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.
All rights reserved. For permissions, please email: email@example.com
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
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