Gastrointestinal follicular lymphoma: review of the literature
Shuji Yamamoto•Hiroshi Nakase•Kouhei Yamashita•Minoru Matsuura•
Mariko Takada•Chiharu Kawanami•Tsutomu Chiba
Received: 9 October 2009/Accepted: 23 November 2009/Published online: 20 January 2010
? Springer 2010
is a relatively rare disease, accounting for only 1%-3.6% of
gastrointestinal non-Hodgkin’s lymphoma. Although the
duodenum and terminal ileum are considered to be the
most common sites of origin, the development of wireless
capsule endoscopy and double-balloon enteroscopy has
increased the detection of GI-FL in every part of the small
intestine. Approximately 70% of patients with GI-FL are
estimated to have multiple lesions throughout the entire
gastrointestinal tract. FL is a low-grade lymphoma that
usually develops very slowly. If the lymphoma causes no
symptoms, immediate treatment may not be necessary.
Standard therapy has not yet been established for GI-FL,
but chemotherapy, radiotherapy, monoclonal antibody
therapy, or a combination of these therapies, is sometimes
performed based on the therapeutic regimens for nodal FL.
Regimens including conventional chemotherapy with
rituximab, which achieve high response rates in nodal FL,
are commonly used for GI-FL. The long-term clinical
Gastrointestinal follicular lymphoma (GI-FL)
outcome of GI-FL is unclear. The results of a few series on
the long-term outcomes of patients with GI-FL treated with
conventional therapy indicate a median relapse-free time
ranging from 31 to 45 months. On the other hand, in
patients with GI-FL who were followed without treatment,
the median time to disease progression was 37.5 months.
Thus, whether to initiate aggressive therapy or whether to
continue watchful waiting in patients with GI-FL is a
information that will lead to the establishment of a standard
Multiple lymphomatous polyposis
Follicular lymphoma ? Gastrointestinal tract ?
Follicular lymphoma (FL) is one of the most common
subtypes of non-Hodgkin’s lymphoma (NHL) in the Wes-
tern world, although its incidence may be lower in some
parts of the world such as Asia . Most cases of FL are
initially detected in the lymph nodes, and involvement of
extranodal sites usually occurs only as a result of dissem-
inated nodal disease . The gastrointestinal (GI) tract is
the most common site of extranodal NHL, accounting for
30%-40% of all primary extranodal NHL [3, 4]. The
histologic subtypes in most primary GI-NHL are mucosal-
associated lymphoid tissue (MALT) lymphoma or high-
grade B-cell lymphoma [5–8]. GI-FL is rare, and the
frequency of this entity accounts for 1%-3.6% of GI-NHL
[8–10]. The diagnosis, prognosis, and treatment of GI-FL
remain largely unknown because of its rare frequency.
In this article, the clinical, biologic, and endoscopic
S. Yamamoto ? H. Nakase (&) ? M. Matsuura ? T. Chiba
Department of Gastroenterology and Hepatology,
Graduate School of Medicine, Kyoto University,
54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
Japan Society for the Promotion of Science, Tokyo, Japan
Department of Hematology and Oncology,
Graduate School of Medicine, Kyoto University, Kyoto, Japan
M. Takada ? C. Kawanami
Department of Gastroenterology, Kobe City Medical Center
General Hospital, Kobe, Japan
J Gastroenterol (2010) 45:370–388
characteristics, as well as the outcomes of these lymphomas
are reviewed, based on the literature and our experience.
To our knowledge, 244 cases of primary GI-FL have been
reported with precise descriptions in the English-language
literature [2, 8, 11–57]. The clinical features of 249 GI-FLs,
including the 244 reported cases and 5 unpublished cases
that we experienced, are summarized in Table 1.
The median age of patients at diagnosis of GI-FL is
56 years (range, 26–81 years), similar to that of nodal FL
[58, 59]. In several case series of GI-FL, a female pre-
dominance was observed [8, 11, 12], but other case series
have demonstrated an equal sex distribution in GI-FL [15–
18]. Sato et al. , who reported the largest case series of
GI-FL, described an equal sex distribution in GI-FL. Based
on the available data of all reported cases, there is an equal
sex distribution (122 females and 124 males), which is
similar to the sex distribution of nodal FL.
In contrast to the geographic distribution of nodal FL
, of the 249 cases of GI-FL, almost 50% (120) are
Japanese cases [8, 13, 14, 17, 19–39]. This geographic
predominance may be due to the higher frequency of
endoscopic examination in Japan compared with that in
other countries, because 50 (84.7%) of the 59 patients with
GI-FL in Japan, whose clinical symptoms were available,
presented with no symptoms or only vague GI symptoms,
while only 29 (32.2%) of 90 patients from other countries
In most of the asymptomatic patients with GI-FL, the
lesions were incidentally detected during routine esopha-
gogastroduodenoscopy (EGD). Of 150 patients whose
clinical symptoms at presentation are described in the lit-
erature, 65 (43.3%) were asymptomatic and 14 (9.3%)
complained of vague GI symptoms such as abdominal
discomfort or heartburn.
Abdominal pain was present in 43 of 150 patients
(28.7%). Symptoms of intestinal obstruction, such as nau-
sea and vomiting, were present in 12 (8.0%) and symptoms
of intestinal bleeding, such as tarry stool or hematochezia,
were present in 9 (6.0%). Intestinal obstructions usually
occurred in patients with small-intestinal lesions, whereas
bleeding was observed mostly in patients with colorectal
lesions (Table 2). In some cases, patients with GI-FL have
a protein-losing enteropathy [16, 22, 40–43].
In GI-FL, most cases are classified using the Ann Arbor
staging system  or the Lugano staging classification of
GI tract lymphoma, which is a modified version of the Ann
Arbor staging system for GI-NHL  (Table 3).
Whereas most patients with nodal FL have systemic
disease (i.e., stage III or IV) at the time of diagnosis ,
of 193 GI-FL patients with available clinical stage data,
128 (66.3%) were at stage I and 52 (26.9%) were at stage
II. Bende et al.  and Takata et al.  have speculated
that the low tendency of GI-FL to disseminate outside the
GI tract indicates that it is a distinct entity that originates
from local antigen-responsive B cells in the intestinal
mucosa. Bende et al.  demonstrated that GI-FLs
expressed alpha4beta7 integrin, a well-defined mucosal
homing receptor not expressed in nodal FLs. In addition,
GI-FL has a higher frequency of grade 1 lymphoma than
nodal FL (see ‘‘Histologic grading’’). The higher ratio of
localized disease in GI-FL, however, may be due to the
definition of GI lymphoma rather than to different tumor
cell origins, because cases with both intestinal and massive
extraintestinal lesions are excluded from primary GI-FL
(see ‘‘Definition of primary GI lymphoma’’).
On the other hand, GI-FL can involve regional lymph
nodes even in cases in which the primary lesion involves
only the mucosal or submucosal layer [8, 28, 33, 44, 46].
GI-FL tends to involve only regional lymph nodes,
although it occasionally disseminates outside the GI tract
Table 1 Clinical features of patients with GI-FL
Median age (years)56
Male 124 (49.8%)
Unknown 3 (1.2%)
Vague GI symptoms14
Nausea and/or vomiting12
Melena or rectal bleeding9
GI gastrointestinal, FL follicular lymphoma
J Gastroenterol (2010) 45:370–388 371
and its regional lymph nodes. Yoshino et al.  have
suggested that this discrepancy is likely a result of the
intricate muscle layer structures around the ampulla of
Vater, because most intramural FL with regional lymph
node dissemination involves this location [8, 28, 33].
Disease distribution in the GI tract
GI-FL may infiltrate unifocally or multifocally, and disease
distribution is very important for deciding therapy, i.e.,
radiation therapy may be effective for unifocal local dis-
eases and rituximab therapy with or without chemotherapy
may be required for multifocal diseases. A relatively large
case series reported that GI-FL predominantly involved the
duodenum, especially around the ampulla of Vater, or the
terminal ileum unifocally. In the series reported by Sato
et al. , 40 of 52 cases of extranodal FL (a number of
cases with GI-FL were not described) arose in the duode-
num, and in another series reported by Shia et al. ,
duodenal FL accounted for 10 of 26 cases of FL of the GI
tract, while Le Brun et al.  reported that 55% of the
lymphomas occurred in the small intestine, where they
showed a predilection for the terminal ileum. Damaj et al.
 reported that the most frequent site of involvement
was the small intestine, with a predilection for the ileum
and ileocecal region. Huang et al.  reported that the
most frequent site was the ileum (7 of 13 cases; 54%), with
4 tumors in the terminal ileum.
On the other hand, some cases of GI-FL have lesions
resembling multiple lymphomatous polyposis (MLP). MLP
is characterized by numerous polypoid lesions (Fig. 1)
involving long segments of the GI tract, and it is a very rare
entity, accounting for 2% of primary GI lymphomas .
Although first recognized in the 19th century by Cruveil-
hier,  malignant lymphoma that presented as multiple
small nodules affecting the long segment of the GI tract had
been paid little attention until 1961 when Cornes referred to
this disease entity as ‘‘multiple lymphomatous polyposis’’
. MLP was initially considered to be a typical feature of
mantle cell lymphoma (MCL) , but later studies indi-
cated that MLP comprised a heterogeneous group of
neoplasms, including MCL, FL, and MALT lymphomas
[20, 67]. Since Le Brun et al.  reported that 5 of 31 cases
(16.1%) of GI-FL had a multiple polypoid appearance,
Table 2 Clinical symptoms according to GI tract site
No symptomsVague GI symptoms Abdominal pain Nausea and/or vomitingMelena DiarrheaOthers
Esophagus0 case0 case1 case 0 case0 case1 case0 case
Stomach1 case 0 case 4 cases 0 cases0 case 1 case0 case
Duodenum 53 cases13 cases 13 cases2 cases0 case1 case 4 cases
Location unknown0 case 0 case2 cases 5 cases0 case 0 case0 case
Jejunum18 cases 2 cases7 cases 4 cases 1 case3 cases2 cases
Ileum 14 cases3 cases 10 cases4 cases2 cases 3 cases1 case
Colon 3 cases0 case 3 cases 0 case6 cases2 cases 0 case
Rectum 3 cases0 case1 case1 case0 case1 case0 case
Location unknown0 case0 case12 cases0 case0 case3 cases6 cases
Total65 cases14 cases43 cases12 cases9 cases8 cases12 cases
Table 3 Lugano staging
classification of gastrointestinal
tract lymphoma 
Stage I = tumor confined to gastrointestinal (GI) tract
Stage primary site or multiple, noncontiguous lesions
Stage II = tumor extending into abdomen from primary GI site
II1: local (paragastric in cases of gastric lymphoma and paraintestinal for intestinal lymphoma)
II2: distant (mesenteric in the case of an intestinal primary; otherwise paraaortic, paracaval, pelvic,
Stage IIE = penetration of serosa to involve adjacent organs or tissues [enumerate actual site of
involvement, e.g., IIE (pancreas), IIE (large intestine), IIE (post intestinal wall)]
Where there is both nodal involvement and penetration involving adjacent organs, the stage is denoted
using both a subscript (1 or 2) and E, e.g., II1E (pancreas)
Stage IV = disseminated extranodal involvement, or a GI tract lesion with supradiaphragmatic nodal
372 J Gastroenterol (2010) 45:370–388
several case series on GI-FL have demonstrated that
15.0%-46.2% of GI-FL has MLP aspects [12, 16, 18]. In
these reports, however, the whole GI tract was not evaluated
in all cases. Because MLP involves the long segment of the
GI tract and is often discontinuous [23, 65], the frequency of
GI-FL cases with MLP may actually be higher than that in
these reports. Two innovative methods to observe the entire
small intestine were recently introduced: wireless capsule
endoscopy (WCE) and double-balloon enteroscopy (DBE).
Both modalities allow high-resolution visualization of the
whole small intestine (see ‘‘Endoscopic examination’’). At
present, there are 3 case series of GI-FL in which the whole
GI tract was examined using EGD, colonoscopy, and DBE.
In these reports, the proportion of GI-FL with involvement
at two or more sites of the GI tract was much higher than
that in previous reports on GI-FL. Nakamura et al. 
reported that 4 of 5 cases (80%) of GI-FL presented with
multiple polypoid lesions resembling MLP in long seg-
ments of the jejunum or the ileum. In a case series by
Kodama et al. , DBE showed new lesions in the jejunum
or the ileum in 8 of 11 patients (73%) in whom GI-FL was
detected in the duodenum with EGD. Higuchi et al. 
reported that jejunoileal FL lesions were detected with DBE
in 6 of 7 patients (85.7%) with FL in the duodenum.
Data on the disease distribution of GI-FL, based on the
English-language literature and our unpublished cases, are
summarized in Table 4. Before the introduction of WCE
and DBE, it was reported that most GI-FLs were unifocal
(176 of 216 cases; 81.5%) and the most frequent site was
the duodenum (95 cases; 54.0%) followed by the ileum
including the terminal ileum (28 cases; 15.9%). On the
other hand, in 33 patients with GI-FL where the entire
intestine was examined with endoscopy, including WCE or
DBE, 24 patients (72.7%) suffered from GI-FL with mul-
tifocal involvement, and the proximal small intestine
including the duodenum and the jejunum was the most
frequent site of invasion.
Although there is only a small number of cases of GI-FL
in which WCE or DBE was performed, the frequency of
GI-FL with long segmental GI tract involvement appears
to be much higher than previously reported. Further
Fig. 1 Endoscopic findings of gastrointestinal follicular lymphoma
(GI-FL) in a 52-year-old man. Double-balloon enteroscopy (DBE)
revealed multiple confluent polypoid lesions over approximately
50 cm of the ileum proximal to the ileocecal valve 
Fig. 2 Endoscopic findings of GI-FL in a 57-year-old woman. DBE
demonstrated multiple yellow-whitish nodules of various densities in
the duodenum and jejunum 
J Gastroenterol (2010) 45:370–388373
investigation with WCE or DBE will be useful for accu-
rately evaluating the disease distribution of GI-FL.
The diagnosis of primary GI-FL consists of two aspects.
One is to diagnose FL as a clinicopathologic subset, and
the other is to judge whether lymphoma arises from the GI
tract or whether it involves the GI tract as a result of dis-
semination from the primary site.
Definition of primary GI lymphoma
It is not always possible to determine the primary site of
origin of lymphoma involving the GI tract, especially in
cases with both GI and extra-GI involvement. There are
two possibilities of GI involvement of lymphoma cells.
First, lymphoma arising from regions other than the GI
tract presents in the GI tract with an advanced stage of
generalized disease. Second, primary GI lymphomas can
disseminate and involve lymph nodes or other extraintes-
tinal sites. At present, there is no way to distinguish
whether the GI tract is the primary site or a secondary
site representing an advanced stage of FL involving the GI
There are several definitions of primary GI lymphoma
and at least two of them are widely used. One is the defi-
nition by Dawson et al.  put forth in 1961 that restricts
GI lymphoma as a localized disease without involvement
of peripheral or mediastinal lymph nodes, liver, or spleen.
The other is the definition by Lewin et al. , which
extends to a wider range of presentations and requires that
patients exhibit GI symptoms or a predominant lesion with
or without extraintestinal lesions. In most case series of GI-
FL, the definition by Lewin et al. was applied and cases
with massive extraintestinal lesions were excluded from
primary GI-FL [11, 12, 15–17].
Modality of endoscopic examination
Endoscopic examinations allow for direct observation and
biopsy of the GI tract, and biopsy specimens can be sub-
jected to morphologic evaluation as well as immunohisto-
chemical evaluation and molecular analysis. This modality
is essential for diagnosing lymphoma, defining the extent
of bowel involvement, and assessing the efficacy of treat-
ment. However, it is very difficult to observe the entire
small intestine with conventional endoscopy, including
EGD, colonoscopy, and push enteroscopy. The recent
development of WCE and DBE has enabled observation of
the entire GI tract.
WCE, first reported by Iddan et al. , transmits
images at a rate of two frames per second for more than
8 h, permitting the acquisition of more than 50 000 images
. The DBE system developed by Yamamoto et al. 
in 2003 enables deep insertion of an endoscope to the small
intestine by preventing overstretching of the intestinal tract
with an attachable balloon at its tip and a soft overtube with
another balloon at the distal end . These methods allow
for detailed observation of the mucosa of the deep small
intestine and have provided new data regarding the distri-
bution of GI-FL (see ‘‘Disease distribution in GI tract’’).
WCE is a noninvasive outpatient procedure; sedation is
unnecessary and there is no risk of exposure to X-rays.
On the other hand, DBE can be used to obtain biopsy
Table 4 Disease distribution of GI-FL
SiteWCE or DBE was
Esophagus n.d.3 cases n.d. n.d.
Stomach 16 cases9 cases n.d. n.d.
Duodenum 95 cases23 cases6 cases 20 cases
Location unknown18 cases 8 cases n.d. n.d.
Jejunum 5 cases14 cases 2 cases 21cases
Ileum (involved terminal ileum)28 cases (11 cases) 20 cases (13 cases)1 case (n.d.) 11 cases (3 cases)
Colon 11 cases18 cases n.d. n.d.
Rectum3 cases 9 cases n.d.1 case
Total176 cases40 cases9 cases24 cases
WCE wireless capsule endoscopy, DBE double- balloon enteroscopy, n.d. not described
374J Gastroenterol (2010) 45:370–388
specimens of the small intestine far from the mouth or anus
and to perform endoscopic therapeutic interventions, which
cannot be done with WCE. Therefore, WCE appears to be
suitable for screening examinations and for assessing
treatment efficacy, but DBE is recommended for cases in
which histologic evaluation is necessary or intestinal ste-
nosis is suspected.
Characteristic endoscopic findings
For 183 of 249 cases of GI-FL, a precise description of the
endoscopic findings is available, and these are summarized
in Table 5. In 95 of these cases, endoscopic findings rep-
resented small whitish polypoid, confluent or scattered
lesions or nodules, with a 1- to 2-mm-diameter (Figs. 1, 2a,
b), described as ‘‘multiple polypoid lesions’’, ‘‘multiple
whitish small polyps’’, ‘‘dense and numerous sessile pol-
yps’’, ‘‘yellow-whitish multiple granules’’, or ‘‘multiple
nodular lesions’’. Magnifying endoscopic examination
revealed that these whitish small nodules were enlarged
and fused villi and that the mucosa of these lesions had a
normal appearance, which was suggestive of a subepithe-
lial or submucosal lesion (Fig. 3) [23, 25, 36, 38]. Endo-
scopic ultrasonography reveals thickening of the mucosal
and submucosal layers of the intestinal wall with multiple
hypoechoic granules corresponding to the lesions [19, 25,
26, 44]. These findings suggest that each granule is an
enlarged neoplastic follicle that consists of lymphoma cells
in the lamina propria, which has been confirmed with
histologic examination (Fig. 4a–d). Aggregation of such
nodules can be unifocal or multifocal throughout the entire
GI tract (see ‘‘Disease distribution in the GI tract’’) and is
characteristic of lymphoid hyperplasia and low-grade B
cell lymphoma, including MALT lymphoma with follicular
colonization, FL, and MCL. In some cases, macroscopic
findings alone are not sufficient to distinguish between
these disease subsets  (Fig. 5), and pathologic exam-
inations, immunohistochemical staining, and molecular
analysis are necessary in such cases. Because the prognoses
is very important to establish a differential diagnosis of these
diseases. Therefore, obtaining biopsy specimens for histo-
staining and molecular analysis, is strongly recommended
when the above characteristic findings are observed.
The second most common finding is a mass lesion with
or without ulceration (38 cases). Mass lesions sometimes
present with a submucosal tumor-like appearance (Figs. 6a,
b, 7a). In approximately 50% of cases of GI-FL with a
mass lesion, however, multiple nodular lesions are
observed at other sites in the GI tract (Fig. 7b). Therefore,
in most cases of GI-FL, multiple nodular lesions might be
observed in the early stage.
Regarding frequent endoscopic findings in each site of
GI tract, endoscopy usually reveals multiple polypoid
lesions in the duodenum, jejunum, ileum, and colon.
Detailed macroscopic findings are available for only 2 of
13 cases reported as primary gastric FL [21, 37]. In both
cases, the macroscopic appearance of FL was submucosal
tumor-like (Fig. 6a, b) and could not be distinguished from
the other subtypes of GI lymphoma, especially diffuse
large B-cell lymphoma, which is one of the most common
types of high-grade gastric lymphoma. Rectal lesions of
GI-FL sometimes present as a single elevated mass like a
polyp . GI-FL rarely involves the esophagus and there
are only 3 cases in which an esophageal lesion was
observed [20, 22] and in all cases the esophageal lesion
presented as a part of MLP.
Pathology and biology
GI tract and skin are reported to be the most common sites
of primary extranodal FL . Primary cutaneous FL is
considered to be a distinct entity from nodal FL because of
the lack of t(14;18)(q32;q21) and the relatively favorable
response to treatment [72–75], although FL in this site
shares some features with nodal FL, such as cell mor-
phology and growth pattern. These findings raise the
Table 5 Macroscopic findings
Mass lesion with
or without ulcer
Esophagus 3 cases0 case 0 case0 case
Stomach 4 cases 10 cases 0 case1 case
Duodenum 119 cases5 cases6 cases3 cases
Location unknown 12 cases15 cases 0 case0 case
Jejunum30 cases 5 cases 0 case 0 case
Ileum22 cases4 cases 0 case1 case
Colon21 cases 1 case0 case 0 case
Rectum6 cases 1 case 1 case 0 case
J Gastroenterol (2010) 45:370–388 375
possibility that FL arising in the GI tract can be distin-
guished from FL normally found in lymph nodes as con-
sidered in cutaneous FL. In conclusion, the morphologic
features, immunophenotype, and presence of t(14;18)
(q32;q21) suggest that primary GI-FL may be more closely
related to nodal FL than to cutaneous FL or other primary
GI lymphoma, although some reports on GI-FL have
emphasized the differences between GI-FL and nodal FL
[18, 45, 63].
cannot be distinguished from those of nodal FL . In the
typical GI-FL case, the follicles are approximately the
same size as a mature germinal center, uniform in size,
closely packed, and lacking a mantle zone, presenting in
the lamina propria of the intestinal mucosa at the early
stage (Fig. 4a) and transmural at an advanced stage. The
centrocytes, which are usually less than twice the size of
small lymphocytes and whose nuclei are irregular , and
centroblasts, which are usually three to four times the size
of small lymphocytes and whose nuclei are round but may
be irregular , of GI-FL are identical to those of normal
germinal centers. A starry-sky pattern with phagocytic
histiocytes is usually absent in GI-FL , as well as in
nodal FL .
In most cases of GI-FL, the tumor cells do not infiltrate
and destroy the gland epithelium, i.e., there is no
The morphologic features of GI-FL
Fig. 3 Endoscopic findings of GI-FL in a 57-year-old woman.
Esophagogastroduodenoscopy (EGD) showed multiple whitish gran-
ules around the major duodenal papilla. Magnified endoscopic view
revealed that the white granules comprised enlarged and fused villi
Fig. 4 Histologic findings of GI-FL with multiple polypoid lesions in
a 75-year-old woman with duodenal FL. Histologic evaluation of these
granules revealed enlarged neoplastic follicles in the lamina propria of
the duodenum. Lymphoepithelial lesions were absent. H&E, 940 (a).
The lymphoid follicles comprised predominantly unvarying small-
cleaved cells. H&E, 9200 (b). Immunohistochemical staining for both
CD10 (c) and bcl-2 (d) was positive. (c) 940 (d) 9100. The diagnosis
was FL, grade1 according to the WHO classification
376 J Gastroenterol (2010) 45:370–388
lymphoepithelial lesion, which is one of the characteristic
findings of MALT lymphoma. Tzankov et al. , how-
ever, reported a case of gastric FL in which a lymphoepi-
thelial lesion was observed, and Takeshita et al. 
reported that lymphoepithelial lesions occurred in 2 of 12
CD10-positive diffuse large-cell lymphomas of the stom-
ach that had a germinal center B-cell phenotype. Thus, the
presence of a lymphoepithelial lesion may not exclude the
possibility of FL, especially in gastric lymphoma.
nodal FL, FL is categorized into three grades based on the
criteria of Berard and Mann, according to the number
of centroblasts (large nucleolated cells) per high-power
field. In nodal FL, several studies suggest that this grading
is a good predictor of prognosis [79, 80], and grade 3b FL
tends to behave similarly to de-novo diffuse large B-cell
lymphoma, with earlier relapses and a shorter survival .
Frequencies of grade 1, grade 2, and grade 3 in GI-FL are
84.4%, 11.3%, and 4.3%, respectively (Table 6), while
those of grade 1, grade 2, and grade 3 in nodal FL are 40%-
60%, 25%-35%, and approximately 20%, respectively .
This may be one of the reasons why GI-FL tends to be
detected at an earlier stage and have a better overall sur-
vival rate than nodal FL (see ‘‘Clinical stage’’ and ‘‘Prog-
nosis of GI-FL’’).
In most cases of GI-FL as well as
In GI-FL, as well as nodal FL, tumor cells are positive for
pan-B-cell antigens, including CD19, CD20, and CD22,
and negative for CD5 and cyclin D1 , which are
characteristically expressed in MCL and small lymphocytic
lymphoma/chronic lymphocytic leukemia . Immuno-
histochemical staining for CD10 and bcl-2 is useful for
distinguishing FL from lymphoid hyperplasia, MALT
lymphoma, or MCL . Both CD10 and bcl-2 are
expressed in approximately 90% of cases of GI-FL in
which expression of both CD10 and bcl-2 were evaluated
(Table 7; Fig. 4c, d), while normal germinal center cells
express CD10 but not bcl-2 (Fig. 5d, e). MCL expresses
neither CD10 nor bcl-2, and MALT lymphoma is negative
for CD10 and occasionally positive for bcl-2 .
Bende et al.  demonstrated that GI-FL expressed
alpha4beta7 integrin, a well-defined mucosal homing
receptor, and surface IgA, in contrast to nodal FLs, and
speculated that GI-FL is a distinct entity that originates
from local antigen-responsive B cells in the intestinal
mucosa. No other reports, however, have confirmed that
GI-FL expresses alpha4beta7 integrin. In addition, only 1
of 23 other cases in which the surface immunoglobulin of
tumor cells was examined expressed IgA, and GI-FL most
often expressed surface IgM, followed by IgD (Table 7)
[16, 19, 22, 34, 46, 47], similar to nodal FL. Therefore,
further evaluation is necessary to elucidate whether or
not GI-FL has a different immunophenotype, including
alpha4beta7 integrin and surface immunoglobulin, com-
pared to nodal FL.
In 70%-95% of nodal FL, t(14;18)(q32;q21), which causes
a fusion of BCL2 with the immunoglobulin heavy chain
joining region and prevents the normal switching off of
BCL2, is present [83–85]. On the other hand, most primary
cutaneous FL lacks t(14;18)(q32;q21) [72–75]. Thus, in
cases of GI-FL, the presence of this chromosomal rear-
rangement is examined with Southern blotting, polymerase
chain reaction (PCR) (Figs. 7c, 8), or fluorescence in situ
hybridization (FISH) (Fig. 7d).
Southern blotting, PCR, and FISH demonstrated the
presence of an IgH/BCL2 rearrangement in 60%, 57.1%,
and 72% of GI-FLs, respectively (Table 8), the same fre-
quency as that in nodal FL.
PCR analysis for GI-FL seems to be less sensitive than
FISH analysis, as described for nodal FL [86–89]. In all
cases in which t(14;18)(q32;q21) was not detected by PCR
analysis, the breakpoint used for diagnosis was a major
break region (MBR) , at which the breakpoint is
located in only 50%-60% of nodal FL [86, 91], and other
breakpoints, including the minor cluster region (mcr), 3’
BCL2, 5’mcr, and intermediate cluster region (icr) [92–95]
were not evaluated. Therefore, in such cases additional
PCR analysis using primers for other BCL2 breakpoints or
FISH analysis may be more sensitive.
FISH and PCR analysis can be performed on fresh,
frozen, or fixed paraffin-embedded material . In addi-
tion, FISH analysis can demonstrate IgH/BCL2 rearrange-
ment regardless of the location of the BCL2 breakpoint and
its probes do not require absolute sequence complemen-
tarity for detecting the rearrangement . In both nodal
FL  and GI-FL, FISH analysis seems to be superior to
PCR analysis in detecting t(14;18)(q32;q21) (Table 8).
Taken together, the presence of t(14;18)(q32;q21) in
GI-FL suggests that primary GI-FL is more closely related
to nodal FL than cutaneous FL and demonstrates that the
IgH/BCL2 rearrangement is useful for diagnosing not only
nodal FL but also GI-FL, with equivocal morphologic and
immunophenotypic findings. Given its superior diagnostic
sensitivity, FISH should be considered as an initial diag-
nostic method to detect t(14;18)(q32;q21) or as an alterna-
tive method for cases that are negative with PCR, which is a
less expensive and faster technique to perform than FISH.
Therefore, for the diagnosis of GI-FL, biopsy specimens for
fixation with formalin and for FISH or PCR analysis should
be obtained for higher diagnostic sensitivity.
J Gastroenterol (2010) 45:370–388377
Takata et al.  reported that duodenal FL cells
showed accumulation of somatic hypermutation and
ongoing mutations in spite of the lack of activation-induced
cytidine deaminase expression and their follicular dendritic
cell network formation, which is similar to neoplastic
marginal zone-like B cells. In addition, these authors
demonstrated that duodenal FL had a restricted usage of
variable region of immunoglobulin heavy chain gene (VH).
Duodenal FL in their series had a higher usage of VH4 and
VH5 than nodal FL, and VH4-34 and VH5-51 were detected
in many of these cases. They speculated that these findings
could indicate that the lymphoma cells are derived from B
Fig. 5 Endoscopic and c-e histologic findings of lymphoid hyper-
plasia in a 61-year-old woman. EGD showed multiple polypoid
lesions in the duodenal bulb that resembled GI-FL lesions (a, b).
Biopsy revealed lymphoid follicles with normal architecture in the
lamina propria of the duodenum. H&E, 940 (c). Immunohistochem-
ical staining of germinal center cells was weakly positive for CD10
(d), but negative for bcl-2 (e). (d) 940, (e) 940. The diagnosis was
378 J Gastroenterol (2010) 45:370–388
cells reacting with specific antigens, as in the case of
MALT lymphoma, which develops from chronic inflam-
mation such as Helicobacter pylori -related gastritis.
Accurate staging of GI-FL is important because durable
remissions, and in some cases cures, can be achieved with
surgical resection or external-beam radiotherapy of the
affected area in patients with localized disease (see ‘‘Gas-
trointestinal follicular lymphoma treatment’’).
Staging procedures for GI-FL are almost the same as those
routinely used for nodal FL. In addition to a staging
workup, however, including an accurate physical exami-
nation, complete hematologic and biochemical examina-
tions, total-body computerized tomography (CT), and bone
marrow aspirate and biopsy, evaluation of the whole GI
tract using EGD, colonoscopy, and total enteroscopy (i.e.,
WCE or DBE) are necessary to determine GI-FL staging,
because GI-FL often involves long segments of the GI tract
(see ‘‘Disease distribution in the GI tract’’).
Recent advances in gastrointestinal follicular
Fluorine-18 fluorodeoxyglucose positron emission tomog-
raphy (FDG-PET) scanning has recently emerged as a
major imaging modality for the staging and follow up of
patients with lymphoma, especially aggressive lymphomas
[97–99]. FDG-PET scanning has excellent sensitivity and
specificity for staging in nodal FL as well, in contrast to
other indolent lymphomas, including B-cell small-cell
lymphocytic lymphoma, marginal zone lymphoma, and
There are a few reports in which FDG-PET was per-
formed for staging in GI-FL [24, 32, 37, 41, 44]. In 14 of
16 cases of FL of the small intestine, there were no obvious
accumulations of 18F-FDG in the primary lesions. Focal
18F-FDG uptake in the primary site was observed in 1 case
Fig. 6 Endoscopic findings of gastric FL and (c) fluorodeoxyglucose
positron emission tomography (FDG-PET) findings of gastric FL in a
63-year-old man. EGD had revealed a submucosal tumor-like lesion
in the cardia of the stomach 3 years previously (a). This lesion
progressed slowly and ulceration of the lesion was observed at the
time of presentation (b). FDG PET revealed an accumulation of
18F-FDG in this lesion in the stomach (c, arrow). It is noteworthy that
small mediastinal lymph node dissemination was detected with
FDG-PET in this case (c, arrowhead) 
J Gastroenterol (2010) 45:370–388 379
of gastric FL  and 2 cases of FL of the small intestine
. In all of these cases, the primary lesion formed a mass
lesion. It is noteworthy that small mediastinal lymph node
dissemination was detected with FDG-PET in one gastric
FL case (Fig. 6c, arrowhead) . In this case, the dis-
seminated lesion above the diaphragm could not be
detected with CT, which was performed before the FDG-
PET examination. In another case of duodenal FL ,
18F-FDG accumulated in the mesenteric lymph nodes,
whereas there was no obvious uptake in the primary site.
Therefore, this modality may not be useful for evaluating
the spread of the primary lesion, as Hoffman et al.  and
Higuchi et al.  demonstrated, but the modality is useful
for evaluating lymph node dissemination.
Prognosis in patients with gastrointestinal follicular
Prognosis of GI-FL
The long-term clinical outcome of GI-FL remains unclear
because there has been no analysis of a large population-
based registry of survival for patients with GI-FL. In 2 case
Fig. 7 Endoscopic findings of
GI-FL, c polymerase chain
reaction (PCR) analysis of GI-
FL, and d fluorescence in situ
hybridization (FISH) analysis of
GI-FL in a 47-year-old man.
DBE revealed a submucosal
tumor-like lesion with
ulceration in the middle portion
of the small intestine (a). There
were small whitish granular
lesions on the oral side of the
ulcer (b). PCR analysis. IgH/
BCL2 rearrangement was
detected with probes for major
break region (MBR; c). FISH
analysis. t(11;14)(q13;q32) was
demonstrated by the yellow
fusion signals in an abnormal
nucleus (d). mcr, Minor cluster
Table 6 Histologic grade of GI-FL
Grade 1 157 (84.4)
Grade 221 (11.3)
Grade 38 (4.3)
Grade 3a3 (1.6)
Grade 3b1 (0.5)
Details unknown4 (2.2)
Table 7 Immunophenotype of GI-FL
CD10 (?), Bcl-2 (?) 155 (68.9)
CD10 (?), Bcl-2 (-) 3 (1.3)
CD10 (-), Bcl-2 (?) 7 (3.1)
CD10 (-), Bcl-2 (-) 3 (1.3)
CD10 (?), Bcl-2 (?) 51 (22.7)
CD10 (?), Bcl-2 (-) 6 (2.7)
IgM 14 (50.0)
Not detected 3 (11.5)
380 J Gastroenterol (2010) 45:370–388
series on long-term outcomes of patients with GI-FL,
relapse-free median time or median relapse-free survival
was similar to that for nodal FL [12, 15]. Shia et al. 
reported a median relapse-free survival of 63 months in 25
GI-FL patients. Damaj et al.  reported a median time to
progression of 37.5 months in 7 patients without any
treatment and a median time to recurrence of the disease of
31 months in 18 patients with treatment.
On the other hand, based on all available data reported
previously, GI-FL seems to have a better prognosis than
nodal FL. There are only five reported cases in which the
patients died of GI-FL, and, among 249 GI-FL patients, 3
patients died of another disease [12, 20, 22, 54]. In addi-
tion, the median relapse-free survival was 98 months in 96
patients with GI-FL (Fig. 9a), which appears to be a more
favorable outcome compared with that of nodal FL.
In GI-FL, the frequency of grade 1 lymphoma is much
higher compared with that in nodal FL (see ‘‘Histologic
grading’’), and most GI-FL presents as a localized disease
at the time of diagnosis, while most nodal FL involves
multiple sites when staging procedures are performed (see
‘‘Clinical stage’’). These features may indicate that GI-FL
is a distinct entity from nodal FL, and is slower to progress.
There may be other reasons for the better prognosis of
GI-FL compared with that of nodal FL. When lymphoma
cells infiltrate not only the GI tract but also extraintestinal
sites, e.g., peripheral or mediastinal lymph nodes, liver or
spleen, most such cases, especially those with massive
extraintestinal lesions, are excluded from primary GI-FL
[11, 12, 15–17] because of the inability to distinguish
between primary GI-FL with extraintestinal invasion and
secondary GI-FL as a result of dissemination from another
site (see ‘‘Definition of primary GI lymphoma’’). Second,
there are only a few GI-FL patients with a long-term follow
up, because of its rarity. The median follow-up duration of
the reported cases of GI-FL is only 24.5 months, while the
median follow up was more than 50 months in most studies
of the long-term clinical outcome of nodal FL [103–105].
Grade 1 GI-FL tends to have a better relapse-free survival
unclear because ofits rarity. Relapse-free survivalofgrade 1,
grade2,andgrade3is61.6%at180 months(n = 48),41.7%
at 112 months (n = 13), and 100% at 108 months (n = 3),
respectively (Fig. 9b). The difference in overall survival
GI-FL and 3 died of other diseases, based on the data in the
available literature [12, 20, 22, 54].
To compare the prognosis between localized GI-FLs
(i.e., stage I or II) and systemic ones (i.e., stage III or IV) is
difficult, because only 13 of 193 GI-FL patients (6.7%)
with available clinical stage data had a systemic disease.
Recurrence after achieving complete
remission in GI-FL
Of 249 patients with GI-FL, 106 achieved complete
remission with various therapies (see ‘‘Gastrointestinal
follicular lymphoma treatment’’). Of those, FL relapsed in
16 cases from 1 to 98 months after achieving of complete
remission [12, 15–17, 47]. Details of relapsed cases are
summarized in Table 9. Median time to recurrence was
Fig. 8 PCR analysis in an
81-year-old woman with GI-FL.
Primers for MBR failed to
(lane 2), and PCR products
using primers for mcr were
observed in lane 3
Table 8 Genetic features of GI-FL
Positive (MBR)1 (20.0)
Positive (mcr) 1 (20.0)
Positive (break point unknown)1 (20.0)
Negative (MBR and mcr)2 (40.0)
Polymerase chain reaction
Positive (MBR)23 (46.9)
Positive (mcr)1 (2.0)
Positive (break point unknown)4 (8.2)
Negative (MBR)21 (42.9)
Fluorescence in situ hybridization
Negative 7 (28.0)
MBR major breakpoint region, mcr minor cluster region
J Gastroenterol (2010) 45:370–388 381
44.5 months. Initial treatments to induce remission were
surgery (4 cases), radiation (1 case), chemotherapy (4 cases),
radiation plus chemotherapy (2 cases), surgery plus chemo-
therapy (4 cases), and radiation plus surgery following che-
motherapy (1 case). It is noteworthy that FL relapsed outside
the GI tract, including in extraabdominal lymph nodes, the
spleen, and tonsils, in about 50% of the recurrent cases [15–
17]. Therefore, not only evaluation of the GI tract using
endoscopy and abdominal CT scan but also whole-body
be performed for follow-up studies after the achieving of
complete remission. To screen for extraabdominal relapse,
FDG-PET rather than gallium scintigraphy is recommended
because of its sensitivity  (see ‘‘Recent advances in
gastrointestinal follicular lymphoma staging’’).
Gastrointestinal follicular lymphoma treatment
Management of GI-FL is controversial, mainly because of
its rarity. Damaj et al.  reported that there was no
significant difference in the prognosis between patients
without treatment and those with treatment, as in nodal FL
[106–108]. Therefore, a ‘‘watch and wait policy’’ has been
adopted in some asymptomatic patients with GI-FL [13,
15, 17, 18, 20, 23, 54, 55]. In other patients, surgery,
radiotherapy, chemotherapy, monoclonal antibody therapy,
or a combination of these therapies is performed. In addi-
tion, antibiotic therapy has been tried in several patients
with GI-FL [7, 17–19, 24, 25, 34, 50], based on the
established efficacy of antibiotics in patients with other
indolent GI lymphomas, such as gastric MALT lymphoma
or immunoproliferative small intestinal disease (IPSID).
GI-FL treatments and responses are summarized in
Patients with GI-FL have been treated with surgery,
radiotherapy, chemotherapy, or a combination of these
therapies. To compare the effect of each therapy with
another is difficult, however, because the number of
patients receiving each type of treatment is very small and
the background of the cases, including clinical stage and
duration of follow up, varies. In general, a complete
response was achieved in most patients regardless of
treatment modality, reflecting the indolent nature of GI-FL
Fig. 9 a Kaplan–Meier plot of relapse-free survival after achieving
complete remission in patients with GI-FL. b Relapse-free survival
according to histologic grade. Relapse-free survival of grade 1, grade
2, and grade 3 was 61.6% at 180 months (n = 48), 41.7% at
112 months (n = 13), and 100% at 108 months (n = 3), respectively
Table 9 Recurrence after achieving complete remission in GI-FL
Number of cases with recurrence16
Median time to recurrence (months)
Radiation ? chemotherapy2
Surgery ? chemotherapy4
Surgery ? radiation ? chemotherapy1
Outside the GI tract
a6 cases in which the duration of remission was not described were
bRecurrent sites were submandibular lymph nodes (1 case), axillary
and inguinal lymph nodes (1 case), colon and spleen (1 case), tonsil
(1 case), and unknown (3 cases)
382 J Gastroenterol (2010) 45:370–388
(Table 10) (see ‘‘Prognosis in patients with gastrointestinal
Chemotherapy for GI-FL is performed based on the
therapeutic regimens of nodal FL, especially in patients
with systemic disease or widespread GI tract involvement.
After the introduction of therapies using the monoclonal
antibody against CD20, rituximab, several randomized
studies demonstrated that this therapeutic modality, com-
bined with conventional therapies, improved not only the
complete response rate and the duration of the response but
also the overall survival rate of nodal FL [109–111]. In
addition, in GI-FL, immunotherapy using rituximab with or
without chemotherapy has been performed [7, 13, 16–18,
20, 24, 28, 41, 42, 56], although the efficacy of therapy
including rituximab has not been compared with that of
conventional therapy alone. There seems to be no differ-
ence in the response of GI-FL between therapeutic regi-
mens containing rituximab and conventional therapy at
present, which may be due to the disease rarity and the
favorable nature of the disease (Table 10).
Growing evidence indicates that some subtypes of marginal
zone lymphomas are associated with chronic antigen stimu-
is effective in marginal zone lymphoma of MALT type,
including gastric MALT lymphoma and IPSID.
Several studies have revealed a close association of
infection with H. pylori and gastric MALT lymphoma
[112–115], and the eradication of H. pylori infection results
in lymphoma remission in patients with low-grade MALT
lymphoma localized in the stomach [116–122].
IPSID, which is also called ‘‘Mediterranean lymphoma’’
or ‘‘alpha heavy chain disease’’ , is a variant of
MALT lymphoma in the small intestine. Early-stage IPSID
responds to antibiotics such as tetracycline, ampicillin, or
metronidazole . Recently Lecuit et al.  have
reported that IPSID is associated with Campylobacter
Also in GI-FL, some patients were treated with antibi-
otics using an H. pylori eradication regimen, because
H. pylori was detected in the stomach or a diagnosis of
MALT lymphoma was made at first. Most GI-FL lesions,
however, were unchanged or progressed despite the
administration of antibiotic agents [17, 18, 24, 25, 50]. The
fact that antibiotic therapy is ineffective for most patients
with GI-FL may indicate that the neoplastic follicles of
GI-FL are not composed of antigen-driven cells, different
from MALT lymphoma .
In several patients with GI-FL, however, regression of
GI-FL was noted after antibiotic treatment [14, 19, 34].
Toyoda et al. reported a case of duodenal FL that regressed
12 months after eradication of H. pylori although the
immunophenotype of the tumor cells was CD10- and bcl-
2?, which is characteristic of MALT lymphoma rather
than FL . Nakamura et al.  described a patient who
showed regression of GI-FL at 15 months after antibiotic
treatment, and Nomura et al.  reported that duodenal
FL regressed at 12 months after antibiotic therapy. These
cases may suggest that tumor cell growth depends on
stimulation with antigens originating from the gut lumen
via B-cell receptors on the tumor cells in some cases of
Table 10 Therapeutic modalities for GI-FL
Response to the therapies (n = 159)
CR (recurrence)PR NCPD unknown
Surgery 3628 (4)2006
Radiation6 6 (1)0000
Chemotherapy without rituximab44 22 (4)921 10
Chemotherapy ? radiation8 4 (2)1102
Surgery ? chemotherapy2420 (4)2002
Surgery ? radiation1 1 (0)0000
Surgery ? radiation ? chemotherapy11 (1)0000
Rituximab monotherapy86 (0)2000
Chemotherapy ? rituximab1915 (0)4000
Surgery ? chemotherapy ? rituximab1 1 (0)0000
Antibiotic therapy15 2 (0)1921
Total211 106 (16)21 123 21
CR complete response, PR partial response, NC no change, PD progressive disease
J Gastroenterol (2010) 45:370–388 383
GI-FL, as Bende et al.  and Takata et al.  have
Although GI-FL is generally considered to be a rare entity,
the number of reported cases of GI-FL is increasing. A
consensus regarding the management of this disorder,
however, has not yet been established. Irrespective of the
specific therapy, the overall survival of GI-FL appears to be
good. Little is known about long-term clinical outcome of
GI-FL, especially since treatment with rituximab was intro-
duced. Therefore, further studies are necessary to evaluate
how rituximab changes the clinical outcome of GI-FL.
Accurate evaluation of the distribution of the disease,
however, is necessary for deciding on the treatment
modality. WCE and DBE, which provide detailed infor-
mation about the mucosa of the whole small intestine, are
useful for localizing GI-FL because of the potential mul-
tifocal involvement of the GI tract in many cases. GI-FL
tends to be localized in the GI tract and regional lymph
nodes at diagnosis, whereas extraabdominal relapse is
observed in about 50% of recurrent cases. Accordingly,
endoscopic examination throughout the entire GI tract and
whole-body evaluation with FDG-PET is necessary for
staging and follow-up studies.
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