Primary Gastrointestinal Lymphoma in Japan 2003

7/30/2019 Primary Gastrointestinal Lymphoma in Japan 2003

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Primary Gastrointestinal Lymphoma in JapanA Clinicopathologic Analysis of 455 Patients with Special Reference toits 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 Uni-

versity, Fukuoka, Japan.

2 Department of Anatomic Pathology, Pathological

Sciences, Graduate School of Medical Sciences,

Kyushu University, Fukuoka, Japan.

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

Department of Medicine and Clinical Science,

Graduate School of Medical Sciences, Kyushu Uni-

versity, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-

8582, Japan; Fax: (011) 81-92-642-5273;

E-mail: [email protected]

Received December 3, 2002; revision received

February 10, 2003; accepted February 12, 2003.

BACKGROUND. An optimal treatment modality for patients with primary gastroin-

testinal lymphoma has not yet been established. This study aimed to elucidate the

clinicopathologic features of this disease and the influence of therapeutic modal-

ities on the prognosis in Japanese patients

METHODS. The clinicopathologic features of 455 patients with primary gastrointes-

tinal lymphoma were investigated retrospectively regarding treatment modalitiesand 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 classi-

fied as having high-grade B-cell lymphoma including 76 diffuse large cell lym-

phoma 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 localiza-

tion, 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. Cancer2003;97:246273.

2003 American Cancer Society.

DOI 10.1002/cncr.11415

KEYWORDS: gastrointestinal tract, malignant lymphoma, mucosa-associated lym-

phoid tissue, Helicobacter pylori, nonsurgical treatment, time trends.

Primary gastrointestinal lymphoma is the most frequent type ofextranodal malignant lymphoma, accounting for 3045% of allextranodal lymphomas and for 420% of all non-Hodgkin lympho-

mas.14 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

2462

2003 American Cancer Society


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tissue (MALT) lymphoma in 1983. This new categori-

zation of lymphoma has become widely accepted and

has been incorporated into the Revised European-

American Lymphoma27 and World Health Organiza-

tion (WHO) classifications.28 To maintain patients

quality of life, nonsurgical treatments such as Helico-bacter pylori eradication, chemotherapy, and radia-

tion are becoming increasingly popular even for pa-

tients with resectable gastrointestinal lymphoma.2931

However, the optimal treatment for this disease still

remains controversial.

Previous studies on the prognostic factors of pri-

mary gastric32 and intestinal33 lymphomas included

mainly patients who underwent surgical resections.

However, in recent years, patients with gastrointesti-

nal lymphomas have received nonsurgical treatments

at our institution (Kyushu University, Fukuoka, Ja-

pan).34

In addition, the prognostic data on patientswith lymphoma of multiple involvements remain to

be elucidated. To determine the prognostic factors for

gastrointestinal lymphoma and to evaluate the influ-

ence of therapeutic modalities on the prognosis, we

analyzed a large number of patients with special ref-

erence to the MALT concept and time trends.

MATERIALS AND METHODSSubjects

The series consisted of 455 consecutive adult Japa-

nese patients with primary gastrointestinal lym-

phoma who were diagnosed at Kyushu Universitybetween 1963 and 2002. All cases satisfied the crite-

ria for primary gastrointestinal lymphoma as de-

fined by Lewin et al.6 The subjects in our previous

studies3234 were included in the current study. Pe-

diatric 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 seg-

ments were subgrouped into the following three

periods: Period A (19631982, before the introduc-

tion 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 speci-

mens 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 us-

ing antibodies CD5, CD10, CD23, CD30, CD56, cyclin

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

light chains (, ), or F1. All H & E and immunohis-

tochemical 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 toWHO criteria28 with the following modifications:33

low-grade B-cell lymphomas comprised marginal zone

B-cell lymphoma of MALT type (MALT lymphoma), fol-

licular lymphoma, mantle cell lymphoma, and plasma-

cytoma; 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 lym-

phoma) was defined as a diffuse proliferation of

centrocytelike cells with lymphoepithelial le-sions.26,35 Diffuse large B-cell lymphomas were di-

vided into two entities according to the presence or

absence of MALT lymphoma areas.33 Immunopro-

liferative small intestinal disease (IPSID) was classi-

fied into either marginal zone B-cell lymphoma or

DLBL plus MALT lymphoma.35 Therefore, each lym-

phoma was divided histologically into either MALT-

derived lymphoma (marginal zone B-cell lymphoma

and DLBL plus MALT lymphoma) or nonMALT-de-

rived lymphoma (others).33

Staging and Diagnostic Procedures

The stage of lymphoma was determined according

to the Lugano International Conference classifica-

tion (I, II1, II2, IIE, or IV), which was proposed as a

modified version of the Ann Arbor criteria for gas-

trointestinal lymphoma.36 The staging workup in-

cluded physical examination with inspection of the

Waldeyer tonsillar ring, blood cell count and serum

chemistry, chest radiographs (all patients), abdom-

inal ultrasound (416 patients), computed tomogra-

phy scan of the chest and abdomen (334 patients),

gallium scintigraphy (248 patients), and bone mar-

row 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 ra-

diographs with endoscopic findings. The depth of tu-

mor invasion was determined by endoscopic ultra-

sonography in 150 patients.34 Otherwise, the depth

Gastrointestinal Lymphoma in Japan/Nakamura et al. 2463


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was determined by histology of the resected speci-

mens.

Treatment and Response

Therapeutic modalities were divided into either surgi-

cal 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 de-

crease of 50% or greater in the sum of the tumors. No

response was defiend as tumor reduction of less than50%, 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 calcu-

lated 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 haz-

ards model. Other statistical differences were evalu-

ated using either the Fisher exact probability test, the

chi-square test, the MannWhitney U test, or the

KruskalWallis test. A value of Pless than 0.05 for each

test was statistically significant. For multiple compar-

isons, however, P values were interpreted after the

Bonferroni correction. All statistical analyses were per-

formed using the Statistical Software Package for the

Social Sciences version 8.0J (SPSS Japan Inc., Tokyo,

Japan).

RESULTSClinical 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 (gas-

tric group; 342 patients [75%]), followed by the intes-

tine (intestinal group; 96 patients, [21%]). The remain-

ing 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 theintestinal 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 plasma-

cytoma, 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 lym-

phoma, 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 T-

cell lymphoma were the most frequent types in the

intestinal (43%) and combined groups (47%), respec-

tively.

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

TABLE 1Histologic Classification and Sites of Origin

Histologic type

Gastric group

(n 342) (%)

Intestinal group

(n 96) (%)

Combined group

(n 17) (%)

Total

(n 455) (%)

Low-grade B-cell lymphomaMarginal zone lymphoma (MALT) 170 (50) 27 (28) 3 (18) 200 (44)

Follicular lymphoma 20 (6) 7 (7) 0 27 (6)

Mantle cell lymphoma 0 2 (2) 0 2 (0.4)

Plasmacytoma 2 (0.6) 0 0 2 (0.4)

High-grade B-cell lymphoma

DLBL plus MALT lymphoma 52 (15) 20 (21) 4 (23) 76 (17)

DLBL without MALT lymphoma 77 (23) 20 (21) 2 (12) 99 (22)

Burkitt lymphoma 1 (0.3) 5 (5) 0 6 (1.3)

Lymphoblastic lymphoma 1 (0.3) 3 (3) 0 4 (0.8)

T-cell lymphoma 19 (6) 12 (13) 8 (47) 39 (9)

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

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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%) under-

went surgical resection alone, whereas 102 (22%) re-

ceived nonsurgical treatment (60 had H. pylori eradi-

cation 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 inhib-

itor (omeprazole, lansoprazole, or rabeprazole) with a

combination of antibiotics (amoxicillin plus clarithro-

mycin with or without metronidazole) for 14 days. A

combination of both surgery and nonsurgical treat-

ment 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, vin-

cristine, and prednisolone regimen and the remain-

ing 11 patients were treated by oral monochemo-

therapy 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 sub-

group 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

TABLE 2Comparison of Clinicopathologic Features and Sites of Origin

Characteristics

Gastric

(n 342) (%)

Intestinal

(n 96) (%)

Combined

(n 17) (%) Pvaluea

Mean age (yrs) 57.8 58.3 57.6 NSGender

Male 172 (50) 64 (67) 11 (65) 0.0118

Female 170 (50) 32 (33) 6 (35)

Histology

Low-grade B-cell 192 (56) 36 (38) 3 (18)

High-grade B-cell 131 (38) 48 (50) 6 (35) 0.0001

T-cell 19 (6) 12 (13) 8 (47)

Stage

I 215 (63) 30 (31) 3 (18)

II1/II2 94 (28) 53 (55) 4 (24) 0.0001

IIE/IV 33 (10) 13 (14) 10 (59)

Depth of invasion

Mucosa/submucosa 181 (53) 20 (21) 7 (41) 0.0001

Beyond submucosa 161 (47) 76 (79) 10 (59)

Treatment

Surgery alone 178 (52) 45 (47) 0

Nonsurgical 78 (23) 15 (16) 9 (53) 0.0001

Both 82 (24) 34 (35) 4 (24)

No 4 (1) 2 (2) 4 (24)

Response to treatment (n 445) (n 338) (n 94) (n 13)

Complete remission 312 (92) 64 (68) 2 (15) 0.0001

Partial remission 23 (7) 21 (22) 6 (46)

No response 3 (1) 9 (10) 5 (39)

NS: not significant.aP 0.007 is significant using the Bonferroni correction.



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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 com-

bined group than in the other two groups. The re-

sponse 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

number of patients in the gastric and intestinal

groups, increased over time. An analysis of three chro-

nologic periods revealed that 144 patients (32%) be-

longed 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 fre-

quently to the patients in Period C than in the earliertwo 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

Ten patients who did not receive any treatment were

excluded from the follow-up analysis. The follow-upafter 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 intermedi-

ate 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 intesti-

nal 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 lym-

phoma (OS, P 0.0001). Patients with T-cell lym-

phoma 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 differ-

ence was also found between the latter two groups

(OS, P 0.0002). Patients with MALT-derived lym-

phoma demonstrated significantly better OS and EFS

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).



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rates than non-MALT lymphoma patients (P 0.0001;

Fig. 4).

Patients with the following characteristcs had sig-

nificantly better OS and EFS rates: younger age, female

gender, tumors restricted to the submucosa, superfi-

cial tumors, small tumors ( 8 cm), tumors without

perforation, absence of B symptoms, and radical re-

section. Patients who underwent nonsurgical treat-

ment showed a better OS than those who had surgery-

based 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 bet-

ter 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 signif-

icant independent prognostic factor for EFS. A time

trend was a significant prognostic factor for OS, but

not for EFS.

DISCUSSIONThere are many publications regarding the prognosis

of primary gastrointestinal lymphoma. However, most

of these studies analyzed a small number of subjects

and onlyfive 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 popula-

tion-based report by Gurney et al.37 The most com-

mon 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 Ger-

many25 and the value is higher than that observed in

TABLE 3Comparison of the Clinicopathologic Features and Chronologic Periods

Period A

(n 144) (%)

Period B

(n 117) (%)

Period C

(n 194) (%) Pvaluea

Mean age (yrs) 52.0 59.3 61.4 0.0001Gender

Male 79 (55) 67 (57) 101 (52) NS

Female 65 (45) 50 (43) 93 (48)

Site of origin

Gastric 119 (83) 86 (74) 137 (71)

Intestinal 24 (17) 29 (25) 43 (22) 0.0047

Combined 1 (0.7) 2 (2) 14 (7)

Histology

Low-grade B-cell 62 (43) 52 (44) 117 (60)

High-grade B-cell 70 (49) 54 (46) 61 (31) 0.0091

T-cell 12 (8) 11 (9) 16 (8)

Stage

I 90 (63) 51 (44) 107 (55)

II1/II2 44 (31) 54 (46) 53 (27) 0.0004

IIE/IV 10 (7) 12 (10) 34 (18)

Depth of invasion

Mucosa/submucosa 59 (41) 44 (38) 105 (54) 0.0069

Beyond submucosa 85 (59) 73 (62) 89 (46)

Treatment

Surgery alone 114 (79) 70 (60) 39 (20)

Nonsurgical 2 (1) 4 (3) 96 (49) 0.0001

Both 26 (18) 39 (33) 55 (28)

No 2 (1) 4 (3) 4 (2)

Response to treatment (n 445) (n 142) (n 113) (n 190)

Complete remission 123 (87) 98 (87) 157 (83) NS

Partial remission 18 (13) 12 (11) 20 (11)

No response 1 (0.7) 3 (3) 13 (7)

NS: not significant.aP 0.006 is significant using the Bonferroni correction.



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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 fre-

quency of intestinal lymphoma is high (range, 49

81%). This may be partly explained by the high prev-

alence 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-

TABLE 4Significant Prognostic Factors on Univariate Analysis

No. of patients

Overall survival Event-free survival

5-Yr (%) Pvaluea 5-Yr (%) Pvaluea

Age (yrs)

57 or younger 202 81 0.0001 79 0.0001

58 or older 243 64 59

Gender

Male 243 68 0.0022 64 0.0008

Female 202 77 73

Site of origin

Gastric 338 77 74

Intestinal 94 58 0.0001 53 0.0001

Combined 13 16 25

Histology

Low-grade B 228 87 81

High-grade B 181 63 0.0001 60 0.0001

T-cell 36 27 27

MALT-derived

Yes 272 84 0.0001 79 0.0001

No 173 54 52

Depth of tumor

Within submucosa 203 86 0.0001 80 0.0001

Beyond submucosa 242 60 59

Stage

I 244 87 82

II1/II2 148 62 0.0001 60 0.0001

IIE/IV 53 26 23

Macroscopic type

Superficial 154 88 0.0001 82 0.0001

Others 291 64 61

Size of tumor (cm)

8 248 78 0.0149 74 0.02708 or more 197 65 62

Perforation

Yes 10 0 0.0001 0 0.0001

No 435 73 69

B symptoms

Yes 67 45 0.0001 38 0.0001

No 378 77 74

Radical surgery

Yes 158 82 0.0015 80 0.0003

No 287 66 61

Treatment

No surgery 102 86 0.0118 71 0.3056

Surgery-based 343 69 67

Period

A/B (19631992) 255 68 0.0108 68 0.6823C (19932002) 190 79 70

MALT: mucosa-associated lymphoid tissue.aAssessed by the log-rank test.



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grade B-cell lymphomas, most of which were marginal

zone lymphomas. Conversely, the intestinal group

contained a predominance of intermediate-stage (II1or II2), high-grade B-cell lymphomas and the com-

bined group comprised a pedominance of advanced-

stage, 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 al-

though 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.

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

that patients with combined gastric and intestinal in-

volvement showed a significantly poorer survival than

patients with the involvement localized in the stom-

ach 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

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).


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).



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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 lym-

phoma should also be considered. Increasing expo-

sure 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 non-

surgical 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 prog-

nostic 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 heteroge-

neous treatment modalities over a prolonged period.

To our knowledge, 11 English studies performed a mul-


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 modal-

ities. (A) Overall survival (P 0.0118). (B) Event-free survival (P 0.3056).



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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 sur-

vival.9,1114,16,18,19,22,24 The next most frequent inde-

pendent 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 fol-

low-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 sig-

nificance, recent studies have demonstrated that non-

surgical strategies and surgery-based modalities had

an equivalent efficacy.30,31,45 Based on all these obser-

vations, and taking patients quality of life into con-

sideration, nonsurgical treatment is an alternative and

optimal therapeutic modality for gastrointestinal lym-

phoma. Further randomized prospective studies with

a large number of patients are still needed to establish

TABLE 5Independent Prognostic Factors Determined by Multivariate Analysis

Variable

Overall survival Event-free survival

Coefficient/SE Pvalue Coef ficient/SE Pvalue

Stage (I vs. II1/II2 vs. IIE/IV) 5.1198 0.0001 4.7564 0.0001

Age 4.0000 0.0001 3.8143 0.0001

Gastric localization 3.2978 0.0010 3.7568 0.0002

Immunophenotype (B-cell vs. T-cell) 2.3900 0.0168 3.2621 0.0011

B symptoms 2.2113 0.0270 2.4404 0.0147

MALT-derived lymphoma 1.5243 0.1275 2.1081 0.0350

Time trends (19631993 vs. 19932002) 3.0536 0.0023 NE NE

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

TABLE 6Sites of Origin in Primary Gastrointestinal Lymphoma in the Literature

Author (yr) Nation No. of patients

Anatomic sites of origin (%)

Gastric Intestinal Combined Others

Freeman et al. (1972)2 United States 538 346 (64) 192 (36) ND

Radaszkiewicz et al. (1992)17 Austria 372 258 (69) 71 (19) 8 (2.2)a 35 (9.4)b

dAmore et al. (1994)23 Denmark 306 175 (57) 109 (36) 22 (7.2)

Liang et al. (1995)24 Hong Kong 425 238 (56) 184 (43) ND 3 (0.8)c

Gurney et al. (1999)37d United Kingdom 1047 463 (44) 440 (42) ND 144 (14)b

Koch et al. (2001)25 Germany 371 277 (75) 70 (19) 24 (6.5)a

Current study (2003) Japan 455 342 (75) 96 (21) 17 (3.7)

ND: not described.a Cases involving multiple gastrointestinal tract organs.b

Unspecifi

ed.c Cases with primary esophageal lymphoma.d Registry data without prognostic analysis.



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the optimal management for patients with primary

gastrointestinal lymphoma.

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