently, an Austrian group observed a novel transloca-
tion, t(3;14)(p14.1;q32), in a thyroid MALT lymphoma [15].
In a series of 91 patients with MALT lymphoma who did not
demonstrate the three previously recognized translocations,
10% harbored this t(3;14) translocation, including three of
six thyroid, 4 of 20 ocular adnexa, and 2 of 20 cutaneous pri-
maries, but no gastric, lung, or salivary gland lesions.
Some MALT lymphomas transform into diffuse large
B-cell lymphomas (DLBCLs). Starostik and coworkers[16, 17] evaluated genetic abnormalities in MALT lympho-
mas and DLBCL. The t(11;18)(q21;q21) translocation was
not identified in DLBCL. MALT lymphomas expressing
t(11;18)(q21;q21) rarely harbored additional clonal aberra-
tions. In contrast, 67% of t(11;18)(q21;q21)-negative MALT
lymphomas had allelic imbalances, the most common of
which was amplification of 3q26.2-27 (which contains the
BCL-6gene). All allelic imbalances in t(11;18)(q21;q21)-
negative MA LT lymphomas were also identified in
DLBCL. The authors proposed that t(11;18)(q21;q21)-posi-
tive MALT lymphomas are genetically stable and do not
transform into DLBCL, while t(11;18)(q21;q21)-negative
MALT lymphomas with clonal aberrations could transform
into DLBCL [16, 17].
Gastric MALT lymphomas are associated withHelico-
bacter pylori infectionin 85%90% of cases. They are clas-
sified asH. pylori-dependent andH. pylori-independent
according to the presence ofH. pylori infection and response
toH. pylori-directed therapy. The t(11;18)(q21;q21) translo-
cation is more common inH. pylori-negative gastric MALT
lymphoma (53% of cases) than in H. pylori-associated
gastric MALT lymphoma (23.7%50% of cases) [18].H.
pylori-dependent cases exhibit greater methylation of CpG
islands thanH. pylori- independent cases; CpG island meth-
ylation leads to inactivation of tumor suppressor genes [19].
Nuclear expression of Bcl-10 and of NF-B, with or with-
out t(11;18)(q21;q21), has been shown to correlate withH.
pylori independence [20].
Clinical Features
MALT lymphoma is the third most common NHL subtype,
after DLBCL and follicular lymphoma. In a survey con-
ducted by the Non-Hodgkins Lymphoma Classificat ion
Project, MALT lymphomas represented 7.6% of the total
number of cases [21].MALT NHL also represents the most
common type of primary extranodal lymphoma.
The median age at presentation is in the sixth decade
of life and there is a slight female predominance. Patients
often have a history of autoimmune disease or H. pylori gastritis. The signs and symptoms depend on the involved
extranodal site. The clinical course usually is indolent.
MALT lymphoma often remains localized for prolonged
periods of time, without progression even in the absence of
treatment. When dissemination occurs, it is frequently to
other mucosal sites. After therapy, relapse rates approached
40% in one retrospective analysis with a median follow-up
of 47 months (range, 14307 months); gastric MALT lym-
phomas were less likely to relapse than nongastric lesions
(22% versus 48%) [22]. Rarely, the disease undergoes trans-
formation to a more aggressive lymphoma type.
Gastric MALT Lymphoma
Gastric MALT lymphoma, with its unique dependence on
H. pylori infection, has become the model for MALT lym-
phomagenesis. Although the stomach is normally devoid
of mucosal lymphoid tissue, acquired tissue of the MALT
type can develop in the setting of chronicH. pylori infec-
tion [2325]. Many studies have reported the almost uni-
versal presence ofH. pylori in gastric biopsies from patients
with chronic gastritis [25, 26]. Infection withH. pylori, a
Gram-negative organism, is prevalent worldwide. The inci-
dence ofH. pylori infection in the general population in the
U.S. is approximately 30%, and up to 50% in individuals
over age 50 [27]. However, only a small proportion of theH.
pylori-infected population will develop MALT, and an even
smaller fraction will go on to develop a MALT lymphoma.
Genetic and environmental factors and differences in the
virulence ofH. pylori strains must play an important role in
gastric MALT lymphoma development.
Investigation of these associated factors is in its infancy,
but a recent German publication suggests that polymor-
phisms in toll-like receptor 4 (TLR4), the main receptor for
lipopolysaccharide on marginal zone B cells and part of the
innate immune response, may play a role in the neoplastic
process [28]. Data also are accumulating regarding the part
that free radicals may play; antioxidant capacity, affected
by polymorphisms in theIL1RNand GSTT1 genes and the
presence of cytotoxin-associated antigen A (CagA)-posi-
tive strains ofH. pylori, seems to represent an important
component of MALT lymphomagenesis [29, 30].
Data from epidemiological, laboratory, and clinical
studies support the causative role ofH. pylori in MALT
lymphoma development. A strikingly h igh incidence of
gastric lymphoma observed in Northeastern Italy is accom-
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panied by a remarkably high prevalence ofH. pylori infec-
tion [31]. In one case-controlled study, previousH. pylori
infection was associated with subsequent development of
gastric lymphoma [32]. The most compelling evidence that
chronicH. pylori-induced gastritis is a trigger for the devel-
opment of low-grade gastric MALT lymphomas is providedin clinical studies in which eradication ofH. pylori infec-
tion with antibiotics led to complete histologic and endo-
scopic remission of lymphoma [3337].
In in vitro experiments, T cells act ivated byH. pylori
in a strain-specific response stimulate proliferation of
lymphoma cells [38]. In addition, gastric lymphoma
cells show a pattern of somatic hypermutation, indicat-
ing that tumor cells a re positively selected during a sec-
ondary immune response [39, 40]. Therefore, it is likely
that the development of lymphoma is antigen driven in its
early phase. This antigen dependency might explain the
propensity of gastric lymphoma to remain localized forlong periods of time. Interestingly, tumor-derived immu-
noglobulins frequently do not recognizeH. pylori; rather
they recognize autoantigens [41]. In fact, a Dutch group
recently reported that, among B-cell lymphomas, MALT
lymphomas possess a unique ant ibody repertoire; 18% of
gastric and 41% of sal ivary lesions express B-cell antigen
receptors with st rong IgVH-CDR3 homology to rheuma-
toid factors [42]. It seems that a complex cascade of events,
beginning with the interaction of antigen-presenting cells
and T cells with bacterial antigens ultimately leads to the
autonomous clonal proliferation of B cells and develop-
ment of a MALT lymphoma.
C P
Gastric MALT lymphoma affects patients of a wide range
of ages, with a median age at presentation of 57 years.
The incidence in both sexes is similar [43]. The majority
of patients have localized disease at diagnosis. In a Euro-
pean series reporting on 93 patients with low-grade gastric
MALT lymphoma, 88% of patients had disease confined
to the stomach, either primarily in the antrum (41%) or
multifocal (33%) [44]. t(11;18)(q21;q21)-positive lympho-
mas may present with more advanced features than their
t(11;18)(q21;q21)-negative counterparts [17]. Dyspepsia
and epigastric discomfort are the most common presenting
symptoms, but gastric bleeding is rare. Systemic B symp-
toms and bone marrow involvement are present in only
1%8% of patients [44, 45]. Rarely, patients may have ele-
vated lactate dehydrogenase or 2-microglobulin levels. A
majority of patients have no abnormal findings on physical
examination [46]. The endoscopic appearance of gastric
low-grade lymphoma often mimics that of benign diseases
such as chronic gastritis or a peptic ulcer [47].
D
Historical ly, the diagnosis and staging of GI tract lym-
phomas required an invasive surgical approach with
laparotomy and resection. Progress in endoscopic and
immunopathologic techniques now permits accurate
diagnosis by endoscopic biopsy in over 90% of patients.Diagnostic gastric biopsies should be taken from mul-
tiple areas of endoscopically abnormal tissue, and his-
tological gastric mapping should be completed with
random sampling from macroscopically uninvolved
mucosa. Biopsies from gastric low-grade MALT lym-
phoma usually display the characteristic h istological
features, including lymphoepithelial lesions and a dif-
fuse infiltrate of marginal-zone centrocyte-like B
cells (Figs. 13).
Often, it can be difficult to differentiate between a
reactive lymphoid infiltrate and a low-grade MALT lym-
phoma. In such instances, demonstration of monoclonal-ity can be helpful. Monoclonality is established either by
light chain restr iction or by assessment of immunoglobu-
lin heavy chain gene rearrangements by the polymerase
chain reaction (PCR). However, monoclonality also can
be detected in uncomplicated chronic gastritis and has
been shown to precede the histological evidence of malig-
nant transformation [48, 49]. Therefore, gastric MALT
lymphoma should not be diagnosed in the absence of sup-
portive histological evidence.
S
The Ann Arbor classification system developed for nodal
lymphoma has l imited value in staging primar y extra-
nodal tumors. An alternative staging system for GI tract
lymphomas was proposed by Blackledge et al. [50] and
later modif ied by Musshoff [51] and by the International
Workshop in Lugano, Switzerland [52] (Table 2). Stage
I is subclassified into I1 and I2 on the basis of tumor size
(
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macroscopica lly normal regions [53]. In one study, non-
contiguous lesions were shown to originate from the same
malignant clone [54], which may explain reported recur-
rences of MALT lymphomas at the gastric stump follow-
ing par tial gastrectomy with negative margins.
Gastric MALT lymphomas tend to disseminate to other
parts of the GI t ract and to the splenic marginal zone [55].
Overexpression of mucosal-homing receptor 47 integ-
rin, induced in gastric lymphoma cells byH. pylori-acti-
vated T cells, is most likely responsible for this phenom-
enon. The ligand for 47 integrin, the mucosal addressin
cell adhesion molecule (MAdCAM-1), is expressed in the
intestinal mucosa [56] and splenic marginal zone [57].
Gastric lymphoma cells with secondarily overexpressed
homing receptors are attracted to environments with high
concentrations of their ligands. MALT lymphomas that
present in nongastr ic sites develop gastric involvement in
one third of cases [58].
In clinical practice, the staging evaluation includes all
procedures routinely done in NHLs and, in addition, exam-
ination of Waldeyers ring [59] and EUS (Table 3). The pres-
ence ofH. pylori infection also needs to be documented
[60]. Occasionally, patients may require a small bowel
series or barium enema for evaluation of the intestinal
mucosa. The role of positron emission tomography scan-
ning is controversial; some groups find it useful for initial
staging and follow-up [61], while others do not [62].
T
Despite abundant literature on the histopathologic and bio-
logic features of MALT lymphomas, treatment data remain
limited. No publications of randomized, controlled trials
have appeared to date and the results of older studies need to
F 3. Infiltrating lymphoma cells express strong positivitywith anti-CD20 stain, confirming their B-cell origin.
F 1. Lymphocytic infiltrate of gastric glandular epithe-lium with formation of lymphoepithelial lesions.
F 2. Lymphoepithelial lesion with invasion and par tialdestruction of mucosal glands by lymphoma cells.
Although commonly described as a long-standing
localized malignancy, gastric MALT lymphomas dis-
seminate both locally and systemically more frequently
than or iginally believed. Histological examination of
gastrectomy specimens frequently reveals multiple tumor
foci distributed throughout the gastr ic mucosa, including
T 2. Staging of gastrointestinal (GI) tract lymphomas
Stage I Tumor confined to GI tract
Single primary site or multiple, noncontiguous lesions
I1 Infiltration limited to mucosa with or with-out submucosa
I2 Infiltration into muscularis propria, subse-rosa, or serosa, or both
Stage II Tumor extending into abdomen from pri-mary GI site
Nodal involvement
II1 Local (paragastric in gastric lymphoma)
II2 Distant (para-aortic, para-caval, pelvic,inguinal)
Stage II E Penetration of serosa to involve adjacentorgans or tissues
Stage IV Disseminated extranodal, or a GI tract lesionwith supradiaphragmatic involvement
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be interpreted with caution. Variations in diagnostic crite-
ria and staging procedures often preclude meaningful com-
parison of published series [63].
Gastric low-grade MALT lymphoma, in contrast to
other low-grade lymphomas, is localized in over 80% of
patients at presentation. The prognosis is very favorable,
regardless of the type of treatment, with 5-year survival
rates better than 80% [44]. The clinical course is usually
indolent; in fact, some patients remain free of progres-
sion for several years without treatment [64]. The curative
potential of treatment remains unclear as very long follow-
up is needed with relapses reported many years after the
initial diagnosis [65].
Eradication of H. pylori
Based on the close association between gastric MALT lym-
phoma and the presence ofH. pylori infection, Isaacson
and coworkers first examined the hypothesis that eradica-
tion ofH. pylori would remove the driving stimulus for
lymphoma growth and result in lymphoma regression [33].
Six patients withH. pylori infection and MALT lymphoma
were treated with antibiotics.H. pylori infection was eradi-
cated in all six patients and histological complete regres-
sion of lymphoma was observed in f ive of those patients.
These results have been confirmed by several independent
investigators (Table 4), and antibiotic treatment is now the
standard fi rst-line therapy for localized low-grade gastric
MALT lymphoma. Using this strategy, complete remission
(CR) can be expected in over 70% of patients presenting
with localized disease [66].
A variety of regimens can be used to eradicateH. pylori
infection. Each includes a combination of two or three antibi-
otics, such as amoxicillin, clarithromycin, tetracycline, and
metronidazole, with a proton pump inhibitor or H2-receptor
antagonist, with or without bismuth salicylate [67]. The time
interval between eradication ofH. pylori and lymphoma
regression can vary from 6 to 14 months [68].
Unfortunately, 20%30% of gastric MALT lympho-
mas associated withH. pylori do not regress after antibi-
otic therapy. In a study of 34 endosonographically staged
patients, antibiotics induced CR in 70% of patients with
tumor confined to the mucosa and submucosa, but in only
42% of patients with lymphoma involving the muscularis,
subserosa, or perigastric lymph nodes [36]. French inves-
tigators achieved a CR rate of 43% in a series of 46 patients
treated with antibiotics [69]. In their study, the only predic-
tive factor for regression was the absence of nodal involve-
ment (p < .0001), with CR rates of 79% in patients with neg-
ative lymph nodes by EUS and 56% in patients with positive
nodes. The investigators also noted a difference between
the response of superficial tumors and that of more deeply
penetrating, mass lesions, although depth of invasion was
not predictive in a multivariate analysis. Furthermore, none
of theH. pylori-negative patients in that study responded
to antibiotics. The molecular features of lymphoma cells
also can be associated with resistance to antibiotics. Gas-
tric lymphomas harboring translocation t(11;18)(q21;q21),
including those at stage IE, do not respond toH. pylori erad-
ication [70, 71].
An area of active investigation includes the search for
factors associated with tumor recurrence. Neubauer and
coworkers reported 2-year follow-up data for 40 pat ients
who achieved a histologic CR afterH. pylori eradication
[35]. Of these patients, five relapsed, one distally and four
locally. In three of these patients, noH. pylori could be
detected. Fischbach et al. [37] reported on 56 patients with
T 3. Staging evaluation of gastric lymphoma
R x
Detailed history and physical examination
Examination of Waldeyers ring (ENT)
Endoscopy and biopsy (pathology, immunohistochemistry,
stain forH. pylori )Endoscopic ultrasound (if available)
CT scan of the chest, abdomen, and pelvis
Bone marrow biopsy
CBC, LDH,2-microglobulin,H. pylori serology
O x
Small bowel series
Barium enema
Abbreviations: CT, computed tomography; ENT, Ear, Nose,and Throat; LDH, lactate dehydrogenase.
T 4.Helicobacter pylori eradication and treatment ofgastric mucosa-associated lymphoid tissue lymphoma
H. pylori + (n)
H. pylori (n)
H (n/%) S
6 6 5/83% Megraud [27]26 25 15/60% Hellmig et al.
[28]
50 50 40/80% Rollinson et al.[29]
28 ? 14/50% CR Ye et al. [30]
8/29% PR
90 88 56/62% Doglioni et al.[31]
Abbreviations: CR, complete remission; PR, partial response.
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a histologic CR afterH. pylori eradication. With a median
follow-up of 44.6 months, four patients relapsed, one of
whom was found to have evidence ofH. pylori reinfection.
These data suggest that some relapses are a result of the
development of a lymphomatous clone that is independent
of theH.pylori-mediated antigenic drive. Rapid recurrenceof tumor afterH. pylori reinfection has also been described,
suggesting persistence of tumor cells despite histologic
remission [72].
After PCR testing became available, investigators
began to monitor patients for evidence of molecular
remission. The German MALT Lymphoma Study Group
published molecular data for 44 patients with stage IE low-
grade gastric lymphoma who demonstrated PCR B-cell
monoclonality on presentation and achieved histologic
CR after antibiotic treatment [73]. During a median fol-
low-up of 33 months, 45% of those patients had persistent
B-cell monoclonality, despite the disappearance of h isto-logic evidence of MALT lymphoma. Similar findings were
reported by the International Extranodal Lymphoma Study
Group and the United Kingdom Lymphoma Group [74]. A
recently published 10-year follow-up of a Spanish cohort
of 24 patients with stage I low-grade disease treated with
H. pylori eradication therapy revealed persistentIgVHgene
rearrangements in 82% of the histologically cured patients
[75]. Only one of the 19 patients with continued monoclo-
nality relapsed, however. Notably, the t(11;18) translocation
was not present in any of the patients with persistent mono-
clonality. Persistent monoclonality after radiation-induced
histologic cure also has been documented [76].That PCR-detectable monoclonality may persist after
histological disappearance of MALT lymphoma suggests
thatH. pylori eradication suppresses but does not eliminate
lymphoma clones. A recent analysis ofIgVHsequences in
patients with gastric MALT lymphoma revealed clonal
instability, ongoing somatic hypermutation, and antigen
selection after the eradication ofH. pylori [77]. Whether
there are as yet unknown antigens that drive proliferation of
gastric MALT lymphomas and whether low-grade MALT
lymphoma can be cured solely by eradication ofH. pylori
remain unanswered questions. It also remains to be seen
whether long-lasting molecular remissions will translate
into a higher cure fraction.
In clinical practice, close endoscopic follow-up of
patients treated with antibiotics is of utmost importance
(Fig. 4). Eradication ofH. pylori should be documented.
Patients should undergo endoscopy with multiple biopsies
3 months af ter completion of treatment. If histological CR
is achieved, endoscopy should be repeated every 6 months
for 2 years, and then yearly. If only a partial response (PR)
is seen, endoscopy should be repeated every 3 months to
monitor histologic regression of lymphoma. If there is
no histologic response after 3 months or only a PR after
6 months, the patient should be t reated with alternative
modalities (e.g., chemotherapy, antibody therapy, radia-
tion therapy, or surgery).
S
Historically, gastrectomy was the treatment of choice for
patients with localized gastr ic lymphoma [78, 79]. In a
German series, 69 patients with low-grade gastric MALT
lymphoma, 48 stage I patients had additional radiation, 12
received adjuvant chemotherapy, and one patient received
both radiation and chemotherapy postoperatively [80].
The 5-year survival rate was 91% (95% for stage IE and
82% for IIE), with no statistically significant differences
between those patients who had surgery only and those who
received additional treatments. Surgical treatment has sev-
eral important drawbacks. Negative resection margins donot prevent local recurrence because MALT lymphoma is a
multifocal disease [81]. Although total gastrectomy offers a
greater chance for cure than partial resection, it is associated
with significant morbidity and the potential for an impaired
quality of life. Mortality directly related to total gastrec-
tomy can be as high as 4% [81]. Favorable experiences with
local radiotherapy, chemotherapy, and antibody therapy,
allowing for gastric preservation, have limited the role of
surgery even in patients failing primary therapy, although
surgery may still be required for complications [82].
R TAdjuvant radiation occasionally has been added for bulky,
locally advanced, or incompletely resected tumors after
primary surgical excision. Radiation therapy as an organ-
preserving approach became an attractive alternative to
gastrectomy for treatment of localized gastric lymphomas
with the development of endoscopic and radiologic proce-
dures that al lowed physicians to be less dependent on sur-
gery for diagnosis and staging.
Schechter and coworkers treated 17 patients with stage
III2 low-grade gastric MALT lymphoma, either resistant
to antibiotics orH. pylori -negative [46]. Eighty-two percent
of patients had identifiable tumor on EUS, and 36% had
perigastric lymph node involvement. Patients were treated
with a median total radiation dose of 30 Gy, delivered in
1.5-Gy fractions over 4 weeks, to the stomach and adjacent
lymph nodes, and were followed with serial endoscopies
and biopsies. All patients achieved a complete pathologic
response, and at a median follow-up of 27 months, the event-
free-survival rate was 100%. Treatment was well tolerated.
All patients experienced mild fatigue, and 50% had grade
1 or 2 nausea. None of the patients developed diarrhea, GI
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bleeding, or gastric perforation. Park and coworkers treated
six patients with stage IE low-grade gastric MALT lym-
phoma, including one patient with an ulcerative lesion, with
a median total radiation dose of 30.6 Gy. All patients had a
CR, with no evidence of tumor recurrence at a median fol-
low-up of 12 months [83].
F 4. Gastric mucosa-associated lymphoid tissue (MALT) lymphoma treatment algorithm. Abbreviations: CR, completeresponse; EGD, esophagogastroduodenoscopy; NR, no response; PR, partial response.
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Radiation therapy seems to be feasible and effec-
tive, allowing stomach preservation. Longer follow-up is
needed, however, to determine its long-term efficacy and to
quantify the risk for late side effects. Although the risk for
second malignancies is low [84], this cannot be neglected,
especially in patients who may already have an increasedincidence of gastric cancer, because of the link betweenH.
pylori infection and the development of gastric adenocar-
cinoma [85, 86]. Remission with chemotherapy has been
described in a patient who relapsed following partial gas-
trectomy and postoperative radiation [87].
Because MALT lymphomas are radiosensitive and
express the CD20 antigen, delivery of targeted radiation
using an anti-CD20 radioimmunoconjugate may be an
intriguing option for patients with disseminated disease.
Witzig and coworkers treated four patients with stage IV
MALT lymphomas of various primary sites with Zevalin
(Biogen Inc, Cambridge, MA) (the anti-CD20 antibodyibritumomab conjugated to 90Y). Zevalin demonstrated
significant activity in these patients, who were previously
treated with both chemotherapy and radiation therapy.
Three patients achieved a CR and one achieved a PR. Hema-
tological toxicity was tolerable [88].
C
Data on the use of chemotherapy in gastr ic MALT lym-
phoma are limited. Chemotherapy usually is reserved
for patients who fail antibiotic treatment, as well as for
patients with locally advanced disease or simultaneous
extragastric involvement. Regimens include alkylating
agents (chlorambucil or cyclophosphamide), which are
commonly used in low-grade lymphomas, purine ana-
logs, rituximab, and occasionally anthracycline-based
chemotherapy for younger patients with more aggressive
disease. French investigators used continuous oral admin-
istration of a single alkylating agent [89]. Twenty-four
patients were treated with cyclophosphamide or chloram-
bucil for 1224 months. A CR was documented in 75% of
the patients, and partial remission occurred in the remain-
ing 25%. The time to achieve a CR was significantly lon-
ger in more advanced disease (9 months in stage I versus
15 months in stage IV). Five patients (21%) relapsed 18
years after chemotherapy was discontinued. Of note, the
presence of the t(11;18) translocation was associated with
alkylator resistance in this cohort [90]. A Japanese group
has found no difference in outcome between oral mono-
chemotherapy and radiation as second-line therapy in
patients who do not respond to eradication therapy [91].
An ongoing international prospective trial is com-
paring chlorambucil with observation after H. pylori
eradication in primary gastric MALT lymphoma [74,
92]. Preliminary results of the molecular follow-up were
reported, with less than half of the patients achieving con-
tinuous molecular remission after antibiotics. The addi-
tion of chlorambucil as maintenance did not significantly
improve molecular response. These results are not encour-
aging, but the median follow-up was only 2 years. Longerobservation is needed to adequately evaluate treatment
strategies for this indolent lymphoma.
Jager and coworkers reported a phase II study of the
purine analog cladribine in 19 patients with gastric MALT
lymphoma. All patients achieved CR. The median time to
response was 2 months. Three patients relapsed at a median
follow-up of 32 months [93]. Importantly, in applying these
strategies, one must remember that prolonged exposure to
alkylating agents may be associated with a risk for second-
ary myelodysplasia or leukemia, and that treatment with
purine analogs can be profoundly immunosuppressive.
Anti-CD20 monoclonal antibody therapy with ritux-imab shows promising efficacy in relapsing orH. pylori-
negative MALT lymphomas. Raderer and colleagues retro-
spectively evaluated response to rituximab in nine patients.
Three achieved a CR and two achieved a PR for 6 and 14
months [94]. A phase II study of 35 patients by the Interna-
tional Extranodal Lymphoma Study Group documented a
73% response rate, with a median time to best response of
2.2 months. The response rate was higher (87%) in chemo-
therapy-nave patients relative to previously treated patients
(45%,p = .03). The median response duration was 10.5
months. The median time to treatment failure was 22 months
in the chemotherapy-nave patients versus 12 months in the
previously treated patients (p = .001). Thirty-six percent of
responders ultimately relapsed [95].Martinelli et al. [96]
evaluated weekly rituximab in 27 patients with relapsed or
refractory MALT lymphoma, and in those not otherwise
eligible forH. pylori eradication. Seventy-seven percent
achieved an objective response, including 12 (46%) who
had complete pathological and clinical remissions. With
a median follow-up of 33 months, only two patients had
relapsed (14 and 26 months). Fluorescence in situ hybrid-
ization analysis for the translocation t(11;18)(q21;q21) was
not found to be predictive of either response or relapse in
this cohort. In light of synergy between rituximab and che-
motherapy in high-grade lymphomas [97], a randomized
trial to evaluate the combination of rituximab and chloram-
bucil in MALT lymphoma has been initiated [95].
T R
For patients with early-stage gastric MALT lymphoma, the
use of antibiotics as first-line treatment is recommended.
Careful follow-up with endoscopy and biopsy is necessary
to monitor the regression of lymphoma. In patients with
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locally advanced disease (bulky masses, deep infiltration
of gastric wall, regional nodal involvement) or with high-
grade tumors, antibiotics should be combined with che-
motherapy, antibody therapy, or radiation therapy. There
are no clear guidelines for the treatment of relapsed orH.
pylori-negative disease. Chemotherapy, antibody therapy,or radiation can be used, either alone or in combination,
with surgery reserved for those patients with persistent and
refractory symptomatic disease. It is important to remem-
ber that some patients with persistent disease may be man-
aged expectantly without active therapy, and they may go
on to live a normal lifespan with an intact stomach.
H-G G MALT L
Although MALT lymphoma is by definition a low-grade
neoplasm, cases have been reported in which a low-grade
MALT component is mixed with variable numbers of large,
transformed cells. Clinically, these patients demonstrate aless favorable course, with resistance to antibiotic therapy
and more rapid progression [98]. Bayerdorffer and cowork-
ers examined gastrectomy specimens from five patients
whose lymphoma did not respond toH. pylori eradication.
They found unmasked histologically high-grade disease
in all patients [99]. Immunohistochemical studies, as well
as PCR of immunoglobulin heavy chain gene rearrange-
ments, demonstrated that the low- and high-grade compo-
nents derive from the same clone [100].
In an effort to stratify patients with respect to histologic
grade, de Jong and coworkers proposed a grading system
for gastric MALT lymphoma [101]. Category A applies to
classic low-grade MALT lymphoma, with 10%20% blasts or blast clusters of up to 20 cells. Cat-
egory C is consistent with typical high-grade transforma-
tion, in which sheets of blasts and only small foci of low-
grade tumor can be seen. Category D corresponds to large
B-cell lymphoma, without a low-grade component. The
clinical relevance of this grading system remains contro-
versial. Within the spectrum of low-grade lymphomas, a
greater presence of blasts has been associated with inferior
outcome in some studies [101, 102], but not in others [103].
Among cases of gastric DLBCL, the clinical behavior and
outcome seem to be similar regardless of the presence or
absence of a low-grade MALT component [80].
In a retrospective analysis, Cogliatti and coworkers
reported a 5-year survival rate of 73% in surgically treated
patients with stages IE and IIE low-grade lymphoma in
transformation to high-grade lymphoma (lymphomas with
both high-and low-grade components). Postoperative che-
motherapy and/or radiotherapy did not improve survival
[80]. Ranaldi and coworkers reported a 74.1% 5-year sur-
vival rate in patients with both low-grade and high-grade
components. Adjuvant chemotherapy improved survival in
the subset of patients with tumor infiltration of the subsero-
sal fat tissue [104].
High-grade gastric MALT lymphomas generally are
considered to beH. pylori independent. This view wasrecently challenged by the results of a study in which 10
of 15 patients with stage IE high-grade MALT lymphoma
achieved complete histologic remission after anti-H. pylori
therapy [105]. In an effort to identify which patients might
respond to antibiotic therapy, Kuo et al. [106] retrospec-
tively evaluated the expression of CD86 (costimulatory
molecule B7.2) and the infiltration by CD56+ natural killer
cells in tumors from a cohort of patients with high-grade
gastric MALT lymphomas. Both factors were found to cor-
relate withH. pylori dependence and may help direct ther-
apy in this group of patients. Nevertheless, a treating clini-
cian should be reluctant to use antibiotic therapy alone inpatients with high-grade gastric MALT lymphoma who are
otherwise appropriate candidates for chemotherapy.
Nongastric MALT Lymphoma
MALT can develop in nearly every organ in response to per-
sistent stimuli such as chronic infection or an autoimmune
process. In the setting of prolonged lymphoid proliferation,
a malignant clone may emerge, followed by the develop-
ment of a MALT lymphoma. While gastric lymphoma is
the most common and the most extensively studied, lym-
phomas with similar pathology have been found in a variety
of primary sites. The role of infectious agents other than
H. pylori in MALT lymphomagenesis is certainly less well
established, but the list of possible infectious etiologic
agents is growing. A group from Italy has documented the
frequent presence ofChlamydia psittaci in tumor tissue and
peripheral blood mononuclear cells (PBMCs) from patients
with ocular adnexal lymphomas, although it is important to
mention that other data do not support a causative role [107
109].Borrelia burgdorferi infection has been identified in
some skin lymphomas, MALT and otherwise [110, 111]. A
few observational and epidemiologic studies suggest a pos-
sible link between hepatitis C virus infection and the devel-
opment of MALT lymphoma [112114]. Work by Lecuit
et al. [115] suggests that Campylobacter jejuni may play a
role in the development of small bowel MALT lymphomas.
A patient with HIV disease who developed a MALT lym-
phoma with lung, conjunctival, and laryngeal involvement
was effectively treated with antiretroviral therapy alone,
suggesting a possible role for HIV in lymphomagenesis as
well, although there are certainly other explanations for this
response, such as immune reconstitution or the treatment
of another undiagnosed infection [116]. Autoimmunity
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also seems to be implicated in the pathogenesis of non-GI
lesions. In the salivary gland and the thyroid, the develop-
ment of lymphoma is preceded by autoimmune processes
such as myoepithelial sialadenitis [117] and Hashimotos
thyroiditis [118], respectively.
Several large series describe the characteristic featuresand outcome of nongastr ic MALT lymphomas [102, 119
121]. Patients present with localized, indolent disease, and
rarely have adverse prognostic factors. They respond well
to treatment (CR rate, 76%) and have a 10-year expected
survival rate >75% [102]. Although survival data are not
significantly different from those of gastric MALT lym-
phoma, non-GI MALT lymphoma patients tend to relapse
more frequently and late relapses are not uncommon. Up
to 25% of patients may have stage IV disease on presenta-
tion, including bone marrow involvement. In one study, a
high International Prognostic Index score and lymph node
involvement predicted poorer outcomes, but multiple muco-sal sites of involvement did not seem to adversely impact
prognosis [102, 120].
In a series published by the International Extranodal
Lymphoma Study Group, the most common nongastric pri-
mary sites were the salivary glands and the ocular adnexa
(25% of cases each), the lung (14%), and the sk in (12%)
[120]. Localization of the primary site is important when
planning treatment strategies. All modalities, including
surgery, radiation therapy, and chemotherapy, have been
used, in a patient- and site-tailored fashion. The thyroid
and lacrimal gland sites have the longest response duration,
whereas skin lymphomas have had poorer outcomes in at
least one series [119].
S G
MALT lymphoma of the salivary gland arises in a back-
ground of myoepithelial sialadenitis (MESA), usually
in association with Sjogrens syndrome. The distinction
between benign MESA and early lymphoma can be diffi-
cult using histological criteria alone. There is unresolved
controversy regarding the significance of B-cell monoclo-
nality; some authors believe that demonstration of B-cell
clonality in the lymphoepithelial lesion is diagnostic of
lymphoma [122]. Others argue that clonality does not pre-
dict progression to clinically overt lymphoma [123]. MALT
lymphomas can arise in any of the salivary glands, but the
parotid gland is most frequently involved [124]. Salivary
MALT lymphomas demonstrate a very indolent course with
a long time to progression (318 years), even in the absence
of treatment [117].Some patients develop disseminated dis-
ease, usually to other MALT sites (ocular adnexa, stomach)
or to lymph nodes [124]. The optimal therapeutic strategy
is not yet defined. In one retrospective analysis, Ambrosetti
et al. [125] reported no significant differences in outcomes
among patients undergoing a variety of treatment modali-
ties, including surgery, radiotherapy, and chemotherapy. As
in gastric and other nongastric MALT lymphomas, there is
evidence for the safety and activity of rituximab [95].
O Ax L G
Historically diagnosed as small lymphocytic lymphoma
of the ocular adnexa, this low-grade B-cell lymphoma is
frequently of MALT origin [126]. The clinical course is
indolent and the risk for dissemination is low. Patients pres-
ent with painless conjunctival injection and photophobia,
mimicking a llergic conjunctivitis. Examination reveals
orange- or salmon-pink masses in the fornices, which are
frequently multifocal or bilateral [127129]. Radiation
therapy comprises standard treatment; Uno and coworkers
[130] treated 50 patients with radiation in one ser ies. The
CR and PR rates were 52% and 40%, respectively, and the5-year overall survival rate was 91% [130]. Cataracts devel-
oped in six patients, with two patients undergoing cataract
extraction 23 years after radiotherapy. Retinal complica-
tions attributed to radiotherapy developed in two patients,
including radiation retinopathy 72 months after receiving
40 Gy at 2 Gy per fraction and mild retinal bleeding accom-
panied by decreased visual acuity 10 years after 40 Gy.
One patient who underwent an initial excisional biopsy for
a tumor in the orbital soft tissue developed a corneal ulcer
after receiving 40 Gy. There were no severe, late, lacrimal
complications attributable to radiotherapy.
In cases of lacrimal gland involvement, low-dose radia-
tion therapy provides excellent local control and is the treat-
ment of choice [131]. Subconjunctival intralesional injec-
tions of interferon-were tried in a small group of patients,
with promising results [119, 132]. Recently, a pi lot study
ofC. psittaci-eradicating therapy in patients with ocular
MALT lymphoma was undertaken by the Italian group that
initially published data on the association between the two
entities [133]. Nine patients (five with relapsed or refractory
disease) were treated with oral doxycycline (100 mg orally
twice a day for 3 weeks). An objective overall response rate
of 44.4% was seen, with two complete responses, two par-
tial responses, and three minor responses (
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Some patients with lymphocytic interstitial pneumonia
(LIP), an entity encountered in some autoimmune diseases,
were found to harbor low-grade MALT lymphoma, but
the risk for progression to MALT lymphoma from chronic
bronchiolitis or LIP is small [136]. In pathology specimens,
lymphoepithelial lesions with invasion of bronchial epithe-lium and alveolar lining are commonly seen. The tumors are
composed of nodules that form a confluent central mass with
a peripheral lymphangitic pattern [135]. The disease occurs
most commonly in elderly men aged 60 80 [134, 135].
Some of the patients have a history of autoimmune disorders
(Sjogrens disease, rheumatoid arthritis) [137, 138]. About
40% of patients are asymptomatic and present with a soli-
tary pulmonary nodule on chest x-ray. Symptomatic patients
may have fever, weight loss, and pulmonary symptoms such
as cough, dyspnea, and hemoptysis, and have radiological
evidence of bilateral diffuse interstitial infiltrates [139]. The
prognosis is significantly worse when systemic symptomsare present. The disease has a tendency to become multifo-
cal, spreading to other parts of the lung and to distant muco-
sal sites such as the stomach or salivary glands [134, 140].
Treatment comprises limited resection, sometimes with
chemotherapy or low-dose radiation therapy, when the dis-
ease is localized, and chemotherapy when multifocal [135,
141143].In a case series of 48 patients from the Mayo Clinic
who underwent surgery for NHL of the lung, 35 patients had
MALT lymphoma. Complete surgical resection could be
performed in 40% of the patients. Survival rates at 5 and 10
years were 68% and 53%, respectively. Postoperative che-
motherapy did not improve survival. No prognostic factors
could be identified [144]. Zinzani and coworkers reported
a 100% 6-year survival rate in patients with stage I disease
treated with chemotherapy (n = 8) , surgery (n = 2), or both
(n = 2) [145].Chemotherapy regimens comprised of alkyl-
ating agents, anthracyclines, or purine analogs have been
employed, either as single agents or in combination, with
high response rates [146]. Chong et al. [147] reported on a
patient with recurrent disease 4 years following primary
chemotherapy who responded to rituximab, and an Aus-
trian group reported a response to low-dose thalidomide in a
patient refusing other modalities of therapy [148].
T
Primary thyroid lymphomas arise in the setting of chronic
autoimmune thyroiditis. Most lymphomas are of the large-
cell type, arising as a transformation from a low-grade com-
ponent. Pure low-grade MALT lymphomas of the thyroid
are rare, but the risk for thyroid lymphoma in patients with
Hashimotos thyroiditis is 67 times higher than in the gen-
eral population [149]. Clinical features of thyroid MALT
lymphoma may be difficult to distinguish from Hashimotos
thyroiditis. Most commonly, MALT lymphoma presents as
a growing mass in the thyroid gland sometimes associated
with obstructive symptoms. Although fine-needle aspira-
tion is a commonly used procedure for initial pathologic
evaluation of a thyroid nodule, it is not diagnostic in half
of the patients with thyroid lymphoma. Differentiating low-grade lymphoma from Hashimotos thyroiditis by cytology
can be difficult, and open biopsy may be necessary [150].
Interestingly, clonal B-cell populations can be found in
samples of thyroid tissue in patients with Hashimotos thy-
roiditis, in the absence of lymphoma [151]. In one series,
none of the three such patients developed lymphoma over a
follow-up of 1013 years.
In a Cleveland Clinic report describing 53 patients
with NHL of the thyroid, only three patients had low-grade
MALT-type lymphoma [152]. Among 45 patients with
DLBCL, 18 were classified as high-grade MALT type,
defined by the presence of a low-grade component or large-cell lymphoepithelial lesions. All patients with low-grade
MALT-type lymphoma were alive and free of disease at a
mean of 26 months. Patients with high-grade MALT lym-
phoma had worse outcomes than those with classic DLBCL
(5-year survival rates of 25% versus 65%, respectively),
primarily as a result of a more advanced clinical stage at
diagnosis. In general, surgery, radiation, or both is offered
for local disease; supplemental chemotherapy is offered for
advanced disease [153]. Interestingly, Arima and Tsudo
[154] reported a case of thyroid MALT lymphoma that
regressed following anti-H. pylori therapy, even thoughH.
pylori organisms were not detected in the lymphoma [154].
S
Skin MALT lymphomas usually develop in middle-aged
patients. They present as single or multiple brown or red-
brown papulonodular lesions or plaques, predominantly
found on the extremities or the back [155, 156]. They can be
treated by surgical excision, radiation therapy, or observa-
tion (especially in the case of multiple lesions). Nodules can
recur at the same or a new cutaneous site, although there is
usually no extracutaneous dissemination [156]. The clini-
cal course is indolent, with a 5-year survival rate >95%. A
recent report described a skin MALT lymphoma associated
withBorrelia burgdorferi infection that nearly completely
regressed after eradication of the organism, suggesting that
B. burgdorferi infection may play a role in the pathogenesis
of skin lymphoma [110].
B
Primary breast lymphomas are uncommon and tend to be
high grade: large B-cell or Burkitts type. In a large popu-
lation-based registry, they comprised 0.14% (20 of 14,046
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cases) of primary breast malignancies [157]. Low-grade
MALT lymphomas occur in only 10%35% of cases [157,
158]. Most patients are middle-aged women (median age, 57
years) [158]. They usually present with a painless, enlarg-
ing unilateral breast mass detected during physical exami-
nation or on mammogram. Infiltrating breast carcinoma isoften suspected and can be misdiagnosed on frozen section.
The role of lymphocytic mastopathy, a form of autoim-
mune breast disease, as a precursor to breast lymphoma is
controversial [159, 160]. Published data about treatment
are limited. Local excision and/or radiation therapy have
been associated with an excellent prognosis in small series
of patients [161].
D
Although the central nervous system contains no MALT
tissue, it has been hypothesized that meningothelial cells
of the arachnoid system are analogous to epithelial cellsfrom sites where MALTs do arise [162]. In a retrospective
review, several tumors originally diagnosed as small lym-
phocytic lymphomas and plasmacytomas of the dura were
later reclassified as lymphomas of the MALT subtype. All
patients presented with focal neurologic deficits and had
a well-localized dural mass on x-ray, suggesting a preop-
erative diagnosis of meningioma. No recurrences were
reported after surgical removal either with or without radia-
tion therapy or chemotherapy [163166]. Although the first
10 patients reported in the literature were women, a case in
a man was recently described [162].
U T
Primary bladder lymphoma represents 0.2% of all bladder
neoplasms, and is primari ly of the low-grade MALT sub-
type. The prognosis is excellent with local treatment [167],
although transformation into a high-grade large B-cell lym-
phoma has been described [168]. Rarely, primary MALT
lymphomas of the kidney have been reported as well [169].
ConclusionsWith improved recognition of the immunologic and his-
tologic features of MALT NHL, this pathologic entity
has been diagnosed with increased frequency. Although
most clinicians associate this subtype of NHL with gastric
involvement, the frequency of involvement of other extra-
nodal sites is striking. At most extranodal sites, the etiology
of the MALT lymphoma is uncertain.H. pylori ,B. borgdor-
feri, and C. psittaci have been associated with the disease.
Fortunately, this is a highly treatable type of lymphoma,
with excellent anticipated 5-year survival rates.
Because of the relative rarity of MALT NHL at any
given extranodal site, management has been guided byretrospective clinical series. It is unlikely that prospective
clinical trials will be conducted for most of the disease sub-
types beyond gastric MALT NHL, but the development
of appropriate registries should be encouraged to permit
pooled data from single institutions. MALT lymphoma is
well treated by local therapy. Radiation is highly effective
and major surgery can be avoided in most cases. Although
systemic chemotherapy is active, it should be reserved as a
palliative treatment for advanced stage disease. The role of
rituximab remains undefined, but this treatment has high
response rates with low toxicity in MALT lymphoma.
Disclosure of Potential Conflicts
of Interest
The authors indicate no potential conf licts of interest.
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