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1151
Reassessment of Gastric Lymphoma in Light of the
Concept of Mucosa-Associated Lymphoid Tissue
Lymphoma
Analysis of 53 Patients
Yoshihiko Hoshida, M.D.1,2
Hiroshi Kusakabe, M.D.3
Hiroshi Furukawa, M.D.3
Tsutomu Kasugai, M.D.2
Hideaki Miwa, M.D.2
Shingo Ishiguro, M.D.2
Katsuyuki Aozasa, M.D.1
BACKGROUND. The concept of mucosa-associated lymphoid tissue (MALT)
lymphoma is now widely accepted. However, precise characterization of the features of MALT lesions in the stomach is needed. For this, extensive analysis of
resected gastrectomy specimens from a large number of patients with MALT
lymphoma is essential.
METHODS. Fifty-three patients who underwent gastrectomy for the treatment of
primary gastric lymphoma were studied. In the histologic examination, a mean of
1
Department of Pathology, Osaka University
Medical School, Osaka, Japan.
2
Department of Pathology, Osaka Medical Center for Cancer and Cardiovascular Diseases,
Osaka, Japan.
3
Department of Surgery, Osaka Medical Center
for Cancer and Cardiovascular Diseases, Osaka,
Japan.
46 specimens per case were analyzed; the distribution of lymphomatous lesions
was plotted on maps of gastrectomy specimens, input into a computer, and used
to measure the size of lesions.
RESULTS. The median age of the patients was 56 years, and the male-to-female
ratio was 27:26. Stage of disease was IE for 35 patients, IIE for 15, and III for 3.
Histologically, 25 patients had low grade lesions, 18 had combined high and low
grade lesions, and had 10 high grade lesions. Macroscopically, low grade MALT
usually had multiple instances of superficial spreading of lesions without ulceration, whereas high grade MALT exhibited a solitary tumor-forming lesion. All of
the superficial spreading type without ulceration were low grade MALT. The higher
the grade of tumor, the larger the tumor size. Twenty-four patients received chemotherapy. The 5-year survival rate was 67.2%. Multivariate analysis revealed that
only the clinical stage was a significant factor in prognosis.
CONCLUSIONS. Low grade MALT can be differentiated from other types of MALT
by macroscopic findings. When the MALT concept is adopted, stage of disease is
important in relation to survival. Cancer 1997;80:1151?59.
q 1997 American Cancer Society.
KEYWORDS: malignant lymphoma, mucosa-associated lymphoid tissue, stomach,
grade of malignancy.
Supported by a grant from the Vehicle Racing
Commemorative Foundation and Grants
08457061, 08670202, and 08770126 from the
Ministry of Education, Science and Culture, Japan.
Address for reprints: Yoshihiko Hoshida, M.D.
(c/o Prof. Katsuyuki Aozasa), Department of Pathology, Osaka University Medical School, 2-2
Yamadaoka, Suita, Osaka 565, Japan.
Received February 4, 1997; revision received
May 8, 1997; accepted May 8, 1997.
I
n the past, gastric lymphoproliferative diseases were classified as
malignant lymphoma or reactive lymphoid hyperplasia (RLH).1,2 Recently, Isaacson and Wright proposed a concept of lymphoma arising
from mucosa-associated lymphoid tissue (MALT), which largely encompasses the RLH, and referred to it as low grade MALT lymphoma.3
Low grade MALT lymphoma is characterized by a proliferation of
small lymphoid cells with irregularly shaped nuclei and abundant
cytoplasms, i.e., centrocytelike cells, and the presence of lymph follicles, which might be formed in the preceding follicular gastritis caused
by Helicobacter pylori.4 Because of the speculation that the presence
of follicular gastritis is essential to the development of MALT
q 1997 American Cancer Society
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CANCER September 15, 1997 / Volume 80 / Number 6
lymphoma, the administration of antibiotics is proposed as a choice of treatment not only for low grade
but also for high grade MALT lymphoma.5
Little is known about how best to treat MALT
lymphoma. To aid in the establishment of appropriate
therapeutic modalities, we analyzed histologic and clinical findings, including the extent of lesions defined at
macroscopic and microscopic levels, in 53 patients who
underwent gastrectomy for gastric lymphoma. Prognostic
factors, including the expression of p53 and bcl-2 protein
in tumor cells, were also analyzed.
PATIENTS AND METHODS
Fifty-three patients with primary gastric lymphoma
who were admitted to the Osaka Medical Center for
Cancer and Cardiovascular Diseases during the period
1961 ? 1995 were selected for the current study. Total
and subtotal gastrectomy was performed on 44 and 9
patients, respectively. The resected stomach was cut
into serial sections 5 mm wide, and each specimen
was examined microscopically to determine the extent
of lymphomatous lesions. The number of specimens
examined per case ranged from 8 to 104 (mean, 46).
Histologic specimens were fixed in 10% formalin and
routinely processed for paraffin embedding. Histologic
sections 6 mm wide were stained with hematoxylin and
eosin and underwent immunohistochemical procedures. The distribution of lymphomatous lesions was
plotted on maps of gastrectomy specimens and input
into a computer. To measure tumor size, we used the
computer packages known as Adobe Photoshop, version 3.0a (Apple Computer, Inc.), and Mac Scope
(Apple Computer, Inc.).
Macroscopic Findings
Based on macroscopic features, the lymphomatous lesions were categorized into three subtypes: 1) superficial spreading without ulceration, 2) superficial
spreading with ulceration, and 3) tumor-forming type.
Lesions that had superficial spreading without ulceration were slightly elevated or had thickened rugae.
Superficial spreading with ulceration was characterized by an ulcer formation in the superficially spreading lesion. The tumor-forming type was characterized
by a large tumor mass with or without ulcer formation.
Criteria for MALT Lymphoma
The histologic features of MALT lymphoma proposed
by Isaacson were as follows: low grade lymphoma
showed a proliferation of centrocytelike cells that occasionally invaded into glands (lymphoepithelial lesion) and had a marked tendency toward plasma cell
differentiation. The presence of lymph follicles in or
around the tumors was a constant finding. In high
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grade MALT lymphoma, transformed, large, lymphoid
cells showed a diffuse proliferation with or without
areas of low grade MALT lymphoma.6
Immunohistochemical Staining
Immunoperoxidase procedures (the avidin-biotin
complex method) were carried out in 49 cases of MALT
lymphoma. The monoclonal antibodies used were MxpanB (CD20)(Kyowa Medex, Tokyo, Japan) and MB1 (Bioscience, Emmenbrucke, Switzerland), diluted at
1:50, and CD3, UCHL-1 (CD45RO), p53, bcl-2, and
MIB-1 (Dakopatts, Glostrup, Denmark), diluted at
1:100. CD20 and MB-1 were directed against B lymphocytes, CD3 and CD45RO against T lymphocytes,
p53 against wild- and mutant-type p53 protein, and
MIB-1 against proliferating cells. Before incubation
with CD3, sections were pretreated with 200 mg/mL
protease K in Tris buffer (pH7.8). Before incubation
with p53, bcl-2, and MIB-1, antigen retrieval was performed by heating sections in a 400 W microwave oven
(Toshiba ERT 330) for 5 minutes (3 times) in a 10 mmol
citrate buffer. For counting of p53, bcl-2, and MIB-1
positive cells, cells were selected randomly and
counted under a high-power (1400) field. Cases with
more than 10% positive cells were regarded as positive.
Statistical Methods
Actuarial survival curves were calculated by the Kaplan?
Meier method (1958),7 and the differences were estimated
by the log rank test to analyze the significant prognostic
factors.8 Multivariate analysis was performed with factors
that were significant in the univariate analysis by using
the Cox proportional hazards model,9 which estimates
the odds ratios in 95% confidence intervals to determine
the independent prognostic factors. These analyses were
performed with a JMP statistical computer package, version 3.0 (SAS Institute, Cary, NC). Correlations between
the histologic type of lymphoma and other factors, such
as macroscopic tumor type, tumor depth, number of lesions, clinical stage, macroscopic tumor size, microscopic
tumor size, and expression of p53, bcl-2, and MIB-1 protein, were evaluated with the chi-square test.
RESULTS
Clinical Findings
The age of the patients ranged from 27 to 76 (median,
56) years, and the male-to-female ratio was 27:26.
Based on records of physical examinations, surgical
notes, and pathologic examinations of the specimens,
the Ann Arbor staging scheme was applied in all 53
cases. Of these, 35 patients had Stage IE , 15 Stage IIE ,
and 3 Stage III disease. Stage IIE was subdivided according to the modifications proposed by Musshoff;
perigastric lymph node involvement by tumors, Stage
W: Cancer
MALT Lymphoma/Hoshida et al.
1153
TABLE 1
Summary of Microscopic Features
Macroscopic type
Superficial spreading without ulceration
superficial spreading with ulceration
Tumor-forming
Depth of invasion
Within sm
Beyond mp
No. of lesions
1
2
Multiple
Stage
I / II1E
II2E / III
Macroscopic tumor size
Large (� cm2)
Small (� cm2)
Microscopic tumor size
Large (� cm2)
Small (� cm2)
Survival rate (%)
5-yr
10-yr
Immunohistochemistry (frequency of
positive cells)
p53
�%
�%
bcl-2
�%
�%
MIB-1
�%
�%
Low grade MALT
(n � 25)
High and low grade MALT
(n � 18)
High grade MALT
(n � 10)
15
8
2
0
5
13
0
0
10
�0001
17
8
4
14
2
8
0.0029
8
2
15
13
4
1
5
3
2
25
0
10
8
6
4
0.0009
12
13
10
8
7
3
0.4958
17
8
14
4
6
4
0.6396
79.0
79.0
66.7
66.7
48.6
40.5
22
2
12
4
5
4
0.0619
1
23
6
10
7
2
0.0001
17
7
6
10
2
7
0.019
P value
0.0033
MALT: mucosa-associated lymphoid tissue lymphoma; sm: submucosa; mp: muscularis propria.
II1E, and positive intra-abdominal lymph nodes not
contiguous with the site of gastric tumors, Stage II2E .10
Adjuvant chemotherapy was administered to 24 patients; the chemotherapeutic agents mainly included
cyclophosphamide, vincristine, doxorubicin, predonine, methotrexate, bleomycin, mitomycin C, and mercaptopurine. The follow-up period for all patients calculated from the date of initial surgical treatment
ranged from 2 to 167 (median, 56) months. Distant
metastasis occurred in 10 of 53 patients (18.9%). The
5- and 10-year survival rates were 67.2% and 64.5%,
respectively.
Pathologic Findings
Macroscopic findings
Macroscopic findings are given in Table 1. Fifteen
cases were categorized as superficial spreading with-
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out ulceration, 13 as superficial spreading with ulceration, and 25 as tumor-forming type (Fig. 1).
Histologic findings
Histologic findings are given in Table 1. The 53 patients were classified as follows: 25 with low grade
MALT, 18 with combined high grade and low grade
MALT, and 10 with high grade MALT (Fig. 2). The frequency of cases with tumor cells showing plasmacytic
differentiation in low grade MALT, combined high
grade and low grade MALT, and high grade MALT was
30.4%, 25%, and 0%, respectively. As for depth of invasion, the lymphoma cells localized within the submucosal layer in 23 patients, beyond the muscularis propria in 2, and beyond the subserosal tissue in 28. The
low grade MALT lymphoma showed proliferation
within the submucosa, and combined high grade and
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CANCER September 15, 1997 / Volume 80 / Number 6
FIGURE 1. Macroscopic features (upper row) and computerized pictures (lower row) show areas of lymphoma. (A, B) Superficial spreading without
ulceration showed a slightly elevated lesion and thickened rugue. This type is characteristic of low grade MALT. The tumor area defined at the
microscopic level (101.95 cm2) was much larger than that at the macroscopic level (3.86 cm2). (C, D) Superficial spreading with ulceration is shown.
Two skip lesions were found in the posterior wall of the fundus. (E, F) Tumor-forming type with a single lesion is shown. Black areas in lower row:
macrocopic tumor; gray areas: microscopic tumor.
low grade MALT and high grade MALT lymphoma
showed proliferation beyond the muscularis propria
(P � 0.0029). The number of lesions was 1 in 26 cases,
2 in 9, and more than 3 in 18. The mean number of
lesions in the stomach was larger in the low grade
cases (3.84) than in the high grade cases with (1.33)
and without (1.90) low grade components (P � 0.01).
All of the cases of high grade MALT were tumor-forming type, and all of the cases of superficial spreading
without ulceration were low grade MALT (P � 0.01).
The number of cases in Stage I, II1E , II2E , and III in
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low grade cases and high grade cases with or without
low grade components was 21, 4, 0, and 0 and 14, 2,
9, and 3, respectively. This difference in the distribution of stage between low and high grade cases was
statistically significant (P � 0.01).
Immunohistochemical findings
Tumors in all but one patient examined were of Bcell type: CD20/, MB-1/, CD45RO0, CD30 in 33 and
CD20/, MB-10, CD45RO0, CD30 in 11. Tumor cells in
one case were CD200, MB-1/, CD45RO/, CD30; there-
W: Cancer
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1155
FIGURE 2. Histologic features of MALT lymphoma are shown. (A) This low grade MALT lymphoma shows a proliferation of centrocytelike cells
with small-to-medium-sized nuclei and scanty cytoplasm. (B) This combined high grade and low grade MALT lymphoma consists of centrocytelike
cells and large, transformed cells. (C) This high grade MALT lymphoma shows monomorphous proliferation of large, noncleaved cells (H & E,
original magnification 1200).
fore, the immunophenotype of this case could not be
determined. CD45RO gave membrane staining. The
numbers of positive cases (more than 10% positive
cells) for p53, bcl-2, and MIB-1 were 10, 35, and 24,
respectively (Table 1). Low grade MALT cases and high
grade MALT cases showed inverse patterns of expression of bcl-2 and MIB-1 by tumor cells: low grade cases
were bcl-2 positive and MIB-1 negative, and high grade
cases were bcl-2 negative (less than 10% positive cells)
and MIB-1 positive. As for p53, the higher the tumor
grade, the higher the number of positive cases.
The prognostic significance of each factor for overall
survival is shown in Table 2. Macroscopic features (P �
0.05), macroscopic tumor size (P � 0.01), microscopic
tumor size (P � 0.05), histologic classification (P �
0.05), and clinical stage (P � 0.01) (Fig. 3) were significant for survival.
Multivariate analysis
The results of multivariate analysis, performed with
factors significant in univariate analysis, are shown in
Table 3. Only the clinical stage proved to be a significant prognostic factor.
Sizes of the tumorous lesions
Tumor sizes at the macroscopic and microscopic levels ranged from 0.01 to 155.28 (mean, 38.6) cm2 and
1.24 to 155.39 (mean, 44.1) cm2, respectively. The
mean sizes of tumorous lesions defined at the macroscopic and microscopic levels were 34.6 and 40.4 cm2
for low grade MALT, 40.6 and 44.0 cm2 for combined
high grade and low grade MALT, and 45.5 and 54.9
cm2 for high grade MALT, respectively.
Prognostic Factors
Univariate analysis
The 5- and 10-year survival rates for patients with low
grade MALT, combined high grade and low grade
MALT, and high grade MALT were 79.0% and 79.0%,
66.7% and 66.7%, and 48.6% and 40.5%, respectively.
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DISCUSSION
The concept of MALT lymphoma is now widely accepted,
and the number of cases diagnosed as MALT lymphoma,
especially low grade, has increased. However, little is
known about how to treat the disease. For a precise characterization of MALT lymphoma, extensive study of resected gastrectomy specimens is necessary. In the current
study, a mean number of 46 specimens from gastric lesions were examined per case.
The median ages of the patients with low grade,
combined high grade and low grade, and high grade
MALT were 56.4, 55.0, and 57.0 years, respectively,
showing no differences among each histologic types.
Castrillo et al.11 reported no difference in the median
ages between patients with high grade and low grade
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1156
CANCER September 15, 1997 / Volume 80 / Number 6
TABLE 2
Univariate Analysis for Disease Free Survival
Factors
Gender
Male
Female
Age (yrs)
�
�
Tumor depth
Within sm
Beyond mp
Macroscopic tumor type
Superficial spreading without ulceration
Superficial spreading with ulceration
Tumor-forming
Histologic classification
Low-grade MALT
High and low-grade MALT
High grade MALT
Macroscopic tumor size
Large (� cm2)
Small (� cm2)
Microscopic tumor size
Large (� cm2)
Small (� cm2)
Number of lesions
Solitary
Multiple
Surgery
Total gastrectomy
Subtotal gastrectomy
Stage
I / II1E
II2E / III
Therapy
Surgery
Surgery / adjuvant therapy
p53
�%
�%
bcl-2
�%
�%
MIB-1
�%
�%
5-yr survival rate
(%)
10-yr survival rate
(%)
P value
63.8
67.5
63.8
63.0
0.960
83.3
59.3
83.3
55.6
0.080
70.7
62.0
70.7
57.6
0.165
91.7
63.6
51.9
91.7
63.6
46.7
79.0
66.7
48.6
79.0
66.7
40.5
0.040
78.7
50.8
78.7
50.8
0.007
83.1
59.4
83.1
55.7
0.033
54.5
80.5
49.5
80.5
0.062
65.2
66.7
62.1
66.7
0.689
81.7
16.7
78.1
16.7
0.000
73.8
53.2
73.8
53.2
0.100
65.1
87.5
61.5
87.5
0.440
69.2
69.2
69.2
65.4
0.758
76.5
60.5
76.5
54.4
0.346
0.034
MALT: mucosa-associated lymphoid tissue lymphoma; sm: submucosa; mp: muscularis propria.
MALT. Instead, Kath et al.12 reported a difference in
the median ages between patients with low grade (median, 58.5 years) and high grade tumors (median, 66
years). They believed that high grade MALT often
evolved from low grade MALT. The number of males
and females was nearly equal in the current study,
whereas a slight male preponderance was found in the
majority of previous studies.13 ? 15 The reported fre-
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quency of early stage disease in primary gastric
lymphoma has increased since the acceptance of the
MALT concept. In the current study, the percentage
of Stage I cases was 66.0%. The percentages of patients
with Stage I in previous reports adopting and not
adopting the MALT concept were approximately 50%
and 26%, respectively.16 ? 18
In previous reports,13 ? 16,18 ? 22 macroscopic tumor
W: Cancer
MALT Lymphoma/Hoshida et al.
FIGURE 3. The 5-year survival rate in patients with Stage I / II1E disease
(81.7%) is much better than that for patients with Stage II2E / III disease
(16.7%) (P � 0.000).
size was measured at the largest diameter. A more
accurate measurement was performed in the current
study; the extent of lymphomatous lesions plotted on
maps of gastrectomy specimens were measured with
the use of a computer. Tumor sizes were larger at the
microscopic level than at the macroscopic level in both
the low grade and the high grade tumors. The higher
the grade of malignancy, the larger the area of tumor.
Filippa et al.22 also reported the orthograde association
of tumor size and grade of malignancy in the Kiel classification.
In the current series, the frequency of cases showing solitary lesions (49.1%) was lower than that in previous reports (73.1 ? 92.7%).15,17,19,20 This might be due
to the large numbers of specimens examined (mean,
46) relative to previous reports.13 The mean number
of lesions in the low grade cases (3.84) was higher than
in high grade cases with (1.33) and without (1.90) low
grade components (P � 0.01). Consistently, high grade
MALT lesions were of tumor-forming type, and the
cases of superficial spreading without ulceration were
low grade MALT (P � 0.01).
The frequency of low grade type, combined high
and low grade type, and high grade type in the current
study was 43%, 32%, and 18%, respectively, showing
a lower frequency of high grade MALT and a higher
frequency of combined high grade and low grade
MALT than in previous reports (i.e., 32.4 ? 54.2% and
11.8 ? 20.8%).11 ? 13,16,17 Chan et al.13 suggested that inad-
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1157
equate sampling made detection of low grade components difficult. Therefore, differences in the frequency
of high grade cases between the current study and
previous studies might be due to the detailed microscopic study of resected specimens in our study (the
mean number of specimens examined per case in our
study was 46). Depth of lymphoma invasion was
strongly correlated with histologic type within the submucosa in the low grade MALT and beyond the muscularis propria in the combined high grade and low
grade MALT and high grade MALT. This difference of
depth of invasion between each grade of MALT was
significant (P � 0.0029).
The p53 gene, a tumor suppressor gene located on
the short arm of chromosome 17, is known to mutate
frequently in different types of tumors.23 ? 25 Although
transcripts of the p53 gene are usually undetectable
at the protein level, point mutation results in accumulation of mutant p53 protein.26 It was reported that
p53 mutation is frequently involved in the histologic
transformation of follicular lymphoma27 or marginal
zone splenic lymphoma.28 In the current study, the p53
positive rate increased in proportion to the amount of
high grade components, though the relation was not
significant. These findings were in agreement with a
previous study in which the accumulation of p53 abnormalities was associated with progression of MALT
lymphoma.29
The bcl-2 protein is encoded in 18q21, which is
frequently involved in t(14; 18)(q32; q21) in follicular
lymphoma.30 This protein prolongs programmed cell
death, i.e., apoptosis, and thus plays a positive role in
tumor growth.31 Rates of bcl-2 positivity in the current
study were higher for the low grade than for the high
grade tumors, as in previous reports describing MALT
lymphomas.32,33 A monoclonal antibody, MIB-1, reacts
with an epitope of the Ki-67 protein, which is expressed at all stages of the cell cycle other than G0,34
thus reflecting the proliferative activity of cells. In the
current study, the MIB-1 positive rate was higher in
the high grade than in the low grade tumors. Low
grade MALT exhibited low proliferative activity with
increased expression of bcl-2; this was suggestive of
prolonged programmed cell death. High grade MALT
showed high proliferative activity and high frequency
of p53 overexpression relative to low grade MALT.
Univariate analysis showed that the clinical stage,
macroscopic tumor features, macroscopic and microscopic tumor sizes, and histologic classification were
significant factors in the prognosis of patients. The
patients with tumors smaller than 25 cm2 at the macroscopic level and 18 cm2 at the microscopic level had
a better prognosis than those with larger tumors. Multivariate analysis using the Cox proportional hazards
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CANCER September 15, 1997 / Volume 80 / Number 6
TABLE 3
Multivariate Analysis for Disease Free Survival
Factors
Category
Odds ratio
95% CI
P value
Macroscopic tumor type
Histologic classification
Macroscopic tumor size
Microscopic tumor size
Stage
Superficial spreading without ulceration vs. others
Low grade MALT vs. others
Large (� cm2 vs. small (� cm2)
Large (� cm2) vs. small (� cm2)
I / II1E vs. II2E / III
4.964
0.556
0.923
1.525
8.833
0.627?101.1
0.093?3.298
0.152?6.001
0.209?12.73
1.808?65.15
0.132
0.503
0.929
0.669
0.005
MALT: mucosa-associated lymphoid tissue lymphoma; CI: confidence interval.
TABLE 4
Characteristics of Each Grade of MALT
Macroscopic feature
No. of lesions
Stage
Depth of invasion
Microscopic features
Low grade MALT
High and low grade MALT
High grade MALT
Mostly superficial spreading
without ulcer
Mostly multiple
I, II1E
Majority within sm
Centrocytelike cells bcl-2(/),
MIB-1(0)
Superficial spreading with ulceration
or tumor-forming
Mostly solitary
I, II1E , II2E , III
Majority beyond mp
Centrocytelike cells and transformed
large cells
Tumor-forming
Mostly solitary
I, II1E , II2E , III
Majority beyond mp
Transformed large cells
bcl-2(0), MIB-1(/)
MALT: mucosa-associated lymphoid tissue lymphoma; sm: submucosa; mp: muscularis propria.
model revealed that only the clinical stage was an independent factor for the survival of patients, as in previous studies.14 ? 16,18,21,35,36
In conclusion, low grade MALT lymphomas had
the following characteristics: multiple superficial
spreading without ulceration, restricted invasion
within the submucosa, early stage (Stage I or II1E) at
presentation, and low proliferative activity (Table 4).
Features of high grade MALT were quite different and
could be differentiated from those of low grade MALT
by clinical findings.
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