Annals of Oncology 19: 1992–1999, 2008
Published online 22 July 2008
Primary extranodal lymphomas of stomach: clinical
presentation, diagnostic pitfalls and management
A. Psyrri1,2, S. Papageorgiou1* & T. Economopoulos1
1Second Department of Internal Medicine Propaedeutic, Athens University Medical School, University General Hospital ‘Attikon’, Haidari, Greece;2Department of Internal
Medicine, Yale University School of Medicine, New Haven, USA
Received 25 January 2008; revised 17 June 2008; accepted 20 June 2008
Gastrointestinal lymphoma is the most common form of extranodal lymphoma, accounting for 30%–40% of
cases. The most commonly involved site is the stomach (60%–75% of cases), followed by the small bowel,
ileum, cecum, colon and rectum. The most common histological subtypes are diffuse large B-cell lymphoma
(DLBCL) and marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT). Helicobacter
pylori infection has been implicated in the pathogenesis of MALT gastric lymphoma, but its role in gastric diffuse
large B-cell non-Hodgkin’s lymphoma (NHL) is controversial. The therapeutic approach for patients with gastric
NHL has been revised over the last 10 years. Conservative treatment with anthracycline-based chemotherapy
alone or in combination with involved-field radiotherapy has replaced gastrectomy as standard therapy in cases
with DLBCL. Additionally, MALT lymphomas are mainly treated with antibiotics alone, which can induce lasting
remissions in those cases associated with H. pylori infection. Nevertheless, various therapeutic aspects for
primary gastric lymphomas are still controversial and several questions remain unanswered. Among others, the
role of rituximab, consolidation radiotherapy as well as H. pylori eradication in histological aggressive subtypes
warrants better clarification.
Key words: diffuse large B-cell lymphomas, extranodal lymphomas, Helicobacter pylori infection, mucosa-
associated lymphoid tissue, primary gastric lymphomas
The term primary extranodal non-Hodgkin’s lymphoma (PE-
NHL) refers to lymphomas which present with disease at any
organ or tissue other than lymph nodes or spleen; the
symptoms at initial presentation are caused mainly from
extranodal involvement and after routine staging procedures,
the extranodal involvement remains the clinically dominant
site of the disease. PE-NHL comprise ?25%–40% of non-
Hodgkin’s lymphoma (NHL) and may occur at any organ
Primary non-Hodgkin’s lymphoma of the gastrointestinal
tract is the most commonly involved extranodal site and
represents 10%–15% of all NHL cases and 30%–40% of all
extranodal sites . The most commonly involved site is the
stomach (60%–75% of cases), followed by the small bowel,
ileum, cecum, colon and rectum [4, 5]. All histological
categories of nodal lymphomas may also arise in the
gastrointestinal (GI), but the main two histological subtypes
(>90% of cases) are mucosa-associated lymphoid tissue
(MALT) NHL and diffuse large B-cell (DLBC) NHL (Table 1).
Primary gastric non-Hodgkin’s lymphoma (PG-NHL) is
localized in the stomach, with or without perigastric and/or
abdominal lymph node involvement, and constitutes 20%–30%
of all PE-NHL. PG-NHL shows an incidence of 1 per 100 000
of the population in Western countries, but the incidence is
progressively increasing. Any histological subtype can arise in
the stomach, but the main two histological subtypes (>90% of
cases) are MALT NHL and DLBC NHL. Helicobacter pylori
infection has been implicated in the pathogenesis of MALT PG-
NHL [6, 7], but its role in gastric DLBC NHL is controversial
The present review summarizes the clinical presentation,
diagnostic work-up and management of patients with primary
diagnosis and staging
Clinical presentation of PG-NHL is not specific and varied,
with abdominal pain being the most common symptom
followed by dyspepsia, vomiting nausea and anorexia. Weight
loss is common, but it is mainly associated with the localization
of the disease. Gastric bleeding as presenting symptom occurs
in 20%–30% of patients, while gastric occlusion and
perforation are less common . Bone marrow involvement,
elevated lactate dehydrogenase (LDH) and B symptoms are less
*Correspondence to: Dr S. Papageorgiou, Second Department of Internal Medicine
Propaedeutic, Atttikon General Hospital, 1 Rimini street, 124 62 Haidari, Greece.
Tel: +30-210-58-31-663; Fax: +30-210-53-26-454;
ª The Author 2008. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
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common in gastric compared with nodal lymphomas.
Endoscopy usually reveals nonspecific gastritis or peptic ulcer
with mass lesions being unusual . Occasionally, PG-NHL
can present as a multifocal stomach disease with numerous
clonally identical foci in macroscopically unaffected tissue .
Therefore, gastric mapping of unaffected mucosa is crucially
recommended in order to establish diagnosis. Gastric MALT
lymphoma is characterized by the presence of lymphoepithelial
lesions that are formed by invasion of single glands by
aggregates of neoplastic cells with centrocyte morphology ,
in contrast to aggressive lymphoma where lymphoma-
infiltrating cells show a centroblastic morphology .
Staging work-up for PG-NHL include complete
hematological biochemical examinations (including LDH and
b2-microglobulin), computerized tomography (CT) of chest,
abdomen and pelvis and bone marrow aspiration and biopsy.
Upper GI endoscopy and multiple biopsies from stomach,
duodenum, gastroesophageal junction and from abnormal-
appearing lesions are required. An endoscopic ultrasound
should be carried out to determine the depth of invasion and
the presence of perigastric nodes. Examination of the pharynx
by an otorhinolaryngologist should be carried out to exclude
infiltration of Waldeyer ring that is occasionally associated with
PG-NHL [13, 14]. In addition to routine histology and
immunohistochemistry, cytogenetic studies should be carried
out. FISH for the detection of three specific MALT-related
translocations is recommended. The pertinent genotypic
evaluations should be carried out at the time of diagnosis to
guide treatment decisions. Histochemistry (Genta stain or
Warthin–Starry stain) and breath test should be carried out to
determine the presence of an active H. pylori infection. If
histology is negative, serology should be undertaken to identify
truly negative H. pylori gastric MALT NHL which is ?10% of
Positron emission tomography (PET) scan bears
a documented diagnostic value only for DLBCLs but is
controversial for MALT lymphomas, which are frequently
reported as PET negative due to their indolent behavior and
small tumor volume of disease [15, 16].
The Ann-Arbor classification system  is not easily applied
to GI tract lymphomas and although alternative staging systems
have been proposed, the problem of ‘staging’ a PG-NHL is
controversial even today. The use of different staging systems
combined with the variability in staging procedures hamper
meaningful comparisons of published series. However, factors
that have consistently been associated with poor prognosis in
these series are involvement of paraortic (versus local) lymph
nodes, serosal penetration and intestinal (versus gastric) origin.
An International Workshop in 1994, during the fifth
International Conference on Malignant Lymphoma, proposed
a modification to Blackledge’s system, known as ‘Lugano
staging’ which examines separately local spreading to
neighboring anatomic sites . More recently, in 2003,
a modified tumor–node–metastasis classification system—the
Paris staging system—was proposed in order to describe more
efficiently (i) the depth of tumor infiltration, (ii) extent of
nodal involvement and (iii) extent of local tissue infiltration by
lymphoma  (Table 2).
PG MALT lymphomas
Isaacson and Wright  first observed in 1983 that primary
low-grade gastric B-cell lymphoma and immunoproliferative
small intestinal disease share histological characteristics more
similar to MALT than those of peripheral lymph nodes. Gastric
MALT lymphomas represent the vast majority of the three
different types of marginal zone B-cell lymphomas (MZBCLs)
according to the Revised European-American Lymphoma
(REAL) classification . MALT lymphomas comprise 50% of
PG-NHL and are often multifocal. They occur predominantly
in individuals >50 years, with a peak in the seventh decade, but
cases have been reported in younger patients (third decade or
even earlier). In ?90% of cases, a strong association between
chronic H. pylori infection and MALT gastric lymphoma has
been found . It is accepted that gastric MALT lymphomas
arise from MALT acquired as a consequence of H. pylori
infection and the bacterial infection plays a crucial role in the
genesis and development of this tumor . H. pylori can be
demonstrated in the gastric mucosa of most cases with gastric
MALT lymphomas . In addition, epidemiological studies
have demonstrated the association between H. pylori infection
and development of gastric lymphoma [24, 25]. Nevertheless,
host immune responses play a less well-defined role in MALT
lymphoma formation as indicated by the fact that only
a minority of H. pylori-infected patients will eventually develop
As with other MZBCL, the cells of PG MALT are typically
CD20 positive and express surface and, to a lesser extent,
cytoplasmic immunoglobulin (Ig) showing light chain
restriction. Most cases express IgM and a few IgA or IgG, but
IgD expression is rare. In ?50% of cases, they aberrantly
express CD43. In addition, MALT lymphomas contain
moderately high concentrations of CD3+ and CD5+ T cells, but
in the majority of cases the lymphoma cells themselves are CD5
Three translocations, t(11;18)(q21;q21), t(1;14)(p22;q32)
and t(14;18)(q32;q21), are specifically associated with MALT
lymphomas and the genes involved have been characterized.
Although these three translocations involve different genes,
they all converge on the activation of the same nuclear factor
Table 1. Distribution of the main histological types (according to the
REAL classification) in the Greek and German study for gastrointestinal
non-Hodgkin’s lymphoma [4, 5]
Histological typeGreek study
Diffuse large B-cell lymphoma
With MALT component
Without MALT component
MALT lymphoma of the marginal zone 48
Mantle cell lymphoma
Peripheral T-cell lymphoma
REAL, Revised European-American Lymphoma; MALT, mucosa-associated
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Volume 19|No. 12| December 2008 doi:10.1093/annonc/mdn525 | 1993
kB (NF-kB) oncogenic pathway . Translocation t(11;18),
very common in gastric MALT lymphomas as well as MALT
lymphomas at other anatomic sites (30% of MALT
lymphomas) , results in a chimeric fusion between AP12
and MALT1 genes [27, 28]. This translocation is not seen in H.
pylori gastritis and its presence is associated with extension of
the disease outside the stomach (regional lymph nodes and/or
distal sites) . The t(11;18)(q21;q21) translocation as well as
the t(1;14)(p22;q32) can identify cases that will not respond to
H. Pylori eradication .
In H. Pylori-associated gastritis and at the early stages of
MALT lymphoma, development antigens expressed by H.
pylori in conjunction with antigen-specific T cells activate the
antigen receptor of polyclonal B cells and lead to the
interaction of BCL10 and MALT1 proteins and consequently
the activation of NF-kB pathway. During the long course of
a chronic infection and persistent antigenic stimulation,
a subclone may acquire one of the MALT lymphoma-specific
translocations and develop a growth advantage. As a result,
constitutive activation of NF-kB pathway occurs
independently of H. pylori infection and the eradication of the
bacterium does not reverse the disease process . The
scoring system proposed by Wotherspoon et al.  reflects
this spectrum of proliferation from polyclonal to monoclonal
High-grade MALT lymphomas are equivalent to DLBCL in
the REAL classification  and they have probably
transformed from low-grade MALT lymphomas as they share
common clone-specific Ig heavy chain gene rearrangements
with low-grade lesions .
treatment of early stage gastric MALT
More than 20 studies have shown a high rate of complete
remission (CR) of low-grade MALT lymphomas confined to
the stomach following eradication of H. pylori with antibiotics
[32–36]. Therefore, antibiotic treatment is a reasonable initial
treatment in low-grade gastric MALT lymphoma provided
thorough hematological and endoscopic follow-up takes place.
Thorough endoscopic follow-up is recommended because
initial diagnostic gastric biopsies do not exclude the coexistence
of aggressive lymphoma which requires cytotoxic
chemotherapy. Breath test 2 months after treatment to confirm
H. pylori eradication and repeat endoscopies with biopsies
every 6 months for 2 years and then annually to document
remission of the lymphoma are recommended. Despite the fact
that eradication of H. pylori may take place within 1 month of
completion of drug therapy, disappearance of lymphoma may
take several months and histologic CR may be delayed up to 18
months. When remission occurs, it appears to be stable. If
relapse occurs, it is usually associated with H. pylori reinfection.
Indications also exist that stage I patients with minimal
histological lymphoma residuals after H. pylori eradication
show a favorable course when treated only by regular follow-up
with endoscopies and multiple biopsies without administration
of oncological therapy, suggesting the potential role of watch
and wait strategy in these patients [37, 38]. In patients with
histological CR, lymphoma clone can be detected by PCR
analysis of the rearranged Ig gene on postremission gastric
Table 2. Comparison of ‘Lugano’ and ‘Paris’ staging system for primary GI lymphomas
Lougano staging system  TNM Paris system  Lymphoma extension
Stage IT1–3 N0 M0 Lymphoma confined to GI tract.
Single primary site or noncontiguous lesions.
Confined to mucosa
Lymphoma infiltrates the submucosa
Lymphoma infiltrates muscularis propria or subserosa
Lymphoma penetrates serosa
Lymphoma extending to abdominal lymph nodes
Involvement of local (paragastric) lymph nodes
Involvement of distant (mesenteric, para-aortic,
paracaval, pelvic, inguinal) lymph nodes
Infiltration of adjacent organs or tissues by direct infiltration
Spread to extraabdominal lymph nodes
Noncontinuous involvement of separate site in
GI tract (e.g. stomach and rectum)
Noncontinuous involvement of other organs
(e.g. tonsils, parotid gland, ocular adnexa, liver and spleen)
or tissues (e.g. peritoneum and pleura)
Bone marrow not involved
Lymphomas infiltrates bone marrow
Presence of systemic symptoms
(fever, night sweats and weight loss >10% BW)
Absence of systemic symptoms
Bulky mass (lesion of 10 cm or more in the longest diameter)
Stage I2: infiltrating the
gastric wall up to the serosa
T1m N0 M0
T1sm N0 M0
T2 N0 M0
T3 N0 M0
T1–3 N1–2 M0
T1–3 N1 M0
T1–3 N2 M0
Stage IV: extranodal involvement
or concomitant supradiaphragmatic
T4 N0–2 M0
T1–4 N3 M0
T1–4 N0–3 M1
T1–4 N0–3 M2
T1–4 N0–3 M0–2 B0
T1–4 N0–3 M0–2 B1
GI, gastrointestinal; TNM, tumor–node–metastasis; BM, body weight.
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1994 | Psyrri et al. Volume 19| No. 12|December 2008
biopsies in 50% of the cases. This group should be observed
closely, whereas long-term negative PCR may indicate cure of
the disease .
therapy of cases refractory to antibiotics
or H. Pylori negative
There are no treatment guidelines for the management of
patients who show unresponsiveness to antibiotics or for the
subset of H. pylori-negative cases. This latter group of patients
usually does not respond to antibiotics. A choice can be made
between conventional therapeutic approaches.
Radiation therapy (RT) alone is a reasonable treatment
option in patients with early-stage (stages I and II) gastric
MALT lymphomas refractory to antibiotics. Two small
prospective series have shown a 100% complete response rate
following RT with a median dose of 30 Gy. The first study by
Yahalom  from Memorial Sloan-Kettering Cancer Center
demonstrated only one treatment failure at a median follow-up
of 18 months, whereas the one from Schechter et al. 
showed no treatment failure at a median follow-up of 27
months. Additionally, Tsang et al.  reported on 85 patients
with MALT lymphoma (17 patients with gastric MALT NHL)
receiving RT alone that up to 90% of patients attained a CR
with excellent 5-year progression free and overall survival (OS)
rates of 98% and 77%, respectively. With the recent evolvement
of CT radiotherapy planning, advanced techniques such as
three-dimensional conformal radiotherapy and intensity
modulated radiotherapy have facilitated the determination of
the clinical target volume, thereby reducing the toxicity that is
related to the irradiation of normal gastric mucosa and of
nearby organs (especially the left kidney). However, side-effects
of RT are encountered, most frequently anorexia, nausea and
vomiting. Although with the standard dose (30–35 Gy), no
delayed toxicity (such as peptic ulcers or GI haemorrhaging)
has been reported; the long-term effects of RT on the structure
and function of the gastric mucosa remain to be clarified.
There is no consensus regarding the role of adjuvant
chemotherapy after antibiotic treatment. The role of
chemotherapeutic agents such as alkylating agents, nucleoside
analogues or combination chemotherapy for gastric MALT
lymphomas refractory to antibiotics has been tested, but only
limited data especially on untreated patients with localized
disease exist to date. Recently, Nakamura et al.  reported
CR rates of 89% after oral monotherapy with
cyclophosphamide 100 mg/day on patients with gastric MALT
NHL, refractory to antibiotic therapy. In this study, the results
were comparable to the results achieved after RT; hence, oral
monotherapy with cyclophosphamide might also be a suitable
second-line therapeutic option after failure of H. pylori
eradication therapy. The role of the translocation t(11;18) for
the prediction of response to chemotherapy is yet under
investigation. Recent data support that for oral alkylating
agents such as chlorambucil or cyclophhosphamide, the
presence of this translocation in gastric MALT NHL is
predictive of resistance . CR rates after 1 and 8 years were
42% and 8% for t(11;18)-positive and 89% for t(11;18)-
negative patients, respectively (P = 0.0003, 8 years). Hence, oral
alkylating agents might only be administered in patients
without the translocation t(11;18). Nucleoside analogue named
cladribine or 2-chlorodeoxyadenosine has been tested in
a phase II study in patients with gastric (n = 19) and no-gastric
MALT NHL at any stage . Patients had to be chemotherapy
naive, not responding to H. pylori eradication therapy in case of
gastric NHL or suffering from relapse after RT. 2-
Chlorodeoxyadenosine was administered at a dose of 0.12 mg/
kg body weight by i.v. infusion over 2 h on days 1–5 and was
repeated every 4 weeks. All patients responded to treatment
after a median number of four cycles, and 84% achieved CR
including all patients with gastric NHL. Three patients with
gastric NHL have relapsed locally after 13, 18 and 22 months
and were salvaged with RT. Grade 3 or 4 toxicity World Health
Organisation (WHO) is observed in 38% of patients including
mainly leukocytopenia, a herpes zoster in one patient and
cardiac toxicity in another. In addition, Streubel et al.  have
shown that the presence of the translocation t(11;18) does not
adversely affect the response to 2-chlorodeoxyadenosine
chemotherapy. Therefore, 2-chlorodeoxyadenosine can be
considered as an effective and relatively safe drug and seems to
be a good therapeutic option for patients with gastric MALT
NHL being H. pylori negative or unresponsive to eradication
The efficacy of rituximab (monoclonal anti-CD20 antibody)
in patients with gastric MALT NHL has not been extensively
evaluated. Martinelli et al.  reported on 27 patients with
gastric MALT NHL, refractory or not eligible for antibiotic
therapy, who were treated with rituximab monotherapy at
doses of 375 mg/m2once weekly for 4 weeks. Forty-six percent
of patients had a pathological and clinical CR and 31% had
a partial response (PR). With a median follow-up of 33
months, only two patients relapsed whereas there was no
association between t(11;18) (q21;21) translocation by FISH
and response to treatment. Nevertheless, extrapolating data
from randomized studies showing survival advantage in
patients with low-grade NHL when rituximab is added to the
treatment, we can assume that rituximab is reasonable
therapeutic option in patients with gastric MALT NHL
refractory to the first-line treatment or in H. pylori-negative
In the past, gastrectomy was the treatment of choice in
patients with PG-NHL. However, the high morbidity rates
associated with this procedure led to attempts to preserve the
organ using radiation and combination chemotherapy
approaches. Aviles et al.  reported the results of a three-arm
randomized trial in patients with gastric MALT lymphomas
treated in Mexico. They randomized 241 patients to surgery
(total gastrectomy) alone versus radiation (30 Gy to the entire
abdomen, increased to 40 Gy for the upper abdomen only)
alone or chemotherapy [three cycles of combination
chemotherapy with cyclophosphamide, doxorubicin,
vincristine and prednisone (CHOP)-21 followed by four cycles
COP-14] alone with median follow-up of 7.5 years. All patients
in the three arms achieved CR. Event free survival (EFS) was
significantly inferior in radiation (52%) and surgery (52%)
arms compared with the chemotherapy arm (87%) (P < 0.01).
The 5-year OS tended to be superior in the chemotherapy-
treated group (87%) versus the surgery (80%) and RT (75%)
arms but this did not reach significance (P = 0.4) probably due
to the lack of power. The authors concluded that chemotherapy
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Volume 19|No. 12| December 2008doi:10.1093/annonc/mdn525 | 1995
is an effective and well-tolerated treatment for patients with
gastric MALT lymphoma. Although this study investigated the
role of surgery versus radiation versus chemotherapy as
primary treatment of gastric MALT lymphoma, it provides
some evidence that combination chemotherapy is more
efficacious and durable than radiation in patients with gastric
MALT lymphoma who have failed H. pylori eradication or for
the subset of H. pylori-negative cases. In addition, in the
German Multicenter Study Group trial, patients with low-grade
gastric lymphomas who were treated with surgery and radiation
or radiation and COP regimen (six cycles) had equal rates of
EFS and 5-year OS (83% and 80%, respectively) . Taken
together, these results indicate that organ preservation with
chemotherapy combined with radiation can yield equal results
to surgery plus radiation in this group of patients.
The addition of rituximab to anthracycline-based
combination chemotherapy has not been extensively tested in
patients with relapsed gastric MALT lymphomas. In a small
retrospective study by Raderer et al. , 26 patients with
relapsed MALT NHL were treated with rituximab plus CHOP
or CNOP. Twenty of 26 patients (77%) achieved a CR and six
patients a PR. Toxic effects were mainly hematological, with
WHO grade leukocytopenia occurring in 20% of patients. With
a median follow-up of 19 months (range 10–45), all patients
were alive: 22 were in ongoing remission, while four relapsed
between 12 and 19 months after treatment. A clinical trial
conducted by the International Extranodal Lymphoma Study
Group is currently evaluating the activity of the combination of
rituximab and chemotherapy in MALT NHL.
On the basis of combination of the published data, we
recommend an algorithm for the treatment of low-grade MALT
lymphomas of the stomach. H. pylori-positive patients with
stage I should have an initial treatment of H. Pylori eradication.
If H. Pylori infection is persistent, reeradication should be
attempted. Close follow-up with upper endoscopy and biopsies
every 3–6 months is recommended. If complete regression of
macroscopic disease is not attained after 12 months, patients
should receive radiation alone or rituximab or single-agent
chemotherapy if RT is contraindicated. These therapies should
be instituted more quickly in patients with progressive disease
after antibiotic treatment. In patients with macroscopic
remission but with minimal lymphoma histological residuals,
watchful waiting with regular endoscopies and multiple
biopsies (every 3 months) should be considered. H. pylori-
negative patients, as well as patients with stage II or/and with
t(11;18) translocation should receive antibiotic treatment in
addition to close follow-up with endoscopy every 3 months.
Combined chemotherapy alone or plus radiation should be
initiated if no regression is seen. Nevertheless, the issue is open
and further studies are needed to determine the optimal
therapy of patients with gastric MALT lymphomas refractory to
treatment of advanced stage gastric
Gastric MALT lymphomas rarely present at advanced stage.
Similar to other categories of indolent lymphomas,
chemotherapy is not curative and asymptomatic patients can be
observed without treatment. Indications for therapy include
candidacy for a clinical trial, symptoms, GI bleeding,
threatened end-organ function, bulky disease, steady
progression and patient preference. Chemotherapy (single-
agent or combination regimens) is the treatment of choice in
most cases . Locoregional RT is utilized in specific cases
such as superior vena cava syndrome. If there is evidence of
recurrence, endoscopy is recommended. Management of
recurrent cases is similar to follicular lymphomas. Platinum
analogues have shown promise .
practice points in primary gastric MALT
? The t(11;18) translocation as well as the translocation
t(1;14)(p22;q32) can identify cases that will not respond to
H. Pylori eradication.
? Antibiotic treatment is a reasonable initial treatment in low-
grade gastric MALT lymphoma provided that thorough
hematological and endoscopic follow-up takes place.
? Thorough endoscopic follow-up is recommended because
initial diagnostic gastric biopsies do not exclude the
coexistence of aggressive lymphoma which requires cytotoxic
? Radiotherapy alone or rituximab or single-agent
chemotherapy should be used for the treatment of patients
who fail to response to antibiotics or for the subset of
H. pylori-negative cases.
DLBCL of the stomach
DLBCL of the stomach is an aggressive lymphoma that might
arise de novo or from MALT lymphoma transformation. This
malignancy constitutes 40%–70% of all gastric lymphomas [4,
5]. High-grade lymphomas bearing the same Ig light chain
restriction and identical rearranged Ig gene with coexistent low-
grade MALT lymphoma represent transformed cases [31, 53].
Foci of DLBCL may be seen in MALT lymphomas but the
extent of this high-grade component varies from a small
proportion of transformed blasts with the indolent MALT
lymphoma to a dominant large cell component with only small
residual foci of MALT lymphoma. The differentiation of the
latter group from de novo large cell lymphomas becomes very
difficult. DLBCLs with germinal center-like phenotype (bcl6-
and CD10 positive and a proportion bcl2 positive) are not
confused with transformed MALT lymphomas. Transformed
MALT lymphomas are CD10- and bcl2 negative and bcl6
positive . In most cases, however, immunophenotype as
well as molecular genetics cannot reliably distinguish
transformed MALT from PG-DLBCL. However, the
differentiation between transformed MALT and de novo PG-
DLBCL is not clinically important since the two entities behave
similarly . PG-DLBCL occurs more frequently in males,
with median age range of occurrence of 50–60 years [4, 5, 56].
Clinical presentation is similar to that of gastric cancer. The
majority of patients report epigastric pain (70% of cases) or
dyspepsia (30%). Weight loss is observed in 40% of patients,
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1996 | Psyrri et al.Volume 19| No. 12|December 2008
more frequently as a result of dyspepsia and less often as a B
symptom. Bleeding and perforation are rare at the time of
diagnosis. No risk factors have been clearly demonstrated in
patients with PG-DLBCL. However, there is some evidence that
atrophic gastritis, especially in the setting of immunodeficiency,
may be a risk factor for this neoplasm .
The role of H. Pylori infection in PG-DLBCL is controversial.
This bacterium is detected in 35% of DLBCL of the stomach,
mainly in cases with concomitant MALT areas (65% versus
15%) . This suggests that most DLBCL may arise from
long-standing H. pylori-associated MALT lymphomas. In
contrast to early reports, recent data have supported that
H. pylori eradication results in durable histological CR in
50%–63% of patients with gastric DLBCL with concomitant
MALT areas . These findings suggest that, at least in the
initial phase, high-grade transformation is not necessarily
associated with the loss of H. pylori dependence.
treatment of DLBCL of the stomach
Treatment of choice for DLBCL irrespective of anatomic site of
the lesion is rituximab plus anthracycline-based combination
chemotherapy: epirubicin, or adriamycin or mitoxantrone
combined with cyclophosphamide, vincristine and prednisone
(CHOP, CEOP or CNOP regimen). Although the impact of the
addition of rituximab to chemotherapy regimens has not been
tested in large clinical trials in patients with PG-DLBCL ,
treatment must include rituximab due to its proven therapeutic
benefit in DLBCL [60, 61]. Complications of chemotherapy
include gastric outlet obstruction and bleeding while gastric
perforation is rare. Therefore, irrespective of the role of
gastrectomy as primary treatment of patients with DLBCL of
the stomach which as explained below remains controversial,
the role of surgical consultant remains essential in the
management of DLBCL of the stomach.
The role of surgery in the management of PG-DLBCL is
controversial. Many previous studies have suggested that
gastrectomy, particularly in stages I and II patients, significantly
improves survival [62–65]. In addition, complications such as
perforation, obstruction and hemorrhage can be prevented or
treated with surgery. However, these complications are rare.
Several studies have shown that patients undergoing
gastrectomy have a better outcome compared with those having
incomplete resection or biopsy alone [66–68]. It is unclear,
however, whether the improved outcome is related to low
tumor burden which allows complete resection, similarly to low
LDH, or the surgery itself. Contrary to the aforementioned
reports, other studies have shown that the extent of surgery
(excision or biopsy) has no impact on outcome of GI
lymphomas [3, 69, 70]. The excellent results obtained with the
use of combination chemotherapy, sometimes combined with
radiation, have challenged the role of gastrectomy in the
management of patients with PG-DLBCL [71, 72]. Some
retrospective and prospective studies suggested that
conservative nonsurgical treatment achieves equal or better
results than gastrectomy (reviewed recently by Ferreri and
Montalban ). In our study, patients treated with surgery
plus chemotherapy had similar OS and disease-free survival
after 38 months of median follow-up with patients treated with
chemotherapy alone . In addition, a small prospective
randomized trial comparing patients with PG-DLBCL treated
with combination chemotherapy alone or with surgical
resection followed by chemotherapy concluded that
gastrectomy is unnecessary (10-year survival rates 96% and
91%, respectively) . However, the question is open and
further prospective trials are required to determine the optimal
management of this disease.
The role of consolidation radiotherapy is debated. In
retrospective studies, the addition of RT was associated with
a lower local relapse rate compared with chemotherapy alone
. In a prospective study, the combination of six cycles of
CHOP-14 followed by involved-field RT (40 Gy) has been
associated with a survival rate at 42 months of 91% .
Further prospective randomized trials are required in order to
answer the question about the role of RT in the treatment of
In addition to chemotherapy, H. pylori eradication with
antibiotic therapy should always be carried out in localized or
extensive PG-DLBCL, especially in cases of PG-DLBCL with
concomitant low-grade MALT component . Although PG-
DLBCL with MALT component appeared to be independent of
the H. Pylori antigen drive, two recent studies showed that 60%
of patients with PG-DLBCL with MALT areas achieved
histological CR after H. Pylori eradication, which have been
maintained after long follow-up [78, 79].
The choice of treatment for patients with relapsed or
refractory disease depends on patient’s age, performance status,
extension of relapse and previous therapies. At present, high-
dose therapy followed by autologous stem-cell transplantation
is the treatment of choice for patients in whom
chemosensitivity to some kind of salvage treatment is still
present. However, only young patients with good performance
status and without comorbidities are candidates for this
therapy. Gastrectomy can be a suitable approach in elderly
patients who experience relapse limited to the gastric wall and
exhibit clear contraindications to chemotherapy. Finally, new
combinations of chemotherapeutic regimens, immunotherapy
and radioimmunotherapy should be tested in prospective phase
II trials on patients with relapsed or refractory PG-DLBCL.
practice points in PG-DLBCL
? The treatment of choice is combination of rituximab plus
chemotherapy with anthracycline-based regimens (CHOP,
CEOP and CNOP).
? The role of gastrectomy is limited in localized disease due to
the similar effectiveness of organ-preserving chemotherapy
treatment, alone or in combination with radiation.
? H. pylori eradication with antibiotic therapy should always be
carried out in localized or extensive disease, especially in cases
with concomitant low-grade MALT component.
In conclusion, the therapeutic approach for patients with PG-
NHL has been revised over the last 10 years. It is widely
Annals of Oncology
Volume 19|No. 12| December 2008 doi:10.1093/annonc/mdn525 | 1997
accepted that MALT lymphomas are mainly treated with H.
pylori-eradicating antibiotics, which can induce lasting
remissions in those cases associated with H. pylori infection.
Conservative treatment with anthracycline-based
chemotherapy alone or in combination with involved-field
RT has replaced gastrectomy as treatment of choice in
patients with DLBCL. Nevertheless, various therapeutic
aspects for PG-NHL are still controversial and several
questions remain unanswered. Among others, the role of
rituximab, consolidation RT as well as H. pylori eradication
in histological aggressive subtypes warrants further
1. Zucca E, Roggero E, Bertoni F, Cavalli F. Primary extranodal non-Hodgkin’s
lymphomas. Part 1: gastrointestinal, cutaneous and genitourinary lymphomas.
Ann Oncol 1997; 8: 727–737.
2. Economopoulos T, Papageorgiou S, Dimopoulos MA et al. Non-Hodgkin’s
lymphomas in Greece according to the WHO classification of lymphoid
neoplasms. A retrospective analysis of 810 cases. Acta Haematol 2005; 113:
3. d’Amore F, Brincker H, Gronbaek K et al. Non-Hodgkin’s lymphoma of the
gastrointestinal tract: a population-based analysis of incidence, geographic
distribution, clinicopathologic presentation features, and prognosis. Danish
Lymphoma Study Group. J Clin Oncol 1994; 12: 1673–1684.
4. Koch P, del Valle F, Berdel WE et al. Primary gastrointestinal non-Hodgkin’s
lymphoma: I. Anatomic and histologic distribution, clinical features, and survival
data of 371 patients registered in the German Multicenter Study GIT NHL 01/92.
J Clin Oncol 2001; 19: 3861–3873.
5. Papaxoinis G, Papageorgiou S, Rontogianni D et al. Primary gastrointestinal non-
Hodgkin’s lymphoma: a clinicopathologic study of 128 cases in Greece. A
Hellenic Cooperative Oncology Group study (HeCOG). Leuk Lymphoma 2006; 47:
6. Nakamura S, Yao T, Aoyagi K et al. Helicobacter pylori and primary gastric
lymphoma. A histopathologic and immunohistochemical analysis of 237 patients.
Cancer 1997; 79: 3–11.
7. Hussell T, Isaacson PG, Crabtree JE, Spencer J. The response of cells from low-
grade B-cell gastric lymphomas of mucosa-associated lymphoid tissue to
Helicobacter pylori. Lancet 1993; 342: 571–574.
8. Chen LT, Lin JT, Tai JJ et al. Long-term results of anti-Helicobacter pylori
therapy in early stage gastric high-grade transformed MALT lymphoma. J Natl
Cancer Inst 2005; 97: 1345–1353.
9. Andriani A, Zullo A, Di Raimondo F et al. Clinical and endoscopic presentation of
primary gastric lymphoma: a multicentre study. Aliment Pharmacol Ther 2006;
10. Wotherspoon A, Doglioni C, Isaacson PG. Low-grade gastric B-cell lymphoma of
mucosa-associated lymphoid tissue (MALT): a multifocal disease. Histopathology
1992; 20: 29–34.
11. Papadaki L, Wotherspoon AC, Isaacson PG. The lymphoepithelial lesion of gastric
low-grade B-cell lymphoma of mucosa-associated lymphoid tissue (MALT): an
ultrastructural study. Histopathology 1992; 21: 415–421.
12. Isaacson PG, Du MQ. Gastrointestinal lymphoma: where morphology meets
molecular biology. J Pathol 2005; 205: 255–274.
13. Economopoulos T, Asprou N, Stathakis N et al. Primary extranodal non-
Hodgkin’s lymphoma of the head and neck. Oncology 1992; 49: 484–488.
14. Bertoni F, Sanna P, Tinguely M et al. Association of gastric and Waldeyer’s ring
lymphoma: a molecular study. Hematol Oncol 2000; 18: 15–19.
15. Elstrom R, Guan L, Baker G et al. Utility of FDG-PET scanning in lymphoma by
WHO classification. Blood 2003; 101: 3875–3876.
16. Alinari L, Castellucci P, Elstrom R et al. 18F-FDG PET in mucosa-associated
lymphoid tissue (MALT) lymphoma. Leuk Lymphoma 2006; 10: 2096–2101.
17. Carbone PP, Kaplan HS, Musshoff K et al. Report of the committee on Hodgkin’s
disease staging classification. Cancer Res 1971; 31: 1860–1861.
18. Rohatiner A, D’Amore 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: 397–400.
19. Rouskone-Fourmerstraux A, Dragosics B, Morgner A et al. Paris staging system
for primary gastrointestinal lymphomas. Gut 2003; 52: 912–913.
20. Isaacson P, Wright DH. Malignant lymphoma of mucosa-associated lymphoid
tissue. A distinctive type of B-cell lymphoma. Cancer 1983; 52: 1410–1416.
21. Harris NL, Jaffe ES, Stein H et al. A revised European-American Classification of
lymphoid neoplasms: a proposal from International Lymphoma Study Group.
Blood 1994; 84: 1361–1392.
22. Wotherspoon AC, Ortiz-Hidalgo C, Falzon MR, Isaacson PG. Helicobacter pylori-
associated gastritis and primary B-cell gastric lymphoma. Lancet 1991; 338:
23. Farinha P, Gascoyne RD. Molecular pathogenesis of mucosa-associated
lymphoid tissue lymphoma. J Clin Oncol 2005; 23: 6370–6378.
24. Doglioni C, Wotherspoon AC, Moschini A et al. High incidence of primary gastric
lymphoma in northeastern Italy. Lancet 1992; 339: 834–835.
25. Parsonnet J, Hansen S, Rodriguez L et al. Helicobacter pylori infection and
gastric lymphoma. N Engl J Med 1994; 330: 1267–1271.
26. 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: 979–985.
27. Dierlamm J, Baens M, Wlodarska I et al. The apoptosis inhibitor gene AP12 and
a novel 18q gene, MLT, are recurrently rearranged in the t(11;18)(q21;q21)
associated with mucosa-associated lymphoid tissue lymphomas. Blood 1999;
28. 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-cell lymphoma of mucsa-assciated
lymphoid tissue. Oncogene 1999; 18: 5785–5794.
29. Liu H, Ye H, Dogan A et al. t(11;18)(q21;q21) is associated with advanced
mucosa-associated lymphoid tissue lymphoma that expresses nuclear BCL10.
Blood 2001; 98: 1182–1187.
30. 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: 39–40.
31. Peng H, Du M, Diss TC et al. Genetic evidence for a clonal link between low and
high-grade components in gastric MALT B-cell lymphoma. Histopathology 1997;
32. Bayerdorffer E, Neubauer A, Rudolph B et al. Regression of primary gastric
lymphoma of mucosa-associated lymphoid tissue type after cure of Helicobacter
pylori infection. MALT Lymphoma Study Group. Lancet 1995; 345: 1591–1594.
33. Roggero E, Zucca E, Pinotti G et al. Eradication of Helicobacter pylori infection in
primary low-grade gastric lymphoma of mucosa-associated lymphoid tissue. Ann
Intern Med 1995; 122: 767–769.
34. Ruskone-Fourmestraux A. Gastrointestinal lymphomas: the French experience of
the Groupe D’etude des Lymphomes Digestifs (GELD). Recent Results Cancer
Res 2000; 156: 99–103.
35. Wundisch T, Thiede C, Morgner A et al. Long-term follow-up of gastric MALT
lymphoma after Helicobacter pylori eradication. J Clin Oncol 2005; 23:
36. Wundisch T, Mosch C, Neubauer A, Stolte M. Helicobacter pylori eradication in
gastric mucosa-associated lymphoid tissue lymphoma: results of a 196-patient
series. Leuk Lymphoma 2006; 47: 2110–2114.
37. Zucca E, Cavalli F. Are antibiotics the treatment of choice for gastric lymphomas?
Curr Hematol Rep 2004; 3: 11–16.
38. Fischbach W, Goebeler ME, Ruskone-Fourmestraux A et al. Most patients with
minimal histological residuals of gastric MALT lymphoma after successful
eradication of Helicobacter pylori can be managed safely by a watch and wait
strategy: experience from a large international series. Gut 2007; 56:
39. Thiede C, Wundisch T, Alpen B et al. Long-term persistence of monoclonal B
cells after cure of Helicobacter pylori infection and complete histologic remission
in gastric mucosa-associated lymphoid tissue B-cell lymphoma. J Clin Oncol
2001; 19: 1600–1609.
40. Yahalom J. MALT lymphomas: a radiation oncology viewpoint. Ann Hematol
2001; 80 (Suppl 3): B100–B105.
Annals of Oncology
1998 | Psyrri et al. Volume 19| No. 12|December 2008
41. Schechter NR, Portlock CS, Yahalom J. Treatment of mucosa-associated Download full-text
lymphoid tissue lymphoma of the stomach with radiation alone. J Clin Oncol
1998; 16: 1916–1921.
42. Tsang RW, Gospodarowicz MK, Pintilie M et al. Localized mucosa-associated
lymphoid tissue lymphoma treated with radiation therapy has excellent clinical
outcome. J Clin Oncol 2003; 21: 4157–4164.
43. Nakamura S, Matsumoto T, Suekane H et al. Long-term clinical outcome of
Helicobacter pylori eradication for gastric mucosa-associated lymphoid tissue
44. Levy M, Copie-Bergman C, Gameiro C et al. Prognostic value of translocation
t(11;18) in tumoral response of low-grade gastric lymphoma of mucosa-
associated lymphoid tissue type to oral chemotherapy. J Clin Oncol 2005; 23:
45. Jager G, Neumeister P, Brezinschek R et al. Treatment of extranodal marginal
zone B-cell lymphoma of mucosa-associated lymphoid tissue type with
cladribine: a phase II study. J Clin Oncol 2002; 20: 3872–3877.
46. Streubel B, Ye H, Du MQ et al. Translocation t(11;18)(q21;q21) is not predictive
of response to chemotherapy with 2CdA in patients with gastric MALT
lymphoma. Oncology 2004; 66: 476–480.
47. Martinelli G, Laszlo D, Ferreri AJ et al. Clinical activity of rituximab in gastric
marginal zone non-Hodgkin’s lymphoma resistant to or not eligible for anti-
Helicobacter pylori therapy. J Clin Oncol 2005; 23: 1979–1983.
48. Aviles A, Nambo MJ, Neri N et al. Mucosa-associated lymphoid tissue (MALT)
lymphoma of the stomach: results of a controlled clinical trial. Med Oncol 2005;
49. Koch P, del Valle F, Berdel WE et al. Primary gastrointestinal non-Hodgkin’s
lymphoma: II. Combined surgical and conservative or conservative management
only in localized gastric lymphoma—results of the prospective German
Multicenter Study GIT NHL 01/92. J Clin Oncol 2001; 19: 3874–3883.
50. Raderer M, Wohrer S, Streubel B et al. Activity of rituximab plus
cyclophosphamide, doxorubicin/mitoxantrone, vincristine and prednisone in
patients with relapsed MALT lymphoma. Oncology 2006; 70: 411–417.
51. Bertoni F, Zouca E. State-of-the-art theraputics: marginal zone lymphomas. J
Clin Oncol 2005; 23: 6415–6420.
52. Raderer M, Wohrer S, Bartsch R et al. Phase II study of oxaliplatin for treatment
of patients with mucosa-associated lymphoid tissue lymphoma. J Clin Oncol
2005; 23: 8442–8446.
53. Chan JK, Ng CS, Isaacson PG. Relationship between high-grade lymphoma and
low-grade B-cell mucosa-associated lymphoid tissue lymphoma (MALToma) of
the stomach. Am J Pathol 1990; 136: 1153–1164.
54. Yoshino T, Omonishi K, Kobayashi K et al. Clinicopathological features of gastric
mucosa associated lymphoid tissue (MALT) lymphomas: high grade
transformation and comparison with diffuse large B cell lymphomas without
MALT lymphoma features. J Clin Pathol 2000; 53: 187–190.
55. Cogliatti SB, Schmid U, Schumacher U et al. Primary B-cell gastric lymphoma:
a clinicopathological study of 145 patients. Gastroenterology 1991; 101:
56. Ullrich A, Fischbach W, Blettner M. Incidence of gastric B-cell lymphomas:
a population-based study in Germany. Ann Oncol 2002; 13: 1120–1127.
57. Freeman C, Berg JW, Cutler SJ. Occurrence and prognosis of extranodal
lymphomas. Cancer 1972; 29: 252–260.
58. Ferreri AJ, Freschi M, Dell’Oro S et al. Prognostic significance of the
histopathologic recognition of low- and high-grade components in stage I-II B-
cell gastric lymphomas. Am J Surg Pathol 2001; 25: 95–102.
59. Wohrer S, Puspok A, Drach J et al. Rituximab, cyclophosphamide, doxorubicin,
vincristine and prednisone (R-CHOP) for treatment of early-stage gastric diffuse
large B-cell lymphoma. Ann Oncol 2004; 15: 1086–1090.
60. Habermann TM, Weller EA, Morrison VA et al. Rituximab-CHOP versus CHOP
alone or with maintenance rituximab in older patients with diffuse large B-cell
lymphoma. J Clin Oncol 2006; 24: 3121–3127.
61. Feugier P, Van Hoof A, Sebban C et al. Long-term results of the R-CHOP study in
the treatment of elderly patients with diffuse large B-cell lymphoma: a study by
the Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol 2005; 23:
62. Economopoulos T, Alexopoulos C, Stathakis N et al. Primary gastric
lymphoma—the experience of a general hospital. Br J Cancer 1985; 52:
63. Azab MB, Henry-Amar M, Rougier P et al. Prognostic factors in primary
gastrointestinal non-Hodgkin’s lymphoma. A multivariate analysis, report of 106
cases, and review of the literature. Cancer 1989; 64: 1208–1217.
64. Tondini C, Giardini R, Bozzetti F et al. Combined modality treatment for primary
gastrointestinal non-Hodgkin’s lymphoma: the Milan Cancer Institute experience.
Ann Oncol 1993; 4: 831–837.
65. Tedeschi L, Romanelli A, Dallavalle G et al. Stages I and II non-Hodgkin’s
lymphoma of gastrointestinal tract. Retrospective analysis of 79 patients and
review of the literature. J Clin Gastroenterol 1994; 18: 99–104.
66. Economopoulos T, Alexopoulos C, Stathakis N et al. Primary gastric lymphoma.
Eur J Cancer 1990; 26: 855.
67. Liang R, Todd D, Chan TK et al. Prognostic factors for primary gastrointestinal
lymphoma. Hematol Oncol 1995; 13: 153–163.
68. Ruskone-Fourmestraux A, Aegerter P, Delmer A et al. Primary digestive tract
lymphoma: a prospective multicentric study of 91 patients. Groupe d’Etude des
Lymphomes Digestifs. Gastroenterology 1993; 105: 1662–1671.
69. Morton JE, Leyland MJ, Vaughan Hudson G et al. Primary gastrointestinal non-
Hodgkin’s lymphoma: a review of 175 British National Lymphoma Investigation
cases. Br J Cancer 1993; 67: 776–782.
70. Salles G, Herbrecht R, Tilly H et al. Aggressive primary gastrointestinal
lymphomas: review of 91 patients treated with the LNH-84 regimen. A study
of the Groupe d’Etude des Lymphomes Aggressifs. Am J Med 1991; 90:
71. Willich NA, Reinartz G, Horst EJ et al. Operative and conservative management of
primary gastric lymphoma: interim results of a German multicenter study. Int J
Radiat Oncol Biol Phys 2000; 46: 895–901.
72. Coiffier B, Salles G. Does surgery belong to medical history for gastric
lymphomas? Ann Oncol 1997; 8: 419–421.
73. Ferreri AJ, Montalban C. Primary diffuse large B-cell lymphoma of the stomach.
Crit Rev Oncol Hematol 2007; 63: 65–71.
74. Aviles A, Nambo MJ, Neri N et al. The role of surgery in primary gastric
lymphoma: results of a controlled clinical trial. Ann Surg 2004; 240: 44–50.
75. Ferreri AJ, Cordio S, Ponzoni M, Villa E. Non-surgical treatment with primary
chemotherapy, with or without radiation therapy, of stage I-II high-grade gastric
lymphoma. Leuk Lymphoma 1999; 33: 531–541.
76. Koch P, Probst A, Berdel WE et al. Treatment results in localized primary gastric
lymphoma: data of patients registered within the German multicenter study (GIT
NHL 02/96). J Clin Oncol 2005; 23: 7050–7059.
77. Raderer M, Chott A, Drach J et al. Chemotherapy for management of localised
high-grade gastric B-cell lymphoma: how much is necessary? Ann Oncol 2002;
78. Morgner A, Miehlke S, Fischbach W et al. Complete remission of primary high-
grade B-cell gastric lymphoma after cure of Helicobacter pylori infection. J Clin
Oncol 2001; 19: 2041–2048.
79. Chen LT, Lin JT, Shyu RY et al. Prospective study of Helicobacter pylori
eradication therapy in stage I(E) high-grade mucosa-associated lymphoid tissue
lymphoma of the stomach. J Clin Oncol 2001; 19: 4245–4251.
Annals of Oncology
Volume 19|No. 12| December 2008doi:10.1093/annonc/mdn525 | 1999