2462

Primary Gastrointestinal Lymphoma in Japan

A Clinicopathologic Analysis of 455 Patients with Special Reference to
its Time Trends

Shotaro Nakamura, M.D.1

Takayuki Matsumoto, M.D.1
Mitsuo Iida, M.D.1
Takashi Yao, M.D.2
Masazumi Tsuneyoshi, M.D.2
1

Department of Medicine and Clinical Science,

Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Department of Anatomic Pathology, Pathological

Sciences, Graduate School of Medical Sciences,
Kyushu University, Fukuoka, Japan.

BACKGROUND. An optimal treatment modality for patients with primary gastrointestinal lymphoma has not yet been established. This study aimed to elucidate the
clinicopathologic features of this disease and the influence of therapeutic modalities on the prognosis in Japanese patients
METHODS. The clinicopathologic features of 455 patients with primary gastrointestinal lymphoma were investigated retrospectively regarding treatment modalities
and time trends.

RESULTS. This study comprised 342 patients (75%) with gastric lymphoma, 96
patients (22%) with intestinal lymphoma, and 17 patients (4%) with both gastric
and intestinal lymphoma. Two hundred thirty-one (51%) patients were classified as
having low-grade B-cell lymphoma including 200 marginal zone lymphoma of
mucosa-associated lymphoid tissue (MALT) type, 185 (41%) patients were classified as having high-grade B-cell lymphoma including 76 diffuse large cell lymphoma plus MALT lymphoma, and 39 (9%) patients were classified as having T-cell
lymphoma. The frequency of nonsurgical treatment, including Helicobacter pylori
eradication, chemotherapy, and radiation, increased during the latest decade.
Patients who received nonsurgical treatment showed a better overall survival than
those treated by surgery, but event-free survival did not differ between two groups.
Cox multivariate analysis revealed that early stage, younger age, gastric localization, B-cell phenotype, and absence of B symptoms were independent prognostic
factors for better overall and event-free survivals. Mucosa-associated lymphoid
tissue-derived lymphoma was also an independent prognostic factor for event-free
survival, but not for overall survival.
CONCLUSIONS. Nonsurgical treatment may be an optimal therapeutic modality for
patients with primary gastrointestinal lymphoma. Cancer 2003;97:246273.
2003 American Cancer Society.
DOI 10.1002/cncr.11415
KEYWORDS: gastrointestinal tract, malignant lymphoma, mucosa-associated lymphoid tissue, Helicobacter pylori, nonsurgical treatment, time trends.

Address for reprints: Shotaro Nakamura, M.D.,

Department of Medicine and Clinical Science,
Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 8128582, Japan; Fax: (011) 81-92-642-5273;
E-mail: shonaka@intmed2.med.kyushu-u.ac.jp
Received December 3, 2002; revision received
February 10, 2003; accepted February 12, 2003.
2003 American Cancer Society

rimary gastrointestinal lymphoma is the most frequent type of

extranodal malignant lymphoma, accounting for 30 45% of all
extranodal lymphomas and for 4 20% of all non-Hodgkin lymphomas.1 4 Although many published articles have reported on various
prognostic factors for primary gastrointestinal lymphoma,525 the
number of subjects in such series was small. In addition, the majority
of patients in these reports were treated by surgery-based modalities.
During the past two decades, the diagnosis and treatment of
gastrointestinal lymphoma have changed tremendously. Isaacson
and Wright26 introduced the concept of mucosa-associated lymphoid

Gastrointestinal Lymphoma in Japan/Nakamura et al.

tissue (MALT) lymphoma in 1983. This new categorization of lymphoma has become widely accepted and
has been incorporated into the Revised EuropeanAmerican Lymphoma27 and World Health Organization (WHO) classifications.28 To maintain patients
quality of life, nonsurgical treatments such as Helicobacter pylori eradication, chemotherapy, and radiation are becoming increasingly popular even for patients with resectable gastrointestinal lymphoma.29 31
However, the optimal treatment for this disease still
remains controversial.
Previous studies on the prognostic factors of primary gastric32 and intestinal33 lymphomas included
mainly patients who underwent surgical resections.
However, in recent years, patients with gastrointestinal lymphomas have received nonsurgical treatments
at our institution (Kyushu University, Fukuoka, Japan).34 In addition, the prognostic data on patients
with lymphoma of multiple involvements remain to
be elucidated. To determine the prognostic factors for
gastrointestinal lymphoma and to evaluate the influence of therapeutic modalities on the prognosis, we
analyzed a large number of patients with special reference to the MALT concept and time trends.

MATERIALS AND METHODS

Subjects
The series consisted of 455 consecutive adult Japanese patients with primary gastrointestinal lymphoma who were diagnosed at Kyushu University
between 1963 and 2002. All cases satisfied the criteria for primary gastrointestinal lymphoma as defined by Lewin et al.6 The subjects in our previous
studies3234 were included in the current study. Pediatric patients younger than 15 years of age were
excluded from this study. Based on the time of the
initial diagnosis, we divided the times into eight
segments of 5 years each. Subsequently, these segments were subgrouped into the following three
periods: Period A (19631982, before the introduction of MALT lymphoma26); Period B (19831992,
after the introduction of MALT lymphoma); and Period
C (19932002, after the introduction of H. pylori
eradication for gastric MALT lymphoma29).

Histologic Classification
All histologic materials were obtained by endoscopic
biopsy, surgery, and/or autopsy. These tissue specimens were stained routinely with hematoxylin and
eosin (H & E). Immunohistochemical staining for CD3
and CD20 was performed on all 455 specimens. In
some selected cases, additional staining was done using antibodies CD5, CD10, CD23, CD30, CD56, cyclin

2463

D1, bcl-2, bcl-6, c-myc, p53, Ki-67, immunoglobulin

light chains (, ), or F1. All H & E and immunohistochemical slides were reviewed separately by two
observers (S.N. and T.Y.) and a common consensus
was reached in all cases.
Histologic classification was done according to
WHO criteria28 with the following modifications:33
low-grade B-cell lymphomas comprised marginal zone
B-cell lymphoma of MALT type (MALT lymphoma), follicular lymphoma, mantle cell lymphoma, and plasmacytoma; high-grade B-cell lymphomas comprised diffuse
large B-cell lymphoma (DLBL) plus MALT lymphoma
(formerly referred to as high-grade MALT lymphoma35),
DLBL without MALT lymphoma, Burkitt lymphoma, or
lymphoblastic lymphoma; and T-cell lymphoma.
Marginal zone B-cell lymphoma (MALT lymphoma) was defined as a diffuse proliferation of
centrocytelike cells with lymphoepithelial lesions.26,35 Diffuse large B-cell lymphomas were divided into two entities according to the presence or
absence of MALT lymphoma areas.33 Immunoproliferative small intestinal disease (IPSID) was classified into either marginal zone B-cell lymphoma or
DLBL plus MALT lymphoma.35 Therefore, each lymphoma was divided histologically into either MALTderived lymphoma (marginal zone B-cell lymphoma
and DLBL plus MALT lymphoma) or nonMALT-derived lymphoma (others).33

Staging and Diagnostic Procedures

The stage of lymphoma was determined according
to the Lugano International Conference classification (I, II1, II2, IIE, or IV), which was proposed as a
modified version of the Ann Arbor criteria for gastrointestinal lymphoma.36 The staging workup included physical examination with inspection of the
Waldeyer tonsillar ring, blood cell count and serum
chemistry, chest radiographs (all patients), abdominal ultrasound (416 patients), computed tomography scan of the chest and abdomen (334 patients),
gallium scintigraphy (248 patients), and bone marrow aspiration or biopsy (357 patients). Endoscopy
with biopsy and/or barium studies of the upper and
lower gastrointestinal tracts were used to assess the
extent of lymphoma.
The macroscopic type of lymphoma was either
superficial, polypoid, ulcerative, polyposis, diffuse, or
mixed type.32,33 This typing was determined based on
the resected specimens or on the double-contrast radiographs with endoscopic findings. The depth of tumor invasion was determined by endoscopic ultrasonography in 150 patients.34 Otherwise, the depth

2464

CANCER May 15, 2003 / Volume 97 / Number 10

TABLE 1
Histologic Classification and Sites of Origin
Histologic type
Low-grade B-cell lymphoma
Marginal zone lymphoma (MALT)
Follicular lymphoma
Mantle cell lymphoma
Plasmacytoma
High-grade B-cell lymphoma
DLBL plus MALT lymphoma
DLBL without MALT lymphoma
Burkitt lymphoma
Lymphoblastic lymphoma
T-cell lymphoma

Gastric group
(n 342) (%)

Intestinal group
(n 96) (%)

Combined group
(n 17) (%)

Total
(n 455) (%)

170 (50)
20 (6)
0
2 (0.6)

27 (28)
7 (7)
2 (2)
0

3 (18)
0
0
0

200 (44)
27 (6)
2 (0.4)
2 (0.4)

52 (15)
77 (23)
1 (0.3)
1 (0.3)
19 (6)

20 (21)
20 (21)
5 (5)
3 (3)
12 (13)

4 (23)
2 (12)
0
0
8 (47)

76 (17)
99 (22)
6 (1.3)
4 (0.8)
39 (9)

MALT: mucosa-associated lymphoid tissue; DLBI: diffuse large B-cell lymphoma.

was determined by histology of the resected specimens.

Treatment and Response

Therapeutic modalities were divided into either surgical resection, nonsurgical treatment (chemotherapy,
radiation, or antibiotic treatment such as H. pylori
eradication), or both. Complete remission (CR) was
defined as the disappearance of all clinical evidence of
lymphoma. Partial remission was defined as a decrease of 50% or greater in the sum of the tumors. No
response was defiend as tumor reduction of less than
50%, or disease progression.

Prognosis and Statistical Analysis

Overall survival (OS) was measured from the date of
diagnosis to death from any cause. Event-free survival
(EFS) was measured from the date of diagnosis to
disease progression, disease recurrence, or death from
any cause. The probability of OS and EFS was calculated by the KaplanMeier method and the value was
compared using the log rank test. All variables that
influenced the prognosis (P 0.1) were put into a
multivariate analysis using the Cox proportional hazards model. Other statistical differences were evaluated using either the Fisher exact probability test, the
chi-square test, the MannWhitney U test, or the
KruskalWallis test. A value of P less than 0.05 for each
test was statistically significant. For multiple comparisons, however, P values were interpreted after the
Bonferroni correction. All statistical analyses were performed using the Statistical Software Package for the
Social Sciences version 8.0J (SPSS Japan Inc., Tokyo,
Japan).

RESULTS
Clinical and Histologic Features
The 455 patients had a mean age of 58 years (range,
16 90 years) and comprised 247 men and 208 women.
The most frequent primary site was the stomach (gastric group; 342 patients [75%]), followed by the intestine (intestinal group; 96 patients, [21%]). The remaining 17 (3.7%) patients had both gastric and intestinal
involvement (combined group). Among patients in the
gastric group, 93 had tumors mainly in the upper third
portion, 132 in the middle third, 76 in the lower third,
and 41 in two or all portions. Among patients in the
intestinal group, 6 had tumors in the duodenum, 10 in
the jejunum, 43 in the ileum, 6 in the duodenum,
jejunum, and ileum, 11 in the ileocecal region, 13 in
the colorectum, 1 in the appendix, and 6 in both small
and large bowel.
The histologic classification and primary site are
shown in Table 1. The study sample comprised 200
(44%) patients who were classified as marginal zone
B-cell lymphoma, 27 (5.9%) as follicular lymphoma, 2
(0.4%) as mantle cell lymphoma, 2 (0.4%) as plasmacytoma, 76 (17%) as DLBL plus MALT lymphoma, 99
(22%) as DLBL without MALT lymphoma, 6 (1.3%) as
Burkitt lymphoma, 4 (0.8%) as lymphoblastic lymphoma, and 39 (9%) as T-cell lymphoma. In the gastric
group, marginal zone B-cell lymphoma was the most
frequent histologic type (50%), whereas DLBL and Tcell lymphoma were the most frequent types in the
intestinal (43%) and combined groups (47%), respectively.
Two hundred forty-eight patients (55%) had Stage
I disease, 95 (21%) had Stage II1 disease, 56 (12%) had
Stage II2 disease, 10 (2.2%) had Stage IIE disease, and

Gastrointestinal Lymphoma in Japan/Nakamura et al.

2465

TABLE 2
Comparison of Clinicopathologic Features and Sites of Origin
Characteristics
Mean age (yrs)
Gender
Male
Female
Histology
Low-grade B-cell
High-grade B-cell
T-cell
Stage
I
II1/II2
IIE/IV
Depth of invasion
Mucosa/submucosa
Beyond submucosa
Treatment
Surgery alone
Nonsurgical
Both
No
Response to treatment (n 445)
Complete remission
Partial remission
No response

Gastric
(n 342) (%)

Intestinal
(n 96) (%)

Combined
(n 17) (%)

P valuea

57.8

58.3

57.6

NS

172 (50)
170 (50)

64 (67)
32 (33)

11 (65)
6 (35)

0.0118

192 (56)
131 (38)
19 (6)

36 (38)
48 (50)
12 (13)

3 (18)
6 (35)
8 (47)

0.0001

215 (63)
94 (28)
33 (10)

30 (31)
53 (55)
13 (14)

3 (18)
4 (24)
10 (59)

0.0001

181 (53)
161 (47)

20 (21)
76 (79)

7 (41)
10 (59)

178 (52)
78 (23)
82 (24)
4 (1)
(n 338)
312 (92)
23 (7)
3 (1)

45 (47)
15 (16)
34 (35)
2 (2)
(n 94)
64 (68)
21 (22)
9 (10)

0
9 (53)
4 (24)
4 (24)
(n 13)
2 (15)
6 (46)
5 (39)

0.0001

0.0001

0.0001

NS: not significant.

a
P 0.007 is significant using the Bonferroni correction.

46 (10%) had Stage IV disease. Macroscopically, 155

tumors (34%) were classified as superficial type, 95
(21%) as polypoid type, 119 (26%) as ulcerative type, 6
(1.3%) as polyposis type, 40 (9%) as diffuse type, and
40 (9%) as mixed type.
Two hundred twenty-three patients (49%) underwent surgical resection alone, whereas 102 (22%) received nonsurgical treatment (60 had H. pylori eradication alone, 16 chemotherapy alone, 15 eradication
plus chemotherapy, 5 eradication plus radiation, 2
chemotherapy plus radiation, and 4 eradication plus
chemotherapy and radiation). Major regimens for H.
pylori eradication consisted of a proton pump inhibitor (omeprazole, lansoprazole, or rabeprazole) with a
combination of antibiotics (amoxicillin plus clarithromycin with or without metronidazole) for 14 days. A
combination of both surgery and nonsurgical treatment was performed in 120 patients (26%); 105 were
treated by surgery plus chemotherapy, 4 by surgery
after eradication, 4 by surgery after eradication plus
chemotherapy, and 7 by surgery plus chemotherapy
and radiation. The remaining 10 patients (2%) did
not receive any treatment. Among the 153 patients

treated by chemotherapy, 142 received four or six

cycles of the cyclophosphamide, doxorubicin, vincristine, and prednisolone regimen and the remaining 11 patients were treated by oral monochemotherapy with cyclophosphamide.34 Of the 445
treated patients, 378 patients (83%) achieved a CR,
50 (11%) achieved a partial remission, and 17 (4%)
showed no response.

Relationship between Clinicopathologic Features and

Primary Site of Lymphoma
Table 2 indicates the clinicopathologic features of the
three groups classified by primary site of lymphoma.
Male patients predominated in both the intestinal and
combined groups. The most frequent histologic subgroup was low-grade B-cell lymphoma in the gastric
group, high-grade B-cell lymphoma in the intestinal
group, and T-cell lymphoma in the combined group
(P 0.0001). The clinical stage also differed among
the three groups: 63% of the patients in the gastric
group had Stage I disease, 55% of patients in the
intestinal group had intermediate-stage disease (i.e.,
Stage II1 or II2), and 59% of patients in the combined

2466

CANCER May 15, 2003 / Volume 97 / Number 10

number of patients in the gastric and intestinal

groups, increased over time. An analysis of three chronologic periods revealed that 144 patients (32%) belonged to Period A, 117 (26%) to Period B, and 194
(43%) to Period C. Table 3 comparatively shows the
clinicopathologic findings of patients in Periods AC.
Over these three periods, the average age of patients
increased from 52 years to 61 years (P 0.0001),
whereas the male-to-female ratio did not change. The
histology and depth of tumor invasion did not differ
between Periods A and B. However, the frequency of
low-grade B-cell lymphomas and tumors restricted to
the submucosa increased in Period C. In addition, the
frequency of the combined group, as well as that of
advanced-stage disease (i.e., Stage IIE or IV), increased
in Period C.
Nonsurgical treatment was applied more frequently to the patients in Period C than in the earlier
two periods (P 0.0001). Antibiotic treatment such as
H. pylori eradication was performed in 91 of the 194
(47%) patients in Period C, but only in two patients
with IPSID in the former two periods. The response to
treatment did not change over the three periods.
Greater than 80% of the patients achieved CR in each
period.

Survival and Prognostic Factors

FIGURE 1.

Trends in the number of patients with primary gastrointestinal

lymphoma among eight chronologic segments. (A) All patients (n 455). (B)
Patients with gastric lymphoma (n 342) and intestinal lymphoma (n 96).

group had advanced-stage disease (i.e., Stage IIE or

IV). Tumor invasion was deeper among patients in the
intestinal group compared with the other two groups.
The therapeutic modalities did not differ between
the gastric group and intestinal groups. Nonsurgical
treatment was applied more frequently in the combined group than in the other two groups. The response to treatment differed among the three groups:
CR was achieved in 92% of the patients in the gastric
group compared with 68% of patients in the intestinal
group and only 15% of patients in the combined group.

Time Trends of Gastrointestinal Lymphoma

There were 14, 30, 48, 52, 58, 59, 96, and 98 patients,
respectively, in eight chronologic segments. As shown
in Figure 1, the number of all patients, as well as the

Ten patients who did not receive any treatment were

excluded from the follow-up analysis. The follow-up
after the diagnosis in 445 treated patients ranged from
1 to 366 months (mean, 56 months). The OS and EFS
rates after 5 years were 72% and 68%, respectively.
Among the three groups classified by site (Table
4), the gastric group showed the highest OS and EFS
rates, whereas the intestinal group showed intermediate values and the combined group showed the lowest
values (P 0.0001; Fig. 2). Significant differences were
also observed between the gastric and intestinal
groups (OS, P 0.0001), but not between the intestinal and combined groups (OS, P 0.2269). Patients
with low-grade B-cell lymphoma had better OS and
EFS rates than patients with high-grade B-cell lymphoma (OS, P 0.0001). Patients with T-cell lymphoma had poorer OS and EFS rates compared with
patients with high-grade B-cell lymphoma (OS, P
0.0001; Fig. 3). Patients with Stage I disease had
better OS and EFS rates compared with patients with
Stage II1 or II2 (OS, P 0.0001) or patients with Stage
IIE or IV disease (OS, P 0.0001). A significant difference was also found between the latter two groups
(OS, P 0.0002). Patients with MALT-derived lymphoma demonstrated significantly better OS and EFS

Gastrointestinal Lymphoma in Japan/Nakamura et al.

2467

TABLE 3
Comparison of the Clinicopathologic Features and Chronologic Periods

Mean age (yrs)

Gender
Male
Female
Site of origin
Gastric
Intestinal
Combined
Histology
Low-grade B-cell
High-grade B-cell
T-cell
Stage
I
II1/II2
IIE/IV
Depth of invasion
Mucosa/submucosa
Beyond submucosa
Treatment
Surgery alone
Nonsurgical
Both
No
Response to treatment (n 445)
Complete remission
Partial remission
No response

Period A
(n 144) (%)

Period B
(n 117) (%)

Period C
(n 194) (%)

P valuea

52.0

59.3

61.4

0.0001

79 (55)
65 (45)

67 (57)
50 (43)

101 (52)
93 (48)

NS

119 (83)
24 (17)
1 (0.7)

86 (74)
29 (25)
2 (2)

137 (71)
43 (22)
14 (7)

0.0047

62 (43)
70 (49)
12 (8)

52 (44)
54 (46)
11 (9)

117 (60)
61 (31)
16 (8)

0.0091

90 (63)
44 (31)
10 (7)

51 (44)
54 (46)
12 (10)

107 (55)
53 (27)
34 (18)

0.0004

59 (41)
85 (59)

44 (38)
73 (62)

105 (54)
89 (46)

70 (60)
4 (3)
39 (33)
4 (3)
(n 113)
98 (87)
12 (11)
3 (3)

39 (20)
96 (49)
55 (28)
4 (2)
(n 190)
157 (83)
20 (11)
13 (7)

114 (79)
2 (1)
26 (18)
2 (1)
(n 142)
123 (87)
18 (13)
1 (0.7)

0.0069

0.0001

NS

NS: not significant.

a
P 0.006 is significant using the Bonferroni correction.

rates than non-MALT lymphoma patients (P 0.0001;

Fig. 4).
Patients with the following characteristcs had significantly better OS and EFS rates: younger age, female
gender, tumors restricted to the submucosa, superficial tumors, small tumors ( 8 cm), tumors without
perforation, absence of B symptoms, and radical resection. Patients who underwent nonsurgical treatment showed a better OS than those who had surgerybased modalities (P 0.0118). However, such a
difference was not found in EFS (P 0.3056; Fig. 5).
Chronologically, patients in Period C (19932002)
demonstrated a better OS than those in the earlier two
periods (P 0.0108), but EFS did not differ among the
groups (P 0.6823).
Results of multivariate analysis are shown in Table
5. Significant independent prognostic factors for better OS and EFS were early stage, younger age, gastric
localization, B-cell phenotype, and absence of B
symptoms. The presence of MALT-derived lymphoma

was not a significant factor for OS, but it was a significant independent prognostic factor for EFS. A time
trend was a significant prognostic factor for OS, but
not for EFS.

DISCUSSION
There are many publications regarding the prognosis
of primary gastrointestinal lymphoma. However, most
of these studies analyzed a small number of subjects
and only five recruited more than 300 patients.2,17,2325
The current study is the second largest series, which
follows an earlier study by Freeman et al.2 Table 6
shows the primary site of gastrointestinal lymphoma
in five studies,2,17,2325 together with a larger population-based report by Gurney et al.37 The most common primary site was the stomach with a frequency
ranging from 44% to 75%. In our series, the gastric
group comprised 75% of all patients. This percentage
was similar to that in studies from Austria17 and Germany25 and the value is higher than that observed in

2468

CANCER May 15, 2003 / Volume 97 / Number 10

TABLE 4
Significant Prognostic Factors on Univariate Analysis
Overall survival

Age (yrs)
57 or younger
58 or older
Gender
Male
Female
Site of origin
Gastric
Intestinal
Combined
Histology
Low-grade B
High-grade B
T-cell
MALT-derived
Yes
No
Depth of tumor
Within submucosa
Beyond submucosa
Stage
I
II1/II2
IIE/IV
Macroscopic type
Superficial
Others
Size of tumor (cm)
8
8 or more
Perforation
Yes
No
B symptoms
Yes
No
Radical surgery
Yes
No
Treatment
No surgery
Surgery-based
Period
A/B (19631992)
C (19932002)

Event-free survival

No. of patients

5-Yr (%)

P valuea

5-Yr (%)

P valuea

202
243

81
64

0.0001

79
59

0.0001

243
202

68
77

0.0022

64
73

0.0008

338
94
13

77
58
16

0.0001

74
53
25

0.0001

228
181
36

87
63
27

0.0001

81
60
27

0.0001

272
173

84
54

0.0001

79
52

0.0001

203
242

86
60

0.0001

80
59

0.0001

244
148
53

87
62
26

154
291

88
64

0.0001

82
61

0.0001

248
197

78
65

0.0149

74
62

0.0270

10
435

0
73

0.0001

0
69

0.0001

67
378

45
77

0.0001

38
74

0.0001

158
287

82
66

0.0015

80
61

0.0003

102
343

86
69

0.0118

71
67

0.3056

255
190

68
79

0.0108

68
70

0.6823

0.0001

82
60
23

0.0001

MALT: mucosa-associated lymphoid tissue.

a
Assessed by the log-rank test.

four other studies.2,23,24,37 Geographic variations in the

prevalence of H. pylori infection, celiac disease, or
other environmental factors may be the cause of the
difference.35,38,39 In Middle Eastern countries, the frequency of intestinal lymphoma is high (range, 49

81%). This may be partly explained by the high prevalence of IPSID in these areas.22,40,41
Among the three groups classified by primary site,
histology and clinical stage were different. The gastric
group contained a predominance of early-stage, low-

Gastrointestinal Lymphoma in Japan/Nakamura et al.

FIGURE 2. The survival curves for 445 patients with primary gastrointestinal
lymphoma as stratified by the three groups according to anatomic site of origin.
(A) Overall survival among three groups (P 0.0001). Gastric versus intestinal
group (P 0.0001) and intestinal versus combined group (P 0.2269). (B)
Event-free survival among three groups (P 0.0001). Gastric versus intestinal
group (P 0.0001) and intestinal versus combined group (P 0.4832).

grade B-cell lymphomas, most of which were marginal

zone lymphomas. Conversely, the intestinal group
contained a predominance of intermediate-stage (II1
or II2), high-grade B-cell lymphomas and the combined group comprised a pedominance of advancedstage, T-cell lymphoma. These differences may have
been associated with the difference in response to
treatment and patient survival. A better prognosis for
gastric lymphoma compared with other localizations
has been described previously,1,4,8,11,17,18,21,24,25 although several authors showed no difference in the
prognosis between gastric lymphoma and intestinal
lymphoma.5,9,1315,19,20,22,23
Few publications have shown prognostic data on
patients with both gastric and intestinal involvement.

2469

FIGURE 3. The survival curves for 445 patients with primary gastrointestinal
lymphoma as stratified by the three histologic subgroups. (A) Overall survival
among the three groups (P 0.0001). Low-grade versus high-grade B-cell
type (P 0.0001) and high-grade B-cell versus T-cell type (P 0.0001). (B)
Event-free survival among the three groups (P 0.0001). Low-grade versus
high-grade B-cell type (P 0.0001) and high-grade B-cell versus T-cell type
(P 0.0001).

As found in our study, dAmore et al.23 demonstrated

that patients with combined gastric and intestinal involvement showed a significantly poorer survival than
patients with the involvement localized in the stomach or in the intestine. Similar results were reported
by Ruskone -Fourmestraux et al.18 and Koch et al.25
The poor prognosis of the combined group in our
study may have been associated with more frequent
T-cell phenotype and more advanced-stage disease. In
three studies,18,23,25 however, T-cell lymphomas were
extremely rare. This discrepancy may correlate with
the difference in the incidence of T-cell lymphoma
between Western countries and Japan.28,42

2470

CANCER May 15, 2003 / Volume 97 / Number 10

FIGURE 4. The survival curves for 445 patients with primary gastrointestinal

FIGURE 5. The survival curves for 445 patients with primary gastrointestinal

lymphoma as stratified by mucosa-associated lymphoid tissue (MALT)-derived

lymphoma versus non-MALT lymphoma. (A) Overall survival (P 0.0001). (B)
Event-free survival (P 0.0001).

lymphoma as stratified by nonsurgical treatment versus surgery-based modalities. (A) Overall survival (P 0.0118). (B) Event-free survival (P 0.3056).

The incidence of gastric and intestinal lymphoma

in the U.S.43,44 and Europe37 has increased over the
past two decades. Our data confirmed this trend even
in Japan (Fig. 1). Advances in diagnostic procedures
may have led to an improvement in the accuracy in
the diagnosis of lymphoma. In addition, an actual
increase in the occurrence of gastrointestinal lymphoma should also be considered. Increasing exposure or susceptibility to risk factors, such as H. pylori
infection, ultraviolet light, chemicals, and excessive
protein or fat in the diet, also may have contributed to
this increase.37,38
In Period C (19932002), both the number and the
proportion of low-grade B-cell lymphoma increased.
This is attributable to an increase in the diagnosis of
gastric MALT lymphoma by endoscopy with biopsy. In
earlier periods, a considerable number of patients

with gastric MALT lymphoma were diagnosed with

reactive lymphoid hyperplasia (pseudolymphoma) or
chronic gastritis.32,35 In addition, the increase in nonsurgical treatment in Period C seems to have owed to the
application of H. pylori eradication. Furthermore, the
increase in the number of patients in the combined
group and advanced-stage patients in Period C may be
due to recent improvements in staging modalities such
as colonoscopy.
Our multivariate analysis revealed an earlier stage,
younger age, gastric localization, B-cell phenotype,
and absence of B symptoms to be independent prognostic factors for better OS and EFS. However, these
prognostic factors may have a limited value because
this study was based on a retrospective analysis of
patients with different histologic types and heterogeneous treatment modalities over a prolonged period.
To our knowledge, 11 English studies performed a mul-

Gastrointestinal Lymphoma in Japan/Nakamura et al.

2471

TABLE 5
Independent Prognostic Factors Determined by Multivariate Analysis
Overall survival

Event-free survival

Variable

Coefficient/SE

P value

Coefficient/SE

P value

Stage (I vs. II1/II2 vs. IIE/IV)

Age
Gastric localization
Immunophenotype (B-cell vs. T-cell)
B symptoms
MALT-derived lymphoma
Time trends (19631993 vs. 19932002)

5.1198
4.0000
3.2978
2.3900
2.2113
1.5243
3.0536

0.0001
0.0001
0.0010
0.0168
0.0270
0.1275
0.0023

4.7564
3.8143
3.7568
3.2621
2.4404
2.1081
NE

0.0001
0.0001
0.0002
0.0011
0.0147
0.0350
NE

SE: standard error; MALT: mucosa-associated lymphoid tissue; NE: not evaluated.

TABLE 6
Sites of Origin in Primary Gastrointestinal Lymphoma in the Literature
Anatomic sites of origin (%)
Author (yr)

Nation

No. of patients

Gastric

Intestinal

Combined

Others

Freeman et al. (1972)2

Radaszkiewicz et al. (1992)17
dAmore et al. (1994)23
Liang et al. (1995)24
Gurney et al. (1999)37d
Koch et al. (2001)25
Current study (2003)

United States
Austria
Denmark
Hong Kong
United Kingdom
Germany
Japan

538
372
306
425
1047
371
455

346 (64)
258 (69)
175 (57)
238 (56)
463 (44)
277 (75)
342 (75)

192 (36)
71 (19)
109 (36)
184 (43)
440 (42)
70 (19)
96 (21)

ND
8 (2.2)a
22 (7.2)
ND
ND
24 (6.5)a
17 (3.7)

35 (9.4)b

3 (0.8)c
144 (14)b

ND: not described.

a
Cases involving multiple gastrointestinal tract organs.
b
Unspecified.
c
Cases with primary esophageal lymphoma.
d
Registry data without prognostic analysis.

tivariate analysis for prognostic factors on patients with

both gastric and intestinal lymphoma.9,1116,18,19,22,24
All but one15 demonstrated an early stage to be the
most significant prognostic factor for better survival.9,1114,16,18,19,22,24 The next most frequent independent prognostic factor was a younger age.11,15,16,18,24
Other factors reported to have contributed to survival
included female gender,11,12,22 surgical resection,13,14,18
low-grade histology,12,13,24 smaller size of tumor,15,24 and
a good performance status.15,22 Anatomic site (gastric
localization) was an independent prognostic factor in
two studies.12,18 No previous studies have shown the
prognostic significance of T/B-cell immunophenotype
in primary gastrointestinal lymphoma. In addition,
MALT-derived lymphoma including DLBL plus MALT
lymphoma was an independent prognostic factor for
EFS in the current study (Table 5). Similar results were
demonstrated in two previous studies.12,19
Chronologic periods significantly influenced OS,
but not EFS in our study. Weingrad et al.9 showed a

similar time trend toward a better survival in the latest

than the earliest period. However, a better OS may
have been biased by differences in the length of follow-up and by the number of deaths unrelated to
lymphoma.
It is important to note the fact that the type of
therapeutic modalities did not influence EFS and that
patients with nonsurgical treatment showed a better
OS than those treated by surgery. The role of surgery
in the treatment of gastrointestinal lymphoma has
been a matter of debate.1318,30,31,45,46 Although past
studies showed that surgical resectability was of significance, recent studies have demonstrated that nonsurgical strategies and surgery-based modalities had
an equivalent efficacy.30,31,45 Based on all these observations, and taking patients quality of life into consideration, nonsurgical treatment is an alternative and
optimal therapeutic modality for gastrointestinal lymphoma. Further randomized prospective studies with
a large number of patients are still needed to establish

2472

CANCER May 15, 2003 / Volume 97 / Number 10

the optimal management for patients with primary

gastrointestinal lymphoma.
20.

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