ORIGINAL ARTICLE
Primary Follicular Lymphoma of the Gastrointestinal Tract
Joseph Misdraji, MD, Nancy Lee Harris, MD, Robert P. Hasserjian, MD,
Gregory Y. Lauwers, MD, and Judith A. Ferry, MD
Background: Follicular lymphoma (FL), a common nodal
lymphoma, is rare in the gastrointestinal (GI) tract. We report
our experience with primary FL of the GI tract.
Methods: The surgical pathology computer files at the Massa-
chusetts General Hospital were searched for cases of FL
involving the GI tract. Patients were included if on staging,
the major site of disease was the GI tract. Thirty-nine cases were
identified. Clinical data were collected from electronic medical
records.
Results: The 27 women and 12 men ranged in age from 29 to 79
years (median, 59 y). Thirty tumors involved the small bowel (19
the duodenum); 8 involved the colon; and 1 involved the
stomach. Eight of 10 tumors that were resected involved the
small bowel (jejunum and/or ileum without duodenum) of which
5 presented with intestinal obstruction. All tumors were grade 1
or 2. Immunostains showed consistent expression of CD20
(100%), CD10 (97%), and Bcl-2 (97%). Among the 34 cases
with Ann Arbor staging information, 22 were stage I, 10 were
stage II, and 2 were (6%) stage IV. Of 36 cases with follow-up
(median, 4.5 y), 27 patients are alive without disease, 7 are alive
with disease, and 2 died of other causes. No lymphoma-related
deaths were recorded.
Conclusions: Primary FL of the GI tract occurs most often in
middle-aged adults with a 2:1 female preponderance. The most
frequent site of involvement is the duodenum, followed by the
ileum and colon. Distal small bowel involvement is more likely
to present as bowel obstruction requiring resection. The disease
is localized in the bowel and regional lymph nodes in the vast
majority of cases. The prognosis is favorable even when the
disease is disseminated.
Key Words: follicular lymphoma, gastrointestinal tract, small
intestine, duodenum
(Am J Surg Pathol 2011;35:1255–1263)
T he gastrointestinal (GI) tract is the most common site
of extranodal lymphoma, accounting for 40% of
extranodal lymphomas.2 Of these, extranodal marginal
From The James Homer Wright Pathology Laboratories, Massachusetts
General Hospital, Harvard Medical School, Boston, MA.
Conflicts of Interest and Sources of Funding: The authors have disclosed
that they have no significant relationships with, or financial interest
in, any commercial companies pertaining to this article.
Correspondence: Joseph Misdraji, MD, Department of Pathology,
Massachusetts General Hospital, Warren Building 105F, Boston,
MA 02114 (e-mail: jmisdraji@partners.org).
Copyright r 2011 by Lippincott Williams & Wilkins
Am J Surg Pathol  Volume 35, Number 9, September 2011
zone lymphoma of mucosa-associated lymphoid tissue
(MALT lymphoma) and diffuse large B-cell lymphoma
are the most common subtypes.8 Conversely, follicular
lymphoma (FL) constitutes only approximately 1% to
3% of primary GI lymphomas,3,6,15,16,21 despite its being
the most common nodal lymphoma in western popula-
tions. The relative importance of this subtype of
lymphoma varies according to the site in the GI tract.
FL represents 0.8% to 3% of gastric lymphomas9,35 and
0% to 2.6% of colonic lymphomas,14,35 but 3.8% to
11.1% of small intestinal lymphomas.14,22,34,35 Several
years ago, we reported a case of FL arising in the ampulla
of Vater in a middle-aged woman who presented with
jaundice,19 and this report was followed by others that
emphasized the predilection of primary GI FL to arise in
the duodenum and to affect women.24,27,28,35 However,
results have not been uniform. We report our experience
with primary GI FL.
METHODS
The anatomic pathology computer files of the
Massachusetts General Hospital were searched for
diagnoses of FL or follicle center lymphoma. Cases were
selected for this study if, after staging, the primary site of
disease was the GI tract and the regional lymph nodes for
the involved segment(s). Patients with a history of FL
outside the GI tract, patients presenting with widespread
lymphoma, and patients diagnosed with distant nodal
disease within 6 months of diagnosis were excluded as it
was felt that origin in the GI tract could not be confirmed
in those circumstances. Patients with multifocal disease,
apart from regional lymph nodes, and patients with
splenic involvement (as judged clinically) were excluded.
Three patients with large B-cell lymphoma arising in
association with FL (FL in transformation) were ex-
cluded. Patients with bone marrow or peripheral blood
involvement were not excluded. From 1995 to 2010,
twenty cases were identified. An additional 19 cases were
obtained from the consultation files of the authors (9
cases obtained from J.A.F., 8 cases obtained from
N.L.H., 1 case obtained from R.P.H., 1 case obtained
from G.Y.L.). The cases sent in consultation tended to be
from younger patients (median age 53 y compared with
64.5 y for the remaining cases; P = not significant), but
otherwise the 2 groups were similar with respect to sex,
distribution in the GI tract, grade, and stage. Two cases
were previously described in detail,19,31 and 1 was
included in a series of lymphomas with concurrent
MYC and BCL2 rearrangements.29
www.ajsp.com | 1255
Misdraji et al Am J Surg Pathol  Volume 35, Number 9, September 2011

TABLE 1. Antibodies and Probes Used for Immunophenotypic TABLE 2. Summary of Cases of Primary FL of the GI Tract
Analysis and In Situ Hybridization (n = 39)
Antibody or Probe Source Dilution Male:Female 12:27
Immunoperoxidase Age in years (median; range) 59; 29-79
Site
Kappa, monoclonal Becton-Dickinson 1:8
Duodenum 16
Lambda, monoclonal Becton-Dickinson 1:12
Kappa, polyclonal Dako corporation 1:2600 Ileum 7
Lambda, polyclonal Dako corporation 1:1400 Jejunum 1
CD20 Ventana Prediluted Small intestine unspecified 2
CD10 Ventana Prediluted Duodenum and jejunum 2
CD3 Ventana Prediluted Duodenum and ileum 1
Jejunum and ileum 1
CD5 Ventana Prediluted
Colon 8
CD21 Ventana Prediluted
CD23 Novocastra 1:20 Stomach 1
CD45 Biogenex 1:40 Stage (n = 34)
Bcl2 Ventana Prediluted 1 22
Bcl6 Dako 1:10 2 10
3 0
Cyclin D1 Neomarkers 1:100
4 2
In situ hybridization
Kappa, lambda Ventana Prediluted Outcome (n = 36)
Alive without evidence of disease 27
Sources: Becton-Dickinson, San Jose, CA; Dako Corporation, Carpinteria, Alive with disease 7
CA; Neomarkers, Fremont, CA; Novocastra, Burlingame, CA; Ventana, Tucson, Dead of causes other than lymphoma 2
AZ; Biogenex.

Hematoxylin and eosin-stained slides for 9 resec- Clinical Data (Table 3)

tions and 30 biopsies and, when available, immunohisto-
chemical stains were reviewed by 2 of the authors (J.M.
and J.A.F.). Immunohistochemical stains were performed
over the course of many years, and the protocols changed
during that time. More recent stains were performed on
the Ventana Benchmark autostainer (Ventana Medical
Systems, Inc., Tucson, AZ) on 3-mm-thick formalin-fixed,
paraffin-embedded sections. Antigen retrieval was per-
formed with Ventana antigen retrieval with Tris pH 8 for
30 minutes. The source and dilution of antibodies are
shown in Table 1.
Information on molecular evaluations was drawn
from the studies performed at the time of diagnosis, and
most of these were performed at various other institu-
tions. In 3 cases, polymerase chain reaction (PCR)
evaluation for IGH-BCL2 was performed by isolating
DNA from paraffin-embedded tissue. PCR/polyacryla-
mide gel electrophoresis technique was used with con-
sensus primers to the variable and joining regions of the
immunoglobulin heavy chain gene and spanning the IGH-
BCL2 fusion associated with t(14;18). In 2 cases,
fluorescence in situ hybridization (FISH) evaluation for
an IGH-BCL2 rearrangement was performed using 50-mm
sections from paraffin-embedded tissue using LSI IGH/
BCL2 Dual Color, Dual Fusion Translocation Probe
(Abbott Molecular/Vysis, Inc.) for IGH at 14q32 and
BCL2 at 18q21. Clinical and follow-up data were
obtained from medical records, physician notes, internet
searches, or death certificates. Lymphomas were staged
according to the Ann Arbor staging system.
RESULTS
Results are summarized in Table 2.
The 27 women and 12 men ranged in age from 29 to
79 years (median, 59 y). One patient had a history of
cutaneous extranodal marginal zone lymphoma 1 year
previously, and 1 patient with duodenal FL was
diagnosed concurrently with extranodal marginal zone
lymphoma of the stomach. None of the patients had a
history of celiac disease, inflammatory bowel disease, or
immune deficiency, except for 1 iatrogenically immuno-
suppressed patient who had undergone orthotopic heart
transplant 10 years earlier.
Presenting Findings
Presenting symptoms and signs were known in 30
cases. Twelve patients presented with abdominal pain,
which was epigastric in 6 patients. Two of these 12
patients were clinically diagnosed with bowel obstruction
on the basis of abdominal pain and vomiting and
underwent intestinal resection. Another had abdominal
pain and vomiting that was evaluated by capsule
endoscopy, and the capsule endoscope was retained
above a narrowed jejunal segment that was resected.
One patient presented with ileal intussusception and also
underwent resection. Twelve tumors were found inciden-
tally: 6 during evaluation of reflux symptoms or Barrett
esophagus, 5 during screening for colorectal carcinoma,
and 1 at resection of a sigmoid carcinoma. One of these
patients developed ileal obstruction 2 years after diag-
nosis and underwent resection at that time. Thirty tumors
(77%) involved the small intestine; 16 of these involved
the duodenum only, 7 were in the ileum only, 1 involved
both the duodenum and ileum, 2 involved the duodenum
and jejunum, 1 involved the jejunum and ileum, 1 arose in
the jejunum only, and 2 were in unspecified segments of
the small intestine. Three patients had extensive evalua-
tion of the small intestine, and all had jejunal lymphoma.

1256 | www.ajsp.com r 2011 Lippincott Williams & Wilkins

Am J Surg Pathol  Volume 35, Number 9, September 2011 Primary Follicular Lymphoma of the GI Tract

TABLE 3. Clinical Details of 39 Cases of Primary FL of the GI Tract

Case Age/ Time to Current
No. Sex Site Signs and Symptoms Stage Other Sites Treatment Site of Relapse Relapse Status Years
1 79/F Duodenum Incidental 1 None None None NA ANED 8.5
2 67/M Duodenum Incidental 1 None Radiation None NA ANED 1.5
3 60/F Duodenum Incidental 1 None Radiation None NA ANED 3
4 65/F Duodenum Incidental 1 None Radiation None NA ANED 3.5
5 46/F Duodenum Epigastric 1 None Radiation None NA ANED 7.5
discomfort,
hematemesis
6 73/M Duodenum Epigastric 1 None Radiation None NA ANED 10
discomfort
7 71/M Duodenum Incidental 1 None None NA NA AWD 8
8 45/F Duodenum Abdominal pain, 2 Para-aortic and pelvic Rituximab, None NA ANED 3
nausea, diarrhea lymph nodes chemotherapy
9 60/F Duodenum Incidental 4 Peripheral blood 2% of Rituximab, None NA ANED 5
lymphocytes chemotherapy,
radiation
10 43/M Duodenum Incidental 2 Mesenteric lymph nodes None None NA ANED 5.5
11 44/F Duodenum Epigastric pain 1 None Rituximab None NA ANED 4.5
12 54/F Duodenum Nausea, vomiting, 1 None Rituximab None NA ANED 4.5
diarrhea
13 59/F Duodenum Abdominal pain Unknown Unknown Unknown NA NA AWD 3
14 46/M Duodenum Epigastric burning, 1 None Radiation None NA ANED 5
bleeding
15 55/F Ampulla of Vater Jaundice 2 Periduodenal lymph Resection, radiation Inguinal lymph 6y DOC 11
nodes node
16 68/F Ampulla of Vater Unknown Unknown Unknown None None NA ANED 8
17 29/F Duodenum and Epigastric pain, 2 Mesenteric lymph nodes Rituximab, None NA ANED 1
proximal nausea, vomiting chemotherapy
jejunum
18 39/M Duodenum and Unknown 1 None None NA NA AWD 2
jejunum
19 53/F Duodenum and Unknown 1 None None NA NA AWD 5
ileum
20 51/F Ileum Blood in stool 1 None Resection None NA ANED 4
21 66/F Ileum Incidental 1 None Resection None NA ANED 14
22 52/F Ileum Abdominal pain, 2 Mesenteric lymph nodes Resection, None NA ANED 5
vomiting rituximab
23 49/F Ileum Blood in stool 2 Mesenteric lymph nodes Resection None NA ANED 11
24 47/F Ileum Intussusception 4 Mesenteric lymph node, Resection, None NA ANED 4
bone marrow <5% rituximab,
chemotherapy
25 39/F Ileum Unknown Unknown Unknown Unknown Unknown Unknown LFU NA
26 60/F Ileum and Incidental 2 Mesenteric lymph nodes None initially, NA NA AWD 4.3
ileocecal valve resected at 2 y
27 68/F Jejunum Abdominal pain, 2 Perijejunal mesenteric Resection None NA ANED 0.5
nausea, vomiting lymph nodes
28 47/M Jejunum Weight loss, anemia 1 None Rituximab, None NA ANED 1
and ileum chemotherapy
29 75/F Small intestine Abdominal pain, 2 Mesenteric lymph node Resection, None NA ANED 4
vomiting rituximab
30 44/M Small intestine Unknown Unknown Unknown Unknown Unknown Unknown LFU NA
31 64/F Colon Unknown 1 None None Retroperitoneal 4y AWD 11
lymph node
32 62/F Colon Unknown 1 None Resection None NA ANED 2.5
33 73/M Colon Unknown 1 None None Bone marrow, 2y ANED 5
CSF
34 65/M Colon Incidental 1 None Rituximab NA NA AWD 4
35 60/F Colon Incidental 1 None Radiation None NA ANED 0.5
36 36/F Colon Unknown Unknown Unknown Unknown None NA ANED 5
37 76/M Colon Incidental 1 None None None NA ANED 2
38 55/M Colon Incidental Unknown Unknown Unknown Unknown Unknown LFU NA
39 67/F Stomach Epigastric 1 None Rituximab None NA DOC 4
discomfort,
nausea

ANED indicates alive no evidence of disease; AWD, alive with disease; DOC, dead of causes other than lymphoma; F, female; LFU, lost to follow-up; M, male; NA,
not applicable.

r 2011 Lippincott Williams & Wilkins www.ajsp.com | 1257

Misdraji et al
One patient with duodenal lymphoma (case 18) had push
endoscopy and was found to have a midjejunal polyp that
proved to be lymphoma. Another patient (case 28)
underwent initial evaluation for abdominal pain by
capsule endoscopy, which showed nonspecific abnorm-
ality of the small bowel. Double balloon enteroscopy
showed diffuse nodularity and white patches of the
jejunum and ileum. The third patient (case 27) required
resection when a jejunal FL caused a capsule endoscope
to become lodged in the jejunum. Eight tumors were in
the colon (3 ascending colon; 3 transverse colon; 1
rectum; and 1 unspecified colonic segment). One tumor
involved the stomach.
Stage at Diagnosis
Stage at diagnosis was known in 34 cases. Twenty-
two (65%) tumors were stage I, 10 were stage II, and 2
were stage IV. Twenty-three patients had a bone marrow
biopsy; 1 bone marrow biopsy was positive, with <30%
of the marrow space involved by lymphoma. The other 22
were negative for FL, although 1 patient (case 37) had
small nonparatrabecular lymphoid aggregates that were
positive for CD5 and negative for CD10 and BCL6, a
pattern consistent with chronic lymphocytic lymphoma
and distinct from the patient’s FL. Two patients had flow
cytometry of peripheral blood performed, and 1 had a
small number of circulating lymphoma cells (2% of all
lymphocytes).
Treatment and Follow-Up
Treatment information was known for 34 patients.
Ten tumors were resected (one of them 2 y after
surveillance due to obstruction). Six of these 10 patients
received no additional therapy; 1 received postoperative
chemotherapy [rituximab, cyclophosphamide, vincristine,
and prednisolone (R-CVP)]; 2 received postoperative
rituximab only; and 1 underwent postoperative radiation
therapy.
Of the patients whose tumors were not resected, 3
were initially treated with antibiotics, all without
response. Nine patients received no lymphoma-specific
therapy. Seven patients underwent radiation therapy only
(1 patient had received antibiotics; 1 patient received
rituximab 3 y later to minimize chances of recurrence); 4
patients received rituximab only (1 patient had received
antibiotics); 2 patients received R-CVP; 1 patient received
R-bendamustine; and 1 patient received rituximab in
combination with cyclophosphamide, adriamycin, vin-
cristine, and prednisone (CHOP) and radiation therapy.
Outcome data are known for 36 patients. Twenty-
seven patients are alive without clinical evidence of
disease 0.5 to 14 years after diagnosis (median, 4.5 y).
Seven patients are alive with disease 2 to 11 years later
(median, 4.3 y). Two patients died of causes other than
lymphoma at 4 and 11 years. No patient in this series died
of lymphoma.
Of the 3 patients initially treated with antibiotics,
none responded. One patient had a gastric FL initially
misclassified as extranodal marginal zone lymphoma of
1258 | www.ajsp.com
Am J Surg Pathol  Volume 35, Number 9, September 2011
MALT type, and 1 had concomitant gastric MALT
lymphoma, which responded to Helicobacter eradication;
the FL failed to respond. The third patient was treated
with R-CHOP and radiation and is currently free of
disease.
Two of the 9 patients who elected observation alone
progressed. One patient developed bone marrow involve-
ment 3 years later by diffuse large B-cell lymphoma with
both BCL2 and MYC rearrangements. He received
rituximab, etoposide, doxorubicin, vincristine, cyclopho-
sphamide, prednisolone (R-EPOCH) with intrathecal
methotrexate and recently relapsed in the cerebrospinal
fluid (CSF). He is currently disease free after spinal
radiation, high-dose methotrexate, temozolomide, ritux-
imab, and intrathecal cytarabine. The other patient had a
grade 1, stage 1 FL of the rectum and developed
retroperitoneal lymph node involvement 4 years after
diagnosis that was treated with rituximab and a trial of
anti-idiotype vaccine and GM-CSF. She has persistent
disease at 11 years.
Among the 10 patients whose tumors were resected,
1 patient who received adjuvant radiation therapy
developed recurrent lymphoma in a groin lymph node 6
years after diagnosis and was treated with chemotherapy.
Three years later, axillary, paratracheal, subcarinal, and
hilar nodes were involved by lymphoma, and she received
rituximab. She died the following year of lung cancer, 11
years after her initial diagnosis of lymphoma. The other 9
patients whose tumors were resected are alive without
disease 0.5 to 14 years after diagnosis (median, 4 y).
Macroscopic Findings
Endoscopically, 4 duodenal tumors presented with
clusters of white patches or plaques in the duodenum, 3
with nodularity or granularity of the duodenal mucosa, 2
with a single villiform or nodular lesion, and 1 with no
endoscopic abnormality. One of the patients with
lymphoma at the ampulla of Vater showed prominence
of the ampulla on endoscopy. Two ileal tumors were
described by the endoscopist as nodules or nodular
polyps. The patient with diffuse jejunal and ileal
nodularity (case 28) is the only one who can be aptly
described as presenting with lymphomatous polyposis.
Five colonic tumors presented as a single polyp (2 cases),
2 polyps (1 case), 3 polyps (1 case), or a submucosal mass
(1 case). The gastric tumor appeared as thickened folds
and nodularity of the cardia, body, and fundus. Descrip-
tions of the gross characteristics of the tumors were
available in 8 of the 10 resection specimens. Three small
intestinal tumors were solitary nodules or masses that
ranged in size from 2.7 to 6 cm. Two cases were described
as nodularity in the ileum. One tumor resected during
surgery for sigmoid adenocarcinoma was described by the
surgeon as a 6 to 8 cm dilated segment of the ileum with
thickening of the small bowel and adjacent mesentery.
The jejunal tumor that caused retention of the capsule
endoscope was described as a thickened area with
mucosal granularity. An ampullary tumor treated with a
Whipple resection was a 4-cm circumferential duodenal
r 2011 Lippincott Williams & Wilkins
Am J Surg Pathol  Volume 35, Number 9, September 2011
tumor extending into the pancreas. Three tumors with
descriptions of their cut surfaces were firm and white-tan
to gray.
Microscopic Findings (Table 4)
On microscopic examination, biopsies typically
showed patchy involvement with some tissue fragments
showing dense lymphocytic infiltrate and 1 to several
discrete or crowded follicles. The enlarged, monotonous
follicle centers had attenuated mantles. In intestinal
biopsies, the lamina propria between follicles and in villi
was densely cellular with numerous lymphocytes consis-
tent with infiltration of the lamina propria by neoplastic
lymphocytes (Fig. 1A), as well as occasional plasma cells
and eosinophils. In some cases, the uniformly cellular
lamina propria was the main finding and sometimes
obscured the follicles, which were highlighted with
immunostains for B cells or follicular dendritic cells
(FDCs). Rarely, the tumor in the duodenal biopsies
created a resemblance to Peyer patches, with abundant
follicular-appearing lymphoid tissue and blunted villi in
the overlying mucosa. In some ileal biopsies, the large
follicles created polypoid nodules on the surface of the
mucosa (Fig. 1B).
In some colonic biopsies, the lymphoma involved
only the submucosa as expansile nodules with overlying
normal or attenuated mucosa. In other cases, the
expansile nodules filled the mucosa, and displaced crypts.
In the 1 case of lymphoma diagnosed on gastric biopsy,
small patches of densely cellular, monotonous lymphoid
tissue displaced glands in fundic-type mucosa. The
background lamina propria showed only mild lympho-
cytic infiltrate, parietal cell hyperplasia, and no Helico-
bacter pylori. In all cases, the neoplastic follicles were
composed of centrocytes with varying numbers of larger
transformed lymphoid cells, and all were either grade 1 or
2 (Fig. 1C).
The resected tumors largely consisted of uniform
enlarged and crowded follicles. In some cases, the
neoplastic follicles were associated with significant
fibrosis or keloidal type collagen. Two of the resected
tumors involved only the mucosa of the involved ileal
segment, although 1 of these showed multifocal mucosal
disease, involvement of the margin, and several positive
mesenteric lymph nodes. Two tumors (1 ileal, 1 colonic)
invaded into the submucosa (Fig. 1D), and another 4
tumors involved the small intestine transmurally to the
serosa. The resected ampullary tumor invaded the
pancreas and peripancreatic adipose tissue. Two tumors
were fairly well circumscribed, 1 of which was associated
with dense hyalinizing fibrosis. The other tumors showed
more irregular infiltration of adipose tissue at the
periphery of the tumors or, in 1 case, around involved
matted mesenteric lymph nodes. Involvement of MALT
at the resection margins was seen in 5 cases (3 ileal, 1
jejunal, 1 ampullary). In 6 of 9 resection specimens, 1 or
more regional lymph nodes were involved by FL.
r 2011 Lippincott Williams & Wilkins
Primary Follicular Lymphoma of the GI Tract
Immunohistochemical Findings
The tumors expressed CD20 and were negative for
CD3, CD5, CD23, and CD43. Tumors were typically
positive for CD10, Bcl2, and Bcl6 (Figs. 2A, B). In cases
with infiltration of the lamina propria by lymphocytes,
CD10 and Bcl2 staining was seen in these lymphocytes,
although less intensely than in the follicles. Cyclin D1 was
negative in all 28 tumors that were tested. Thirteen cases
had CD21 and/or CD23 stains available to evaluate FDC
networks within neoplastic follicles. These were charac-
terized as intact if they showed strong staining through-
out the follicle, disrupted if they showed irregular and
patchy distribution of FDCs in the follicle, or hollow if
FDCs were arranged at the periphery of the follicles with
either a circumferential arrangement or an arc at the edge
of the follicle.30 Four cases had a hollow pattern (Fig.
2C), 3 had a disrupted pattern and 1 case had intact FDC
meshworks. Four cases had a mixture with a hollow
pattern in some follicles. Fourteen cases were evaluated
for monoclonal immunoglobulin expression. Nine cases
were evaluated by immunohistochemistry on frozen
sections (1 case) and/or paraffin (9 cases) sections, 4 cases
were evaluated by in situ hybridization, and 1 case was
evaluated by flow cytometry. Monoclonal light chain
expression was demonstrated in 1 case on paraffin section
immunohistochemistry (IgM l) and in 1 case by flow
cytometry (k excess).
Molecular Genetic Studies
Eleven cases were evaluated by PCR or FISH for
genetic rearrangements. BCL2 rearrangement was de-
tected in 7 grade 1 tumors. The negative cases comprised
1 grade 1 tumor and 3 grade 2 tumors. The translocation
partner was usually IGH, but was sometimes unidentified.
DISCUSSION
In this series of 39 FLs of the GI tract, we found that
primary GI FL affects women more often than men
(approximately 2:1 ratio), and most patients are middle-
aged adults, similar to nodal lymphoma but with a higher
female predominance. Among our cases, as in those
reported in the literature, the small intestine was the site
that was most often affected (77%), with the duodenum
comprising 63% of the cases, followed by other segments of
the small bowel, colon, and stomach. Abdominal pain was
the most common presenting symptom, and symptoms of
intestinal obstruction often indicated the presence of a
small intestinal tumor that required resection. Most cases
were low grade and low stage, although transformation to
high-grade lymphoma and dissemination occurred rarely.
The prognosis for most patients was good, irrespective of
the treatment chosen or the stage at presentation.
Gastrointestinal lymphoma of types other than FL
has been described in patients with inflammatory bowel
disease, celiac disease, immunodeficiency states, and after
solid organ transplantation.4,17,34 FL of the colon has
been reported very rarely in ulcerative colitis.1 However,
only 1 of our patients had a history of solid organ
transplantation. Otherwise we did not identify specific
www.ajsp.com | 1259
Misdraji et al Am J Surg Pathol  Volume 35, Number 9, September 2011

TABLE 4. Pathologic Details of 39 Cases of Primary FL of the GI Tract

Case Cyclin Ki67 FDC Rearranged IGHas
No. Site Grade CD20 CD10 BCL2 BCL6 CD3 CD5 CD23 CD43 D1 (%) Immunoglobulins Pattern BCL2 Partner
1 Duodenum 2 + ND + + ND ND ND ND NE NE NE NA
2 Duodenum 2 + + + ND ND NE Hollow No NA
3 Duodenum 1 + + + + 5 Polyclonal NE NE NA
plasma cells
4 Duodenum 1 + + + + ND ND ND <5 Polyclonal Hollow NE NA
plasma cells
5 Duodenum 1 + + + + ND 10 NE NE NE NA
6 Duodenum 1 + + + ND ND ND ND ND NE NE Yes Yes
7 Duodenum 2 + + + + ND ND ND NE NE Yes Unknown
8 Duodenum 1 + + + ND ND ND ND ND ND NE NE Yes No
9 Duodenum 1 + + + + ND 20 NE Disrupted NE NA
10 Duodenum 1 + + + + ND ND ND 25 Polyclonal NE NE NA
plasma cells
11 Duodenum 1 + + + ND ND ND ND NE NE NE NA
12 Duodenum 1 + + + + ND ND ND Polyclonal Disrupted NE NA
plasma cells
13 Duodenum 2 + + + + ND ND Polyclonal NE No NA
plasma cells
14 Duodenum 1 + + + ND ND ND NE NE NE NA
15 Ampulla of Vater 1 + ND + ND ND ND ND ND ND Polyclonal NE NE NA
plasma cells
16 Ampulla of Vater 1 + + + ND ND ND ND ND Polyclonal NE Yes Yes
plasma cells
17 Duodenum and 1 + + + ND ND ND 5 Polyclonal NE NE NA
proximal plasma cells
jejunum
18 Duodenum and 2 + + + + ND 20 NE NE No NA
jejunum
19 Duodenum and 1 + ND + + ND ND ND NE NE NE NA
Ileum
20 Ileum 1 + + + + ND ND ND 10 Polyclonal Hollow NE NA
plasma cells and intact
21 Ileum 2 + ND + ND ND ND ND ND ND NE NE NE NA
22 Ileum 2 + TS + + ND ND ND ND 40 NE NE NE NA
23 Ileum 1 + + + ND ND 25 NE NE NE NA
24 Ileum 1 + + + + ND NE NE Yes Yes
25 Ileum 2 + + + + ND Polyclonal NE NE NA
plasma cells
26 Ileum and 1 + + + ND ND NE Disrupted NE NA
ileocecal valve
27 Jejunum 1 + + + + ND ND 25 NE Hollow NE NA
and intact
28 Jejunum and 2 + + + + ND ND 20 Polyclonal NE NE NA
ileum plasma cells
29 Small intestine 1 + + + + ND 10 NE Hollow NE NA
and
disrupted
30 Small intestine 1 + + + ND ND ND NE Hollow NE NA
31 Colon 1 + + + ND ND ND ND ND IgM lambda NE Yes Yes
monoclonal
32 Colon 2 + + + ND ND ND 20 Kappa NE NE NA
monoclonal
33 Colon 1 + + + + ND ND ND NE NE Yes Yes
34 Colon 1 + ND + + ND ND 25 NE Hollow NE NA
and
disrupted
35 Colon 1 + + + + ND 20 NE Disrupted NE NA
36 Colon 1 + ND + ND ND ND Polyclonal NE NE NA
plasma cells
37 Colon 1 + + + + ND ND ND ND NE Hollow NE NA
38 Colon 1 + + + ND ND ND ND NE NE NE NA
39 Stomach 1 + + + + ND ND NE Intact No NA

( ) indicates negative; (+), positive; NA, not applicable; ND, not done, NE, not evaluated; TS, technically suboptimal.

1260 | www.ajsp.com r 2011 Lippincott Williams & Wilkins

Am J Surg Pathol  Volume 35, Number 9, September 2011 Primary Follicular Lymphoma of the GI Tract

FIGURE 1. Histologic features of primary FL of the GI tract. A, A biopsy of duodenal FL shows a large follicle composed of small
lymphoid cells in the lower portion of the image. Note the dense lymphoid infiltrate of the lamina propria consistent with
infiltration by neoplastic lymphoid cells. B, A biopsy of ileal FL shows polypoid nodules composed of large follicles with attenuated
mantles. C, High-power magnification of a follicle in grade 1 colonic FL shows a monotonous population of centrocytes with
occasional larger transformed lymphoid cells (arrows). D, A resection specimen of an ileal FL shows mucosal and submucosal
involvement by the tumor, which is composed of crowded indistinct follicles. Note the involvement of MALT on either side of the
tumor, in the form of expansile follicles in the mucosa.

risk factors in the patients’ histories for the development
of GI FL.
The most common endoscopic appearances of FL in
the GI tract among our cases were solitary nodules or
polyps, multiple polyps, white patches or plaques,
and mucosal nodularity in the involved segment,
similar to what others have reported.13,15,27,28,35 Although
presentation as lymphomatous polyposis has been de-
scribed,5,11,12,15,25,33 we encountered only a single case that
we felt could be described as lymphomatous polyposis.
The most common site of involvement of GI FL is
the small bowel, accounting for 77% of our cases, and up
to 85% of reported cases.28 In our series and most others,
most cases arise in the duodenum (either alone or with
involvement of other small intestinal segments).13,28,33,34
However, in the series by LeBrun et al,15 Huang et al,11
and Damaj et al,5 the ileum was the most common site of
involvement (55%, 54%, and 52% of cases, respectively).
The jejunum seems to be the segment of the small
intestine that is least likely to be involved, in only 4 of our
cases. However, the use of double-balloon enteroscopy
and capsule endoscopy has demonstrated jejunal and
proximal ileal involvement in many cases.7,10,13,18,23,33 In
our series, 3 patients were evaluated by capsule endo-
scopy, double balloon endoscopy, or push enteroscopy;
all had jejunal involvement. Therefore, jejunal and
proximal ileal involvement is almost certainly more
common than that is presently reported.
The pathologic features of FL in the GI tract are
similar to nodal lymphomas, namely crowded, poorly
delineated follicles that displace normal structures,
usually with a monotonous population of centrocytes.
Furthermore, affected biopsy fragments frequently
showed 1 or multiple prominent follicles and monotonous

r 2011 Lippincott Williams & Wilkins www.ajsp.com | 1261

Misdraji et al Am J Surg Pathol  Volume 35, Number 9, September 2011

FIGURE 2. Immunohistochemical stains in FL of the GI tract. A, Immunohistochemical stain for CD10 shows strong staining of the
lymphoid cells within a neoplastic follicle. B, Immunohistochemical stain for Bcl2 shows strong staining of the follicle, typical of neoplastic
follicles in FL, and distinguishes it from a reactive follicle. Lymphocytes outside the follicle in the lamina propria are also staining at the top
and bottom of the picture, consistent with infiltration of the lamina propria by neoplastic lymphocytes. C, Immunohistochemical stain for
CD21 shows staining of FDCs around the periphery of this neoplastic follicle, creating a “hollow” pattern.

lymphoid cells in the lamina propria, features that should
raise suspicion for a neoplastic lymphoid disorder. As
with nodal lymphoma, the vast majority of GI FLs
express CD20, Bcl2, Bcl6, and CD10, but they do not
express CD5, CD23, CD43, or cyclin D1.5,27,28 Takata
et al30 noted that FDCs were arranged around the
periphery of the neoplastic follicles in 15 of 17 duodenal
FL cases, whereas in nodal FLs, the FDCs are present
throughout the follicles. We found this “hollow” pattern
in 8 of 14 cases (including 3 of 5 duodenal tumors).
The main differential diagnosis of FL in the GI tract
is with reactive lymphoid hyperplasia, mantle cell lympho-
ma, and extranodal marginal zone lymphoma of mucosa-
associated lymphoid tissue (MALT lymphoma). The
distinction with reactive lymphoid hyperplasia may be
particularly challenging in a biopsy specimen, in which the
full extent of the process may not be visible. In this regard,
the monotonous appearance of the follicle center lympho-
cytes and the coexpression of Bcl2 on CD10-positive, Bcl6-
positive follicle center cells exclude both reactive follicles
and primary follicles. Mantle cell lymphoma more often
affects men and frequently presents with advanced disease
with bone marrow involvement.26 A pattern of multiple
lymphomatous polyposis is a classic clinical and gross
appearance,12 but this is not specific for mantle cell
lymphoma. Similar to low-grade FL, mantle cell lymphoma
is typically composed of a monotonous population of
irregular cells with scant cytoplasm, sometimes with a
vaguely nodular appearance. Immunohistochemistry read-
ily distinguishes mantle cell lymphoma from FL: the former
expresses cyclin D1 but not CD10.26 Extranodal marginal
zone lymphoma shows a vaguely nodular and diffuse
proliferation of atypical lymphocytes with clear cytoplasm,
and reactive germinal centers. However, colonization of
follicles by neoplastic lymphocytes may mimic atypical
follicles and lead to a mistaken diagnosis of FL.
Immunohistochemically, marginal zone lymphomas lack
expression of CD10 and Bcl6. Identification of IGH/BCL2
by routine karyotype, FISH, or PCR enables a specific
diagnosis of FL in difficult cases.
The treatment of FL of the GI tract incorporates
various modalities, including surgery, chemotherapy,
immunotherapy, and radiotherapy. The varied treatments
in our study and the generally good outcome for FL make
it difficult to make recommendations on specific thera-
pies. However, in our series, surveillance did not have a
significantly different outcome than chemotherapy or
radiation therapy. This outcome is similar to Mori et al20
who found that surveillance is an acceptable approach for
most patients with duodenal FL.
Thirty-two (94%) of 34 cases for whom stage is
known were stage I (65%) or II (29%), consistent with the
data in the literature that most primary FLs of the GI tract
are low stage at diagnosis.5,11,13 As cases with widespread
disease are excluded, stage III disease is rare by definition.
In the series by Damaj et al,5 3 (12%) had stage IV with
minimal (<5%) bone marrow infiltration; we found 2
(6%) with blood or bone marrow involvement.
The prognosis for our patients with FL of the GI
tract seems to be very good. Twenty-seven (75%) of 36
patients with known follow-up are alive without clinical
evidence of disease after a median 4.5 years, and none of
our patients died of lymphoma as of yet. However, a few
patients who initially had low-grade lymphoma pro-
gressed with involvement of distant lymph nodes (2 cases)
or suffered transformation to diffuse large B-cell lympho-
ma with “double-hit” rearrangements of BCL2 and MYC
in the bone marrow and CSF (1 case). Shia et al28

1262 | www.ajsp.com r 2011 Lippincott Williams & Wilkins

Am J Surg Pathol  Volume 35, Number 9, September 2011
reported recurrence in 5 of 15 patients who had a
complete response to treatment, but none of their 26
patients died of lymphoma within 4 to 122 months. Their
estimated 5-year disease-free survival rate was 62%.28 In
the series by Damaj et al,5 most patients (20 of 25, 80%)
achieved complete or partial remission or had stable
disease at a median of 34 weeks follow-up. However, 2
patients had progressive disease, and another 2 died of
lymphoma after transformation to a more aggressive
subtype. FL of the GI tract has been described as indolent
relative to nodal FL,11,13 but as most series exclude cases
with widespread nodal disease, the good prognosis may
be a function of low stage. In 1 study comparing
extranodal FL with nodal FL, overall and disease-specific
survival of patients with stage 1E or 2E FL of the GI tract
was similar to patients with stage 1 or 2 nodal FLs.32
In summary, FL restricted to the GI tract and
regional lymph nodes is an uncommon lymphoma that
has a predilection for the duodenum and predominantly
affects middle-aged women. The tumor is almost always
grade 1 to 2 and has morphologic and genetic similarities
to nodal FL. The tumor has a favorable prognosis even
when the disease is disseminated.
REFERENCES
1. Bartolo D, Goepel JR, Parsons MA. Rectal malignant lymphoma in
chronic ulcerative colitis. Gut. 1982;23:164–168.
2. Cirillo M, Federico M, Curci G, et al. Primary gastrointestinal
lymphoma: a clinicopathological study of 58 cases. Haematologica.
1992;77:156–161.
3. Contreary K, Nance FC, Becker WF. Primary lymphoma of the
gastrointestinal tract. Ann Surg. 1980;191:593–598.
4. Crump M, Gospodarowicz M, Shepherd FA. Lymphoma of the
gastrointestinal tract. Semin Oncol. 1999;26:324–337.
5. Damaj G, Verkarre V, Delmer A, et al. Primary follicular lymphoma
of the gastrointestinal tract: a study of 25 cases and a literature
review. Ann Oncol. 2003;14:623–629.
6. Domizio P, Owen RA, Shepherd NA, et al. Primary lymphoma of
the small intestine: a clinicopathological study of 119 cases. Am J
Surg Pathol. 1993;17:429–442.
7. Esaki M, Matsumoto T, Nakamura S, et al. Capsule endoscopy
findings in intestinal follicular lymphoma. Endoscopy. 2007;39
(suppl 1):E86–E87.
8. Franssila KO, Jaser N, Sivula A. Gastrointestinal non-Hodgkin’s
lymphoma: a population-based clinicopathological study of 111 adult
cases with a follow-up of 10 to 15 years. APMIS. 1993;101:631–641.
9. Hatano B, Ohshima K, Tsuchiya T, et al. Clinicopathological
features of gastric B-cell lymphoma: a series of 317 cases. Pathol Int.
2002;52:677–682.
10. Higuchi N, Sumida Y, Nakamura K, et al. Impact of double-
balloon endoscopy on the diagnosis of jejunoileal involvement in
primary intestinal follicular lymphomas: a case series. Endoscopy.
2009;41:175–178.
11. Huang WT, Hsu YH, Yang SF, et al. Primary gastrointestinal
follicular lymphoma: a clinicopathologic study of 13 cases from
Taiwan. J Clin Gastroenterol. 2008;42:997–1002.
12. Kodama T, Ohshima K, Nomura K, et al. Lymphomatous
polyposis of the gastrointestinal tract, including mantle cell
lymphoma, follicular lymphoma and mucosa-associated lymphoid
tissue lymphoma. Histopathology. 2005;47:467–478.
13. Kodama M, Kitadai Y, Shishido T, et al. Primary follicular
lymphoma of the gastrointestinal tract: a retrospective case series.
Endoscopy. 2008;40:343–346.
14. Kojima M, Nakamura S, Kurabayashi Y, et al. Primary malignant
lymphoma of the intestine: clinicopathologic and immunohisto-
chemical studies of 39 cases. Pathol Int. 1995;45:123–130.
r 2011 Lippincott Williams & Wilkins
Primary Follicular Lymphoma of the GI Tract
15. LeBrun DP, Kamel OW, Cleary ML, et al. Follicular lymphomas
of the gastrointestinal tract. Pathologic features in 31 cases and
bcl-2 oncogenic protein expression. Am J Pathol. 1992;140:1327–1335.
16. Lee J, Kim WS, Kim K, et al. Intestinal lymphoma: exploration of
the prognostic factors and the optimal treatment. Leuk Lymphoma.
2004;45:339–344.
17. Lewin KJ, Ranchod M, Dorfman RF. Lymphomas of the
gastrointestinal tract: a study of 117 cases presenting with
gastrointestinal disease. Cancer. 1978;42:693–707.
18. Matsuura M, Nakase H, Mochizuki N. Ileal polyposis caused by
follicular lymphoma. Clin Gastroenterol Hepatol. 2007;5:e30.
19. Misdraji J, Fernandez del Castillo C, Ferry JA. Follicle center
lymphoma of the ampulla of Vater presenting with jaundice: report
of a case. Am J Surg Pathol. 1997;21:484–488.
20. Mori M, Kobayashi Y, Maeshima AM, et al. The indolent course
and high incidence of t(14;18) in primary duodenal follicular
lymphoma. Ann Oncol. 2010;21:1500–1505.
21. 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.
22. Nakamura S, Matsumoto T, Takeshita M, et al. A clinicopathologic
study of primary small intestine lymphoma: prognostic significance
of mucosa-associated lymphoid tissue-derived lymphoma. Cancer.
2000;88:286–294.
23. Nakamura S, Matsumoto T, Umeno J, et al. Endoscopic features of
intestinal follicular lymphoma: the value of double-balloon entero-
scopy. Endoscopy. 2007;39 (suppl 1):E26–E27.
24. Poggi MM, Cong PJ, Coleman CN, et al. Low-grade follicular
lymphoma of the small intestine. J Clin Gastroenterol. 2002;34:155–159.
25. Sakata Y, Iwakiri R, Sakata H, et al. Primary gastrointestinal
follicular center lymphoma resembling multiple lymphomatous
polyposis. Dig Dis Sci. 2001;46:567–570.
26. Salar A, Juanpere N, Bellosillo B, et al. Gastrointestinal involve-
ment in mantle cell lymphoma: a prospective clinic, endoscopic, and
pathologic study. Am J Surg Pathol. 2006;30:1274–1280.
27. Sato Y, Ichimura K, Tanaka T, et al. Duodenal follicular
lymphomas share common characteristics with mucosa-associated
lymphoid tissue lymphomas. J Clin Pathol. 2008;61:377–381.
28. Shia J, Teruya-Feldstein J, Pan D, et al. Primary follicular
lymphoma of the gastrointestinal tract: a clinical and pathologic
study of 26 cases. Am J Surg Pathol. 2002;26:216–224.
29. Snuderl M, Kolman OK, Chen YB, et al. B-cell lymphomas with
concurrent IGH-BCL2 and MYC rearrangements are aggressive
neoplasms with clinical and pathologic features distinct from Burkitt
lymphoma and diffuse large B-cell lymphoma. Am J Surg Pathol.
2010;34:327–340.
30. Takata K, Sato Y, Nakamura N, et al. Duodenal and nodal
follicular lymphomas are distinct: the former lacks activation-
induced cytidine deaminase and follicular dendritic cells despite
ongoing somatic hypermutations. Mod Pathol. 2009;22:940–949.
31. Tang Z, Jing W, Lindeman N, et al. One patient, two lymphomas.
Simultaneous primary gastric marginal zone lymphoma and primary
duodenal follicular lymphoma. Arch Pathol Lab Med. 2004;128:
1035–1038.
32. Weinberg OK, Ma L, Seo K, et al. Low stage follicular lymphoma:
biologic and clinical characterization according to nodal or
extranodal primary origin. Am J Surg Pathol. 2009;33:591–598.
33. Yanai S, Nakamura S, Takeshita M, et al. Translocation t(14;18)/
IGH-BCL2 in gastrointestinal follicular lymphoma: correlation with
clinicopathologic features in 48 patients. Cancer. 2010. [Epub ahead
of print].
34. Yoshida N, Nomura K, Wakabayashi N, et al. Cytogenetic and
clinicopathological characterization by fluorescence in situ hybridi-
zation on paraffin-embedded tissue sections of twenty-six cases with
malignant lymphoma of small intestine. Scand J Gastroenterol.
2006;41:212–222.
35. Yoshino T, Miyake K, Ichimura K, et al. Increased incidence of
follicular lymphoma in the duodenum. Am J Surg Pathol. 2000;
24:688–693.
www.ajsp.com | 1263