The Oncologist 2006 Cohen 1100 17

8/3/2019 The Oncologist 2006 Cohen 1100 17

1/19

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 -

(MALT) w I

W [C 1983;52:14101416] 1983. A

20 MALT

w -H

(NHL) w q , -

, . A NHL

q, .

T w -

, , , ,

- MALT

.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


2/19

Cohen, Petryk, Varma et al. 1101

www.TheOncologist.com

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.


3/19

1102 NHL of MALT

The

Oncologist

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-


4/19



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

(


5/19

1104 NHL of MALT

The

Oncologist

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


6/19



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.


7/19

1106 NHL of MALT

The

Oncologist

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


8/19



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.


9/19

1108 NHL of MALT

The

Oncologist

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


10/19



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


11/19

1110 NHL of MALT

The

Oncologist

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 (


12/19



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


13/19

1112 NHL of MALT

The

Oncologist

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.

References

1 Isaacson P, Wright DH. Malignant lymphoma of mucosa-associated

lymphoid tissue: a distinctive type of B-cell lymphoma. Cancer 1983;52:

14101416.

2 Isaacson P, Wright DH. Extranoda l malignant lymphoma arising from

mucosa-associated lymphoid tissue. Cancer 1984;53:25152524.

3 Harris NL, Jaffe ES, Stein H et al. A revised European-American clas-

sification of lymphoid neoplasms: a proposal from the International Lym-

phoma Study Group. Blood 1994;84:13611392.

4 Nathwani BN, Anderson JR, Armitage JO et al. Marginal zone B-cell

lymphoma: A clinical comparison of nodal and mucosa-associated lym-

phoid tissue types. Non-Hodgkins Lymphoma Classification Project. J

Clin Oncol 1999;17:24862492.

5 Wenzel C, Dieckmann K, Fiebiger W et al. CD5 expression in a lymphoma

of the mucosa-associated lymphoid tissue (MALT)-type as a marker for

early dissemination and aggressive clinical behaviour. Leuk Lymphoma

2001;42:823829.

6 Wohrer S, Streubel B, Bartsch R et al. Monoclonal immunoglobul in pro-

duction is a frequent event in patients with mucosa-associated lymphoid

tissue. Cl in Cancer Res 2004;10:71797181.

7 Asatian i E, Cohen P, Ozdemi rli M et al. Monoclonal gammopat hy in

extranodal margina l zone lymphoma (ENMZL) correlates with advanceddisease and bone marrow involvement. Am J Hematol 200 4;77:144146.

8 Auer IA, Gascoyne RD, Connors JM et al. t(11;18)(q21;q21) is the most

common translocation in MALT lymphomas. Ann Oncol 1997;8:

979985.

9 Ott G, Katzenberger T, Greiner A et al. The t(11;18)(q21;q21) chromosome

translocation is a frequent and specif ic aberration in low-grade but not

high-grade malignant non-Hodgkins lymphomas of the mucosa-associ-

ated lymphoid tissue (MALT) type. Cancer Res 1997;57:39443948.

10 Streubel B, Lampre cht A, Dierlamm J et al. t(14;18)(q32;q21) involving

IGH and MALT1 is a frequent chromosomal aber ration in MALT lym-

phoma. Blood 2003;101:23352339.


14/19



11 Wotherspoon AC, Finn TM, Isaacson P. Trisomy 3 in low-grade B-cell

lymphomas of mucosa-associated lymphoid tissue. Blood 1995;85:

20002004.

12 Dierlamm J, Baens M, Wlodarska I et al. The apoptosis inhibitor gene

API2 and a novel 18q gene, MLT, are recurrently rearra nged in the

t(11;18)(q21;q21) associated with mucosa-ass ociated lymph oid tissue

lymphomas. Blood 1999;93:36013609.13 Morgan JA, Yin Y, Borowsky AD et al. Breakpoints of the t(11;18)(q21;q21)

in mucosa-associated lymphoid tissue (MALT) lymphoma lie within or

near the previously undescribed gene MALT1 in chromosome 18. Cancer

Res 1999;59:6205 6213.

14 Akagi T, Motegi M, Tamura A et al. A novel gene, MALT1 at 18q21, is

involved in t(11;18) (q21;q21) found in low-grade B-cel l lymphoma of

mucosa-associated lymphoid tissue. Oncogene 1999;18:57855794.

15 Streubel B, Vinatzer U, Lamprecht A et al. T(3;14)(p14.1;q32) involving

IGH and FOXP1 is a novel recurrent chromosomal aberration in MALT

lymphoma. Leukemia 2005;19:652658.

16 Starostik P, Greiner A, Schultz A et al. Genetic aberrations common in

gastric high-grade large B-cell lymphoma. Blood 2000;95:11801187.

17 Starostik P, Patzner J, Greiner A et al. Gastric marginal zone B-celllymphomas of MALT type develop along 2 distinct pathways. Blood

2002;99:39.

18 Ye H, Liu H, Raderer M et al. High incidence of t(11;18)(q21;21) inHeli-

cobacter pylori-negative gastric MA LT lymphoma. Blood 2003;101:

25472550.

19 Kaneko Y, Sakurai S, Hirona ka M et al. Distinct methylated profiles in

Helicobacter pylori dependent and independent gastric MALT lympho-

mas. Gut 2003;52:641646.

20 Yeh KH, Kuo SH, Chen LT et al. Nuclear expression of BCL10 or nuclear

factor kappa B helps predictHelicobacter pylori -independent status of

low-grade gastric mucosa-associated lymphoid tissue lymphomas with or

without t(11;18)(q21;q21). Blood 2005;106:10371041.

21 The Non-Hodgkins Lymphoma Classification Project. A clinical evalu-ation of the International Lymphoma Study Group classification of non-

Hodgkins lymphoma. Blood 1997;89:39093918.;

22 Raderer M, Streubel B, Woehrer S et al. High relapse rate in patients

with MALT lymphoma warrants lifelong follow-up. Clin Cancer Res

2005;11:33493352.

23 Wyatt JI, Rathbone BJ. Immune response of the gastric mucosa toCampy-

lobacter pylori. Scand J Gastroenterol 1988;1142(suppl):44 49.

24 Stolte M, Eidt S. Lymphoid follicles in antral mucosa: immune response

to Campylobacter pylori? J Clin Pathol 1989;42:12691271.

25 Wotherspoon A, Ortiz-Hidalgo C, Falzon M et al.Helicobacter pylori -

associated gastritis and primary B-cell gastric lymphoma. Lancet

1991;338:11751176.

26 Nakamura S, Yao T, Aoyagi K et al.Helicobacter pylori and primary gas-tric lymphoma. A histopathologic and immunohistochemica l analysis of

237 patients. Cancer 1997;79:311.

27 Megraud F. Epidemiology ofHelicobacter pylori infection. Gastroenterol

Clin North Am 1993;22:7388.

28 Hellmig S, Fischbach W, Goebeler-Kolve ME et al. Association study

of a functional Toll-like receptor 4 polymorphism with susceptibility to

gastric mucosa-associated lymphoid tissue lymphoma. Leuk Lymphoma

2005;46:869872.

29 Rollinson S, Levene A, Mensah FK et al. Gastric marginal zone lym-

phoma is associated with polymorphisms in genes involved in inflamma-

tory response and antioxidative capacity. Blood 20 03;102:10071011.

30 Ye H, Liu H, Attygalle A et al. Variable frequencies of t(11;18)(q21;q21) in

MALT lymphomas of different sites: significant association with CagA

strains ofH. pylori in gastric MALT lymphoma. Blood 2003;102:10121018.

31 Doglioni C, Wotherspoon AC, Moschini A et al. High incidence of pri-

mary gastric lymphoma in Nor theastern Italy. Lancet 1992;339:834835.

32 Parsonnet J, Hansen S, Rodriguez L et al.Helicobacter pylori infection

and gastric lymphoma. N Engl J Med 1994;330:12671271.

33 Wotherspoon A, Doglioni C, Diss T et al. Regression of primary low-

grade B-cell gastr ic lymphoma of mucosa-associated lymphoid tissue

type after eradication ofHelicobacter pylori. Lancet 1993;342:575577.

34 Roggero E, Zucca E, Pinotti G et al. Eradication ofHelicobacter pylori

infection in primar y low-grade gastric lymphoma of mucosa-associated

lymphoid tissue. Ann Intern Med 1995;122:767769.

35 Neubauer A, Thiede C, Morgner A et al. Cure of Helicobacter pylori

infection and duration of remission of low-grade gastric mucosa-associ-

ated lymphoid tissue lymphoma. J Natl Cancer Inst 1997;89:13501355.

36 Steinbach G, Ford R, Glober G et al. Antibiotic treatment of gastric lym-

phoma of mucosa-associated lymphoid tissue. An uncontrolled trial. Ann

Intern Med 1999;131:8895.

37 Fischbach W, Goebeler-Kolve ME, Dragosics B et al. Long term outcome

of patients with gastric marginal zone B cell lymphoma of mucosa asso-

ciated lymphoid tissue (MALT) following exclusiveHelicobacter pylori

eradication therapy: experience from a large prospective series. Gut

2004;53:3437.

38 Hussell T, Isaacson PG, Crabtree JE et al.Helicobacter pylori -specific

tumour-infilt rating T cells provide contact dependent help for the growth

of malignant B cells in low-grade gastr ic lymphoma of mucosa-associated

lymphoid tissue. J Pathol 1996;178:122127.

39 Qin Y, Greiner A, Trunk MJ et al. Somatic hypermutation in low-grade

mucosa-associated lymphoid tissue-type B-cell lymphoma. Blood

1995;86:35283534.

40 Du M, Diss TC, Xu C et al. Ongoing mutation in MALT lymphoma immu-

noglobulin gene suggests that antigen stimulation plays a role in the clonalexpansion. Leukemia 1996;10:11901197.

41 Hussell T, Isaacson PG, Crabtree JE et al. Immunoglobulin specificity of

low grade B cell gastrointestinal lymphoma of mucosa-associated lym-

phoid tissue (MALT) type. Am J Pathol 1993;142:285292.

42 Bende RJ, Aarts WM, Riedl RG et al. Among B cell non-Hodgkins lym-

phomas, MALT lymphomas express a unique antibody repertoire with

frequent rheumatoid factor reactivity. J Exp Med 2005;201:12291241.

43 Isaacson PG. Gastric MALT lymphoma: from concept to cure. Ann Oncol

1999;10:637645.

44 Pinotti G, Zucca E, Roggero E et al. Clinical features, treatment and out-

come in a series of 93 patients with low-grade gastric MALT lymphoma.

Leuk Lymphoma 1997;26:527537.

45 Zucca E, Bertoni F, Roggero E et al. The gastric marginal zone B-cell lym-phoma of MALT type. Blood 20 00;96:410419.

46 Schechter NR, Portlock CS, Yahalom J. Treatment of mucosa-associated

lymphoid tissue lymphoma of the stomach with radiation alone. J Clin

Oncol 1998;16:19161921.

47 Taal BG, Boot H, van Heerde P et al. Primary non-Hodgkin lymphoma of

the stomach: endoscopic pattern and prognosis in low versus high grade

malignancy in relation to the MALT concept. Gut 1996;39:556561.

48 Zucca E, Bertoni F, Roggero E et al. Molecular analysis of the progres-

sion fromHelicobacter pylori-associated chronic gastritis to mucosa-

associated lymphoid-tissue lymphoma of the stomach. N Engl J Med

1998;338:804810.


15/19

1114 NHL of MALT

The

Oncologist

49 Nakamura S, Aoyagi K, Furuse M et al. B-cell monoclonality precedes the

development of gastric MALT lymphoma inHelicobacter pylori -associ-

ated chronic gastr itis. Am J Pathol 1998;152:12711279.

50 Blackledge G, Bush H, Dodge OG et al. A study of gastro-intestina l lym-

phoma. J Cl in Oncol 1979;5:209219.

51 Musshoff K. Clinical staging classification of non-Hodgkins lymphomas

(authors t ransl). St rahlentherapie 1977;153:218221. German.

52 Rohatiner A, dAmore F, Coiffier B et al. Report on a workshop convened

to discuss the pathological and staging classifications of gastrointestinal

tract lymphoma. Ann Oncol 1994;5:397400.

53 Wotherspoon A, Doglioni C, Isaacson P. Low-grade gastric B-cell lym-

phoma of mucosa-associated lymphoid tissue (MALT): a multifocal dis-

ease. Histopathology 1992;20:2934.

54 Du M, Diss T, Xu C et al. Clonal origin of micro-lymphomas in low-grade

B-cell gast ric MALT lymphoma. J Pathol 1997;181:57 (Abstract).

55 Du MQ, Peng HZ, Dogan A et al. Preferential dissemination of B-cell gas-

tric mucosa-associated lymphoid tissue (MALT) lymphoma to the splenic

marginal zone. Blood 1997;90:40714077.

56 Briskin M, Winsor-Hines D, Shyjan A et al. Human mucosal addressincell adhesion molecule-1 is preferentially expressed in intestinal tract and

associated lymphoid tissue. Am J Pathol 1997;151:97110.

57 Kraa l G, Schornagel K, Streeter PR et al. Expression of the mucosal vas-

cular addressin, MAdCAM-1, on sinus-lining cells in the spleen. Am J

Pathol 1995;147:763771.

58 Dabaja BS, Ha CS, Wilder RB et al. Importance of esophagogastroduo-

denoscopy in the evaluation of non-gastrointestinal mucosa-associated

lymphoid tissue lymphoma. Cancer J 2003;9:321324.

59 Bertoni F, Sanna P, Tinguely M et al. Association of gastric and Waldey-

ers ring lymphoma: a molecular study. Hematol Oncol 2000;18:1519.

60 Suerbaum S, Michetti P.Helicobacter pylori infection. N Engl J Med

2002;347:11751186.

61 Beal KP, Yeung HW, Yahalom J. FDG-PET scanning for detection and

staging of extranodal marg inal zone lymphomas of the MALT type: a

report of 42 cases. Ann Oncol 2005;16:473480.

62 Hoffmann M, Kletter K, Becherer A et al. 18F-fluorodeoxyglucose posi-

tron emission tomography (18F-FDG-PET) for staging and follow-up of

marginal zone B-cell lymphoma. Oncology 2003;64:336340.

63 de Jong D, Aleman BM, Taal BG et al. Controversies and consensus in the

diagnosis, work-up and treatment of gastric lymphoma: an international

survey. Ann Oncol 1999;10:275280.

64 Zucca E, Roggero E, Pileri S. B-cell lymphoma of MALT type: a review

with special emphasis on diagnostic and management problems of low-

grade gastric tumours. Br J Haematol 1998;100:314.

65 Banks PM, Isaacson PG. MALT lymphomas in 1997. Where do we stand?Am J Clin Pathol 1999;111(suppl 1):S75S83.

66 Thiede C, Morgner A, Alpen B et al. What role doesHelicobacter pylori

eradication play in gastric MALT and gastric MALT lymphoma? Gastro-

enterology 1997;113:S61S64.

67 Hunt RH. Peptic ulcer disease: defining the treatment strategies in the era

ofHelicobacter pylori. Am J Gastroenterol 1997;92:36S40S; discussion

40S43S.

68 Sackmann M, Morgner A, Rudolph B et al. Regression of gastric MALT

lymphoma after eradication ofHelicobacter pylori is predicted by endo-

sonographic staging. MALT Lymphoma Study Group. Gastroenterology

1997;113:10871090.

69 Ruskone-Fourmestraux A, Lavergne A, Aegerter P et al. Predictive fac-

tors for regression of gastric MALT lymphoma after anti-Helicobacter

pylori treatment. Gut 2001;48:297303.

70 Liu H, Ruskon-Fourmestraux A, Lavergne-Slove A et al. Resistance of

t(11;18) positive gastric mucosa-associated lymphoid tissue lymphoma to

Helicobacter pylori eradication therapy. Lancet 2001;357:3940.

71 Inagaki H, Nakamura T, Li C et al. Classification of gastric MALT lym-

phoma into three dist inctive subgroups by responsiveness toH. pylori

eradication therapy and dete ction of API2-MALT1 gene fusion. Blood

2003;102:632a.

72 Cammarota G, Montalto M, Tursi A et al.Helicobacter pylori reinfec-

tion and rapid relapse of low-grade B-cell gastric lymphoma. Lancet

1995;345:192.

73 Thiede C, Wundisch T, Alpen B et al. Long-term persistence of mono-

clonal B cells after cure ofHelicobacter pylori infection and complete

histologic remission in gastric mucosa-associated lymphoid tissue B-cell

lymphoma. J Clin Oncol 2001;19:16001069.

74 Bertoni F, Conconi A, Capella C et al. Molecular follow-up in gastric

mucosa-associated lymphoid tissue lymphomas: early analysis of the

LY03 cooperative trial. Blood 2002;99:25412544.

75 Montalban C, Santon A, Redondo C et al. Long-term persistence of molec-

ular disease af ter histological remission in low-grade gastric MALT lym-

phoma treated withH. pylori eradication. Lack of association with trans-

location t(11;18): a 10-year updated follow-up of a prospect ive study. Ann

Oncol 2005;16:15391544.

76 Noy A, Yahalom J, Zaretsky L et al. Gastric mucosa-ass ociated lym-

phoid tissue lymphoma detected by clonotypic polymerase chain reaction

despite continuous pathologic remission induced by involved-field radio-

therapy. J Clin Oncol 2005;23:37683772.

77 Thiede C, Alpen B, Morgner A et al. Ongoing somatic mutations and

clonal expansions after cure ofHelicobacter pylori infection in gastric

mucosa-associated lymphoid tissue B-cell lymphoma. J Clin Oncol

1998;16:38223831.

78 Talamonti MS, Dawes LG, Joehl RJ et al. Gastrointest inal lymphoma. A

case for primary surgical resection. Arch Surg 1990;125:972976; dis-

cussion 976977.

79 Bozzetti F, Audisio R, Giardini R et al. Role of surgery in patients with pri-

mary non-Hodgk ins lymphoma of the stomach: an old problem revisited.

Br J Surg 1993;80:11011106.

80 Cogliatti SB, Schmid U, Schumacher U et al. Primar y B-cell gastric lym-

phoma: a clinicopathological study of 145 patients. Gastroenterology

1991;101:11591170.

81 Montalban C, Castrillo JM, Abraira V et al. Gastric B-cell mucosa-asso-

ciated lymphoid tissue (MALT): clinicopathological study and evaluation

of the prognostic factors in 143 patients. Ann Oncol 1995;6:355362.

82 Maor MH, Velasquez WS, Fuller LM et al. Stomach conservation in stagesIE and IIE gastric non-Hodgkins lymphoma. J Clin Oncol 1990;8:266

271.

83 Park HC, Park W, Hahn JS et al. Low grade MALT lymphoma of the

stomach: treatment outcome with rad iotherapy alone. Yonsei Med J

2002;43:601606.

84 Shani A, Schutt AJ, Weiland LH. Primary gastric malignant lymphoma

followed by gastric adenocarcinoma: report of 4 cases and review of the

literature. Cancer 1978;42:20392044.

85 Montalban C, Castrillo JM, Lopez-Abente G et al. Other cancers in

patients with gastr ic MALT lymphoma. Leuk Lymphoma 1999;33:

161168.


16/19



86 Copie-Bergman C, Locher C, Levy M et al. Metachronous gastric MALT

lymphoma and early gastric cancer: is residual lymphoma a risk factor for

the development of gastric carcinoma? Ann Oncol 2005;16:12321236.

87 Fung CY, Grossbard ML, Linggood RM et al. Mucosa-associated lym-

phoid tissue lymphoma of the stomach: long term outcome after local

treatment. Cancer 1999;85:917.

88 Witzig T, Gordon L, Emmanouilides C et al. Safety and efficacy of Zeva-lin in four patients with mucosa associated lymphoid tissue (MALT) lym-

phoma. Blood 2001;98:254b.

89 Hammel P, Haioun C, Chaumette MT et al. Efficacy of single-agent chemo-

therapy in low-grade B-cell mucosa-associated lymphoid tissue lymphoma

with prominent gastric expression. J Clin Oncol 1995;13:25242529.

90 Levy M, Copie-Bergman C, Gameiro C et al. Prognostic value of trans-

location t(11;18) in tumoral response of low-grade gastric lymphoma of

mucosa-associated lymphoid tissue typ e to oral chemotherapy. J Clin

Oncol 2005;23:50615066.

91 Nakamura S, Matsumoto T, Suekane H et al. Long-term clinical outcome

ofHelicobacter pylori eradication for gastric mucosa-associated lym-

phoid tissue lymphoma with a reference to second-line treatment. Cancer

2005;104:532540.

92 Bertoni F, Conconi A, Capella C et al. Gastric MALT lymphomas pro-

spective LY03 randomized cooperative trial: prelimi nary results of the

molecular follow up. Blood 2001;98:767a.

93 Jager G, Neumeister P, Brezinschek R et al. Treatment of extranodal mar-

ginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type

with cladribine: a phase II study. J Clin Oncol 2002;20:38723877.

94 Raderer M, Jager G, Brugger S et al. Rituximab for treatment of advanced

extranodal marginal zone B cell lymphoma of the mucosa-associated

lymphoid tissue lymphoma. Oncology 2003;65:306 310.

95 Conconi A, Martinelli G, Thieblemont C et al. Clinical activity of ritux-

imab in extranodal marginal zone B-cell lymphoma of MALT type. Blood

2003;102:27412745.

96 Martinelli G, Laszlo D, Ferreri AJ et al. Clinical activity of rituximab ingastric margina l zone non-Hodgkins lymphoma resistant to or not eligible

for anti-Helicobacter pylori therapy. J Clin Oncol 2005;23:19791983.

97 Coiffier B, Lepage E, Brire J et al. CHOP chemotherapy plus rituximab

compared with CHOP alone in elderly patients with diffuse large-B-cell

lymphoma. N Engl J Med 2002;346:235242.

98 de Jong D, Boot H, Taal B. Histological grading with clinical relevance in

gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Recent

Results Cancer Res 2000;156:2732.

99 Bayerdorffer E, Neubauer A, Rudolph B et al. Regression of primary gas-

tric lymphoma of mucosa-associated lymphoid tissue type after cure of

Helicobacter pylori infection. MALT Lymphoma Study Group. Lancet

1995;345:15911594.

100 Peng H, Du M, Diss TC et al. Genetic evidence for a clonal lin k betweenlow and high-grade components in gastric MALT B-cell lymphoma. His-

topathology 1997;30:425429.

101 de Jong D, Boot H, van Heerde P et al. H istological grading in gastr ic lym-

phoma: pretreatment criteria and clinical relevance. Gastroenterology

1997;112:14661474.

102 Thieblemont C, Bastion Y, Berger F et al. Mucosa-associated lymphoid

tissue gastrointestinal and nongastrointestinal lymphoma behavior: anal-

ysis of 108 pat ients. J Cl in Oncol 1997;15:16241630.

103 Castrillo JM, Montalban C, Obeso G et a l. Gastric B-cell mucosa asso-

ciated lymphoid tissue lymphoma: a clinicopathological study in 56

patients. Gut 1997;33:13071311.

104 Ranaldi R, Goteri G, Baccarin i MG et al. A clinicopathological study of

152 surgically treated primary gastr ic lymphomas with survival analysis

of 109 high grade tumours. J Clin Pathol 2002;55:346351.

105 Chen LT, Lin JT, Shyu RY et al. Prospective study ofHelicobacter pylori

eradication therapy in stage I(E) high-grade mucosa-associated lymphoid

tissue lymphoma of the stomach. J Cl in Oncol 2001;19:42454251.

106 Kuo SH, Chen LT, Chen CL et al. Expression of CD86 and increased infil-

tration of NK cells are associated withHelicobacter pylori-dependent

state of early stage high-grade gastr ic MALT lymphoma. World J Gastro-

enterol 2005;11:43574362.

107 Ferreri AJ, Guidoboni M, Ponzoni M et al. Evidence for an association

betweenChlamydia psittaci and ocular adnexal lymphomas. J Natl Can-

cer Inst 2004;96:586594.

108 Mulder MM, Heddema ER, Pannekoek Y et al. No evidence for an asso-

ciation of ocular adnexal lymphoma with Chlamydia psittaci in a cohort

of patients from the Netherlands. Leuk Res 20 06;30:13051307.

109 Rosado MF, Byrne GE Jr, Ding F et al. Ocular adnexal lymphoma: a clin i-

copathologic study of a large cohort of patients with no evidence for an

association with Chlamydia psittaci. Blood 2006;107:467472.

110 Cerroni L, Zochling N, Putz B et al. Infection byBorrelia burgdorferi and

cutaneous B-cel l lymphoma. J Cutan Pathol 1997;24:457461.

111 Roggero E, Zucca E, Mainett i C et al. Eradication ofBorrelia burgdorferi

infection in primary ma rginal zone B-cell lymphoma of the skin. Hum

Pathol 2000;31:263268.

112 Luppi M, Longo G, Ferrari MG et a l. Additional neoplasms a nd HCV

infection in low-grade lymphoma of MALT type. Br J Haematol

1996;94:373375.

113 Ascoli V, Lo Coco F, Artini M et al. Extranoda l lymphomas associated

with hepatitis C virus infection. Am J Clin Pathol 1998;109:600 609.

114 Zucca E, Roggero E , Maggi-Solca N et a l. Prevalence ofHelicobacter

pylori and hepatitis C virus infect ions among non-Hodgkins lymphoma

patients in Southern Switzerland. Haematologica 2000;85:147153.

115 Lecuit M, Abachin E, Ma rtin A et al. Immunoproliferative small intes-

tinal disease associated with Campylobacter jejuni. N Engl J Med

2004;350:239248.

116 Girard T, Luquet-Besson I, Baran-Marsz ak F et al. HIV+ MALT lym-

phoma remission induced by highly active antiretroviral t herapy alone.

Eur J Haematol 2005;74:7072.

117 Diss TC, Wotherspoon AC, Speight P et al. B-cell monoclonality, Epstein

Barr vir us, and t(14;18) in myoepithelial sialadenitis and low grade B-

cell MALT lymphoma of the parotid gland. A m J Surg Pathol 1995;19:

531536.

118 Ansell SM, Grant CS, Haber mann TM. P rimary t hyroid lymphoma.

Semin Oncol 1999;26:316323.

119 Zinzani PL, Magagnoli M, Galieni P et al. Nongastrointestinal low-grademucosa-associa ted lymphoid tissue lymphoma: ana lysis of 75 patients. J

Clin Oncol 1999;17:12541258.

120 Zucca E, Conconi A , Roggero E et al. Non-gastric MA LT lymphomas:

a survey of 369 European patients. The International Extranodal Lym-

phoma Study Group. Ann Oncol 2000;11(suppl 1):99.

121 Zucca E, Conconi A, Pedr inis E et al. Nongastric marginal zone B-cell

lymphoma of mucosa-associated lymphoid t issue. Blood 2003;101:

24892495.

122 Falzon M, Isaacson PG. The natu ral history of benign lymphoepithelial

lesion of the salivary gland in which there is a monoclonal population of B

cells. A report of two cases. Am J Surg Pathol 1991;15:5965.


17/19

1116 NHL of MALT

The

Oncologist

123 Hsi ED, Siddiqui J, Schnitzer B et al. Analysis of immunoglobulin heavy

chain gene rearra ngement in myoepithelial sialadenitis by polymerase

chain reaction. Am J Clin Pathol 1996;106:498503.

124 Isaacson PG. Mucosa-associated lymphoid tissue lymphoma. Semin

Hematol 1999;36:139147.

125 Ambrosetti A, Zanotti R, Pattaro C et al. Most cases of primary salivary

mucosa-associated lymphoid tissue lymphoma are associated either

with Sjoegren syndrome or hepatitis C virus infection. Br J Haematol

2004;126:4349.

126 Wotherspoon AC, Diss TC, Pan LX et al. Prima ry low-grade B-cell lym-

phoma of the conjunctiva: a mucosa-associated lymphoid tissue type lym-

phoma. Histopathology 1993;23:417424.

127 Hardman-Lea S, Kerr-Muir M, Wotherspoon AC et al. Mucosal-associ-

ated lymphoid tissue lymphoma of the conjunctiva. Arch Ophtha lmol

1994;112:12071212.

128 Minasian MC, Sha rma A, Rich man PI et al. Conjunctival MA LT lym-

phoma: an unusual cause of red eye. Postgrad Med J 1999;75:423424.

129 Lee DH, Sohn HW, Park SH et al. Bilateral conjunct ival mucosa-assoc i-

ated lymphoid tissue lymphoma misdiagnosed as allergic conjunct ivitis.

Cornea 2001;20:427429.

130 Uno T, Isobe K, Shikama N et al. Radiotherapy for extranodal, marginal

zone, B-cell lymphoma of mucosa-associated lymphoid tissue originat-

ing in the ocular adnexa: a multiinstitutional, retrospective review of 50

patients. Cancer 2003;98:865871.

131 Agulnik M, Tsang R, Baker MA et al. Malignant lymphoma of mucosa-

associated lymphoid tissue of the lacrimal gland: case report and review

of literature. Am J Clin Oncol 2001;24:6770.

132 Blasi MA, Gherlinzoni F, Calvisi G et

The Oncologist 2006 Cohen 1100 17

Documents

Transcript of The Oncologist 2006 Cohen 1100 17