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Pericolonic tumor deposits in patients with T3N2BM0 colon adenocarcinomas Markers of reduced disease free survival and intra-abdominal metastases and their implications for TNM classification

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2210
A Clinicopathologic Study of Gastric MucosaAssociated Lymphoid Tissue Lymphoma
Shinji Ohashi, M.D.1
Kose Segawa, M.D.1
Shozo Okamura, M.D.1
Humihiro Urano, M.D.1
Shinichi Kanamori, M.D.1
Hideki Ishikawa, M.D.1
Kazuo Hara, M.D.1
Akira Hukutomi, M.D.1
Kennosuke Shirai, M.D.1
Matsuyoshi Maeda, M.D.2
1
Department of Gastroenterology, Toyohashi Municipal Hospital, Toyohashi, Japan.
2
Department of Pathology, Toyohashi Municipal
Hospital, Toyohashi, Japan.
BACKGROUND. It is still unclear which patients with gastric mucosa-associated
lymphoid tissue (MALT) lymphoma will benefit from the eradication of Helicobacter pylori.
METHODS. The authors studied a total of 34 patients. Twenty-three patients had
primary gastric lymphoma and underwent gastric resection as initial treatment.
Eleven patients with gastric MALT lymphoma who received antibiotics against H.
pylori as initial treatment were also included. In all 34 patients, the presence of H.
pylori, endoscopic findings, and pathologic features were evaluated. Immunohistochemical expression of Bcl-2, p53, and proliferating cell nuclear antigen (PCNA)
was classified as follows: (⫺), no reactive cells; (⫹), scattered positive cells; (2⫹),
nests of positive cells; (3⫹), diffuse positive cells.
RESULTS. Patients with low grade MALT lymphoma (LG) tended to be positive for
H. pylori (6 of 9), to localize within the submucosa (7 of 9), not to have lymph node
involvement (7 of 8), and to have lower tumor stage compared with patients with
high grade MALT components (HG). Bcl-2 protein was expressed with high frequency by LG (7 of 9). Strong expression of p 53 was more common in the HG
tumors (4 of 14), and strong expression of PCNA showed a significant difference
between LG (1 of 8) and HG patients (12 of 13). Investigation of the patients with
long term follow-up (n ⫽ 4) revealed that LG remained superficial for a long time
and showed gradual progression. Most of these tumors were Bcl-2⫹/p53⫺⬃⫾/
PCNA⫺⬃⫹. There were two patients whose superficial LG (sm/Bcl-2⫹/p53⫺/
PCNA⫺⬃⫹) regressed after the disappearance of H. pylori. On the other hand, one
patient developed ulcerated LG (sm/Bcl-2⫺/p53⫹/PCNA3⫹) after disappearance
of H. pylori. The authors found complete regression of MALT lymphoma in 9 of 11
patients after H. pylori eradication. Initial tumors of these 9 patients were superficial/sm/n(⫺)/low grade/Bcl-2⫹⬃⫾/p53⫺⬃⫹ (n ⫽ 9), /PCNA⫺⬃⫹(n ⫽ 6),
/PCNA 2⫹ (n ⫽ 3). Two local recurrence and one non-Hodgkin lymphoma in other
sites were observed after initial therapy.
CONCLUSIONS. Gastric MALT lymphoma with (H. pylori positive/superficial/
sm/low grade/Bcl-2⫹/p53⫺⬃⫹/PCNA⫺⬃⫹) pattern will disappear after a patient
is cured of H. pylori infection. Cancer 2000;88:2210 –9.
© 2000 American Cancer Society.
KEYWORDS: gastric mucosa-associated lymphoid tissue lymphoma, eradication of
Helicobacter pylori, submucosa, low grade, Bcl-2, p53, proliferating cell nuclear
antigen.
Address for reprints: Shinji Ohashi, M.D., Department of Gastroenterology, Toyohashi Municipal
Hospital, Aotake-cho 50, Toyohashi 441, Japan.
Received August 23, 1999; revision received January 12, 2000; accepted January 12, 2000.
© 2000 American Cancer Society
A
lthough the stomach is the most common site of extranodal
lymphoma, including lymphoma of mucosa-associated lymphoid
tissue (MALT) type, there is normally no lymphoid tissue in the gastric
mucosa. However, it has been postulated that Helicobacter pylori
infection results in accumulation of gastric MALT, from which low
grade B-cell lymphoma develops.1 These observations led Wother-
Bcl-2, p53, and PCNA in Gastric MALT Lymphoma/Ohashi et al.
spoon et al. to suggest that eradication of H. pylori
could be followed by tumor regression.2
Although several cases of complete tumor regression after H. pylori eradication have been reported,
the results have been somewhat conflicting with regard to the overall tumor regression rate.3 These discrepancies might result from several factors, such as
the inclusion of patients with advanced or high grade
lymphoma.
In addition, it is still unclear which patients with
low grade gastric lymphoma will benefit from the
treatment of H. pylori infection. Assuming that longlasting cure can be achieved by eradication of H. pylori, it will be vital to select those patients who can
benefit from this new approach. However, the natural
history of gastric MALT lymphoma is not well documented.
In the current study, we performed a clinicopathologic investigation of primary gastric lymphomas
based on the MALT concept, and we assessed the
clinical course and treatment outcome of gastric
MALT lymphoma after eradication of H. pylori.
METHODS
Group I
We retrospectively studied 23 patients with primary
gastric lymphoma who underwent gastric resection as
initial treatment (Group I). Most of them were diagnosed at our institution before 1995. They included
four patients with relatively long term follow-up
(Group Ia) and two patients with spontaneous regression (Group Ib).
Group II
Eleven patients with gastric MALT lymphoma who
received antibiotic therapy against H. pylori as their
sole initial treatment after 1996 were also included in
this study. All 11 patients were positive for H. pylori
and were investigated prospectively.
Informed consent was obtained from each patient.
In all of these 34 patients the presence of H. pylori,
endoscopic findings, pathologic features of the biopsy
specimen and resected specimen, and immunohistochemical expression of Bcl-2, p53, and proliferating
cell nuclear antigen (PCNA) were evaluated in order to
perform a clinicopathologic investigation of primary
gastric lymphoma based on the MALT concept.1
H. pylori infection was diagnosed by biopsy, the
urease test, histology, and culture in patients receiving
antibiotic therapy and was diagnosed histologically in
patients who underwent surgical resection as the initial treatment. H. pylori eradication therapy included 2
weeks of treatment with proton pump inhibitor (ome-
2211
TABLE 1
Histologic Classification of Cases with Primary Gastric Lymphoma of
B-Cell Phenotype, with Special Reference to Low Grade B-Cell
Lymphoma of Mucosa-Associated Lymphoid Tissue
Classification
Description
Low
Pure low grade B cell lymphoma of
MALT
Low grade B cell lymphoma of MALT
with small areas of high grade
lymphoma
High grade lymphoma with small areas
of low grade components of MALT
Pure high grade lymphoma
Low ⬎ high
Low ⬍ high
High
MALT: mucosa-associated lymphoid tissue.
TABLE 2
Histologic Grading for Diagnosis of MALT Lymphoma by
Wotherspoon et al.2
Grade
Description
0
1
2
Normal
Chronic active gastritis
Chronic active gastritis with florid lymphoid
follicle formation
Suspicious lymphoid infiltrate in lamina
propria, probably reactive
Suspicious lymphoid infiltrate in lamina
propria, probably lymphoma
Low grade B-cell lymphoma of MALT
3
4
5
MALT: mucosa-associated lymphoid tissue.
prazole 20 mg or lansoprazole 30 mg) and amoxicillin
1.5 g twice a day plus clarithromycin 800 mg twice a
day or metronidazole 500 mg twice a day.
Histologic sections were reexamined, and patients
were reclassified according to the MALT lymphoma
concept (Table 1). The histologic features of MALT
lymphoma proposed by Issacson are as follows: low
grade lymphoma shows proliferation of centrocytelike cells that occasionally invade the glands (lymphoepithelial lesions) and have a marked tendency toward
plasma cell differentiation. The presence of lymphoid
follicles in or around the tumor is a constant finding.
In high grade MALT lymphoma, large, transformed
lymphoid cells show diffuse proliferation with or without areas of low grade MALT lymphoma.1
The lymphoid infiltration in gastric biopsy specimens were classified according to criteria of Wotherspoon et al.2 To assess changes on repeat biopsy, the
confidence in a diagnosis of lymphoma was expressed
on a scale of 0 –5 (Table 2). Patients were staged by
physical and ORL examinations, blood tests, ultrasonography, whole-body computed tomography (CT)
2212
CANCER May 15, 2000 / Volume 88 / Number 10
TABLE 3
Modified Ann Arbor Classification for Extranodal Lymphomas
Classification Description
EI
EII
EIII
EIV
Lymphoma restricted to the gastrointestinal tract on one side of the
diaphragm
EI1 Infiltration limited to the mucosa and submucosa
EI2 Lymphoma extending beyond the submucosa
Lymphoma infiltrating lymph nodes on the same side of the
diaphragm
EII1 Infiltration of the regionary lymph nodes
EII2 Infiltration of lymph nodes beyond the regional
Lymphoma infiltrating the gastrointestinal tract and/or lymph nodes
on both sides of the diaphragm
Localized infiltration of gastrointestinal site with or without infiltration
of associated lymph nodes, together with diffuse or disseminated
involvement of extragastrointestinal organs
scanning, and endoscopic ultrasonography of the gastric lesion, according to modified Ann Arbor classification criteria (Table 3).4,5
Expression of Bcl-2 protein (Bcl-2, DAKO), p53
protein (D0-7, DAKO), and PCNA (PC10, DAKO) was
also assessed in paraffin embedded sections. For immunoperoxidase staining of Bcl-2 protein and p53
protein, we applied the microwave oven heating technique, which has been shown to be effective for the
retrieval of masked epitopes. The findings were classified as follows: (⫺), no reactive cells; (⫹), scattered
positive cells; (2⫹), nests of positive cells; (3⫹), diffuse
positive cells.
The antibiotic-treated group was then prospectively followed with regular endoscopic biopsy, and
each response was histologically evaluated and graded
using the histologic scoring system proposed by
Wotherspoon et al., with a posttreatment score ⬍ 3
considered evidence of lymphoma regression, a score
of 3 indicating partial response, and a score of 4 –5
indicating no response. Follow-up was carried out
every 3– 6 months, with clinical evaluation; upper endoscopy plus multiple biopsies for histologic, bacteriologic, and immunohistochemical studies; and endoscopic ultrasonography (EUM 2 or 3, Olympus).
Data were evaluated with the chi-square test or
the Fisher exact test. A P value ⬍ 0.05 was considered
statistically significant.
RESULTS
Group I
Of the 23 patients with primary gastric lymphoma who
underwent gastric resection as initial treatment, 9
were classified as having low grade MALT lymphoma
and 14 as having high grade MALT components
(low ⬎ high: 3 patients; low ⬍ high: 6 patients; high: 5
patients). The age of the patients with low grade MALT
lymphoma ranged from 29 to 78 years (median, 57.1
years), and the male-to-female ratio was 2:7. The age
of the patients with high grade components ranged
from 34 to 81 years (median, 60.2 years), and the
male-to-female ratio was 9:5. The correlations between the histologic type of lymphoma and other factors, such as the presence of H. pylori, macroscopic
tumor type, depth of invasion, lymph node involvement, clinical stage, and expression of Bcl-2, p53, and
PCNA, are shown in Tables 4 and 5. Data were evaluated with the chi-square test.
Six of 9 patients with low grade MALT lymphoma
were positive for H. pylori on histology, whereas 8 of
14 patients with high grade MALT components were
positive. Six of 9 patients with low grade MALT lymphoma had the superficial spreading type, whereas 8
of 13 patients with high grade components did not.
Regarding the depth of invasion, lymphoma cells
were localized within the submucosa in 7 of 9 patients
with low grade MALT lymphoma and in 8 of 14 patients with high grade components.
As for lymph node metastasis, 1 of 8 patients with
low grade MALT lymphoma and 6 of 14 patients with
high grade components had lymph node involvement.
The numbers of patients in Stages EI1, EI2, EII1,
EII2, EIII, and EIV among low grade and high grade
patients with or without low grade components were
6, 2, 1, 0, 0, and 0 versus 6, 2, 2, 2, 1, and 1, respectively.
Bcl-2 protein expression (⫹⬃⫾) was found in 7 of
9 patients with low grade MALT lymphoma, whereas
Bcl-2 protein was not expressed in 8 of 14 patients
with high grade components.
p53 protein expression (⫺⬃⫹) was detected in all
patients with low grade MALT lymphoma, and p53
protein expression (ⱖ 2⫹ ) was found in 4 of 14 patients with high grade components.
PCNA protein expression (⫺⬃⫹) was found in 8 of
9 patients with low grade MALT lymphoma, whereas
PCNA protein expression (ⱖ 2⫹) was seen in 12 of 13
patients with high grade components (P ⬍ 0.001).
Two of 9 low grade MALT lymphoma patients
showed tumor extension beyond the muscularis propria and were negative for H. pylori.
Group Ia
The four patients with relatively long term follow-up
who underwent gastric resection as initial treatment
were classified as having low grade MALT lymphoma
or low grade MALT lymphoma with small areas of high
grade lymphoma. The presence of H. pylori, the endoscopic appearance, the histologic evidence of lymphoma, and the immunohistochemical data are
shown in Table 6.
Bcl-2, p53, and PCNA in Gastric MALT Lymphoma/Ohashi et al.
2213
TABLE 4
Clinicopathologic Findings and Bcl-2, p53, and PCNA of 23 Patients with Primary Gastric Lymphoma
Case
Age (yrs)
Gender
Hist. HP
Macroscopic
appearance
1
2
3
4
5
6
7
8
9
10
44
48
29
64
65
58
71
57
78
50
F
F
F
M
F
F
F
M
F
F
(⫹)3(⫺)
⫹
⫺
⫹
⫹
⫹
⫹
⫺
⫺
⫹
Ulcerated
Superficial
Superficial
Superficial
Superficial
Superficial
Superficial
Ulcerated
Linitis plastica like
Superficial
11
71
M
⫺
Superficial
12
34
M
⫹
Superficial
13
45
M
⫺
/
14
48
M
⫹
Superficial
15
75
F
⫺
Excavated
16
81
F
⫺
Excavated
17
52
M
⫺
Giant fold
18
60
M
⫹
Excavated
19
20
21
22
23
73
71
57
65
61
F
M
F
M
M
⫹
⫹
⫺
⫹
⫹
Superficial
Excavated
Protruded ⫹ ulcerated
Excavated
Protruded ⫹ ulcerated
Histology
Low
Low
Low
Low
Low
Low
Low
Low
Low
Low ⬎
high
Low ⬎
high
Low ⬎
high
Low ⬍
high
Low ⬍
high
Low ⬍
high
Low ⬍
high
Low ⬍
high
Low ⬍
high
High
High
High
High
High
Invasion
depth
n
Stage
Bcl-2
p53
PCNA
sm
sm
sm
sm suspect
sm
sm
sm
mp
ss
sm
⫺
⫺
⫺
⫺
⫺
⫹
⫺
/
⫺
⫺
EI1
EI1
EI1
EI1
EI1
EII1
EI1
EI2
EI2
EI1
⫺
⫹
⫹
⫹
⫺
⫹
⫹
⫹
⫹
⫺
⫹
⫺
⫺
⫺
⫾
⫺
⫺
⫾
⫺
3⫹
3⫹
⫾
⫾
⫾
⫹
⫹
⫾
⫹
⫺
2⫹
sm
⫺
EI1
⫺
⫺
2⫹
sm
⫺
EI1
⫹
⫾
2⫹
sm
⫺
EI1
⫺
2⫹
2⫹
sm
⫹
EII1
⫺
2⫹
2⫹
mp
⫺
EI2
⫺
⫾
3⫹
mp
⫹
EII1
⫾
⫾
2⫹
ss
⫹
EII2
⫾
2⫹
2⫹
si
⫹
EIV
⫹
⫺
2⫹
sm suspect
sm
sm
se
se
⫺
⫺
⫹
⫺
⫹
EI1
EI1
EII2
EI2
EIII
⫺
⫺
⫺
⫾
⫹
⫹
⫺
⫾
⫾
⫺
⫹
3⫹
3⫹
3⫹
/
PCNA: proliferating cell nuclear antigen; Hist. HP: presence of H. pylori diagnosed histologically; sm: submucosa; mp: muscularis propria; ss: subserosa; se: serosa; si: tumor invading adjacent structures.
Two H. pylori positive patients (Cases 2 and 7)
whose macroscopic appearance and histologic score,
respectively, showed gradual worsening underwent
surgery at 71 and 18 months after the start of followup. In these patients, the initial superficial tumors
(WG3/Bcl-2⫹/p53⫾/PCNA⫺⫾) developed into superficial low grade MALT lymphomas (sm/n[⫺]/Bcl-2⫹/
p53⫺/PCNA⫾).
Repeat biopsies showed disappearance of H. pylori in 1 patient (Case 1) at 69 months after the start of
follow-up. The IIc-like (superficial) lesion at the angulus showed regression to a scar, and its histologic
score decreased to 2. On the other hand, a IIc ⫹
III–like advanced lesion (ulcerated) developed at the
fundus after the disappearance of H. pylori, and surgery was performed 79 months after the start of follow-up. The superficial tumor (WG3/p53⫺/PCNA⫺)
at the angulus regressed to a scarlike feature (WG2),
whereas the ulcerated tumor (WG3/p53⫺/PCNA⫹) at
the fundus progressed to a more ulcerated lesion (sm/
n[⫺]/WG5/Bcl-2⫺/p53⫹/PCNA 3⫹).
In 1 H. pylori positive patient (Case 10), endoscopy revealed progression of the lesion, with the histologic score rising to 5. The patient was referred for
surgical treatment at 28 months after the start of follow-up. The superficial tumor (WG2/p53⫾/PCNA 2⫹)
present 5 months before surgery had progressed to
superficial low grade MALT lymphoma with small areas of high grade lymphoma (sm/n[⫺]/Bcl-2⫺/p53
3⫹/PCNA 2⫹).
Group Ib
The two patients with spontaneous regression who
underwent gastric resection as initial treatment were
classified as having low grade MALT lymphoma. The
presence of H. pylori, the endoscopic appearance, the
histologic evidence of lymphoma, and the immunohistochemical data are shown in Table 7.
2214
CANCER May 15, 2000 / Volume 88 / Number 10
TABLE 5
Patient’s Characteristics in Primary non-Hodgkin Lymphoma of the
Stomach According to the Grade of Malignancy in Relation to the
MALT Concept
Features
HP
HP(⫹)
HP(⫺)
Macroscopic
findigs
Superficial
Not superficial
Tumor depth
ⱕsm
ⱖmp
Lymph node status
N(⫺)
N(⫹)
Stage
EI1
EI2
EII1
EII2
EIII
EIV
Bcl-2 expression
⫹⬃⫾
⫺
p53 expression
⫺⬃⫹
ⱖ2⫹
PCNA expression
⫺⬃⫹
ⱖ2⫹
Pure low grade
MALT (n ⴝ 9)
Lymphoma with high
grade components
(n ⴝ 14)
P value
6( 67% )
3
8( 57% )
6
NS
6( 67% )
3
5( 38% )
8
NS
7( 78% )
2
8( 57% )
6
NS
7( 88% )
1
8( 57% )
6
NS
6( 67% )
2( 22% )
1( 11% )
6( 43% )
2( 14% )
2( 14% )
2( 14% )
1( 7% )
1( 7% )
NS
7( 78% )
2
6( 43% )
8
NS
9( 100% )
10( 71% )
4
NS
1( 8% )
12
P ⬍ 0.001
8( 89% )
1
MALT: mucosa-associated lymphoid tissue; HP: H. pylori infection; PCNA: proliferating cell nuclear
antigen; Lymphoma with high grade components: low ⬎ high or low ⬍ high or high; NS: not significant.
In 1 patient (Case 3), H. pylori was negative at
diagnosis. Endoscopy revealed clear regression of saucerlike tumors and depressed lesions resembling type
IIc early cancer (superficial) in the stomach to benign
healing ulcerlike appearance. Initial superficial tumor
(WG5/Bcl-2⫹/p53⫺/PCNA⫺) regressed to a healing
lesion like a peptic ulcer (sm/n[⫺]/WG4/Bcl-2⫹/
p53⫺/PCNA⫾) at the time of surgery.
The other patient (Case 4) was positive for H.
pylori, and gastrectomy was performed under the diagnosis of malignancy. There was complete histologic
regression, with the initial superficial tumor (WG5/
Bcl-2⫹/p53⫺/PCNA⫾) regressing to no tumor (n[⫺])
at the time of surgery.
Group II
Among the 11 patients with gastric MALT lymphoma
who received antibiotic therapy against H. pylori,
treatment resulted in eradication of H. pylori in all of
them, as assessed by negative culture and histology
(Table 8). Two patients (Cases X and XI) needed second-line treatment with proton pump inhibitor (PPI),
amoxicillin, and metronidazole. Complete regression
of MALT lymphoma, as assessed by endoscopy and
histopathology, was observed in 9 of 11 patients. Clinicopathologic and immunohistochemical studies of
these 9 patients showed that initial tumors were superficial (n ⫽ 9 cases)/sm(EUS) (n ⫽ 9), /n(⫺)(EUS)
(n ⫽ 9), /WG5 (n ⫽ 4), WG4 (n ⫽ 4), WG3 (n ⫽ 1),
/Bcl-2 ⫹⬃⫾ (n ⫽ 9), /p53⫺⬃⫹ (n ⫽ 9), /PCNA⫺⬃⫹
(n ⫽ 6), PCNA 2⫹ (n ⫽ 3).
One patient (Case I) with no regression after successful eradication of H. pylori underwent surgery 2
months after the initial treatment. The final diagnosis
was superficial low grade MALT lymphoma (mp,
n[⫺]), whereas the initial diagnosis was superficial
tumor (mp/WG4/Bcl-2⫹/p53⫺/PCNA⫾).
One patient (Case II) developed aggressive lymph
node type B-cell non-Hodgkin lymphoma (Bcl-2⫹/
p53 2⫹/PCNA 3⫹) at 9 months after the successful
eradication of H. pylori and the regression of gastric
superficial MALT lymphoma (sm/WG5/Bcl-2⫹/p53⫺/
PCNA⫹).
One patient (Case III) had a IIa ⫹ IIc–like gastric
tumor (gastric angulus) at 13 months after successful
eradicaton of H. pylori and regression of the initial
gastric MALT lymphoma (body)(superficial/sm/WG4/
Bcl-2⫹/p53⫹/PCNA⫺) at surgery; the final diagnosis
was high grade lymphoma of diffuse large-cell type
(tumor like/sm /n[⫺]/Bcl-2⫾/p53⫾/PCNA 2⫹) (Figs.
1, 2).
One patient (Case V) had recurrence of superficial
MALT lymphoma (sm/WG4/Bcl-2⫹/p53 2⫹/PCNA
2⫹) at 16 and 21 months after the successful eradication of H. pylori. The diagnosis at 3 months after the
initial treatment was superficial tumor (sm/WG4/Bcl2⫹/p53⫾/PCNA 3⫹).
DISCUSSION
In the current study, we retrospectively assessed patients with primary gastric lymphoma who underwent
gastric resection as their initial treatment. Histologically, these patients were classified into groups with
low grade MALT lymphoma or high grade MALT components. The patients with low grade MALT lymphoma were younger and showed female predominance compared with those who had high grade
MALT components. The patient with low grade MALT
lymphoma tended to be positive for H. pylori and have
superficial spreading tumors. The low grade patients
also tended to localize within the submucosal layer,
Bcl-2, p53, and PCNA in Gastric MALT Lymphoma/Ohashi et al.
2215
TABLE 6
Characteristics of Patients with MALT Lymphoma Who Had Relatively Long Follow-Up before Surgery ( 4 Cases )
Case
Age (yrs)
Gender
1
44
F
Start of follow
up ( mos )
Hist.
H.P.
EUS appearance
tumor depth, n
Macroscopic appearance
Histology
Bcl-2
0
Superficial ( angulus )
WG3 ( angulus)
6
Superficial ( angulus )
WG2 ( angulus)
9
Superficial 2 ( angulus)
WG4 ( angulus)
17
Superficial 2 ( angulus)
WG3 ( angulus)
35
⫹
Ulcer scar ( angulus)
WG2 ( angulus)
54
⫹
Ulcer scar ( angulus)
WG2(EMR,angulus)
68
⫹
Ulcer scar ( angulus), ulcerated (fundus)
WG3 ( fundus )
69
⫺
Ulcer scar ( angulus), ulcerated (fundus)
77
⫺
Ulcer scar ( angulus), ulcerated 1 (fundus) sm, n(⫺)
WG5 ( fundus )
Surgery 79
WG5 ( fundus )
She was treated with surgery 79 mos after the start of follow-up. Final diagnosis: low grade MALT lymphoma, depth sm, no lymph node metastasis.
2
48
F
0
Superficial
WG3
8
Ulcer scars
WG3
31
Ulcer scars
WG3
70
Superficial
sm,n(⫺)
71
⫹
Superficial
WG5 ( EMR )
Surgery 71
WG5
She was treated with surgery 71 mos after the start of follow-up. Final diagnosis: low grade MALT lymphoma, depth sm, no lymph node metastasis.
7
71
F
0
⫹
Ulcer scar
WG3
15
⫹
Superficial
sm,n(⫺)
WG5
17
⫹
Superficial
WG5
Surgery 18
She was treated with surgery 18 mos after the start of follow-up. Final diagnosis; low grade MALT lymphoma, depth sm, no lymph node metastasis.
10
50
F
0
Ulcer
WG0
2
Ulcer scar
WG0
23
Superficial
WG2
26
⫹
Superficial
sm,n(⫺)
WG5
Surgery 28
WG5
She was treated with surgery 28 mos after the start of follow-up.
Final diagnosis: MALT lymphoma with small areas of high grade lymphoma, tumor depth sm, no lymph node metastasis.
p53
PCNA
⫺
⫺
⫺
⫺
⫺
⫹
⫹
⫺
⫺
⫹
⫺
⫹
3⫹
⫹
⫾
⫺
⫺
⫺
⫺
⫹
⫹
⫺
⫾
⫹
⫾
⫾
⫹
⫺
⫾
⫾
2⫹
3⫹
2⫹
⫺
MALT: mucosa-associated lymphoid tissue; PCNA: proliferating cell nuclear antigen; EUS: endoscopic ultrasonography; Hist. H.P.: presence of H. pylori diagnosed histologically; sm: submucosa; WG: histologic
grading for diagnosis of MALT lymphoma by Wotherspoon et al.2
TABLE 7
Characteristics of Patients with Spontaneous Regression of MALT Lymphoma ( 2 Cases )
Case
Age (yrs)
Gender
Start of followup ( mos )
Hist.
H.P.
Macroscopic
appearance
EUS appearance
tumor depth, n
0
⫺
Superficial
sm, n(⫹)
1
⫺
Healing ulcerlike
Surgery 2
She was treated with surgery 2 mos after initial diagnosis.
Final diagnosis: Probably low grade MALT lymphoma, depth sm( susp ), no lymph node metastasis.
4
64
M
0
⫹
Superficial
1
⫹
Superficial 2
Surgery 1
He was treated with surgery 1 mo after initial diagnosis.
Final diagnosis: Depth of invasion unknown because of tumor cell disappearance, no lymph node metastasis.
3
29
F
Histology
Bcl-2
p53
PCNA
WG5
⫹
⫺
⫺
WG4
⫹
⫺
⫾
WG5
WG2
⫹
⫺
⫾
MALT: mucosa-associated lymphoid tissue; EUS: endoscopic ultrasonography; PCNA: proliferating cell nuclear antigen; Hist. H.P.: presence of H. pylori diagnosed histologically; sm: submucosa; WG: histologic
grading for diagnosis of MALT lymphoma by Wotherspoon et al.2
2216
CANCER May 15, 2000 / Volume 88 / Number 10
TABLE 8
Serial Change of Clinicopathologic Factors and Bcl-2, p53, and PCNA in MALT Lymphoma Patients after H. pylori Eradication Therapy
Case
Age (yrs)
Gender
Time after
eradication of H.P.
(mos)
H.P.
Macroscopic appearance
EUS appearance
tumor depth, n
Histology
Bcl-2
0
Hist.⫹ Superficial
mp, n(⫹)
WG4
⫹
1
Superficial
2
Hist.⫺ Superficial
He was treated with surgery 2 mos after eradication of H. pylori. Final diagnosis: low grade MALT lymphoma, tumor depth mp, no lymph node metastasis.
II
58
F
0
⫹
Superficial
sm, n(⫺)
WG5
⫹
2
⫺
Improved
WG1
5
Improved
U1-IIs, n(⫺)
8
⫺
Improved
WG1
9
Improved
14
Improved
15
Improved
Nine mos after, she had an aggressive type B-cell non-Hodgkin lymphoma, diffuse large cell type (Bcl-2⫹, p53 2⫹, PCNA 3⫹) in the distant area.
She received chemotherapy with CHOP but failed to achieve remission and died 16 mos after the start of eradication of H. pylori.
III
69
F
0
⫹
Superficial (body)
sm, n(⫺)
WG4 (body)
⫹
2
⫺
Improved (body)
WG1 (body)
7
⫺
Improved (body)
WG1 (body)
13
⫺
Improved (body),tumor forming
WG1 (body), ML
(anglus)
(angulus)
16
⫺
Improved (body),tumor forming mp?, n(⫺)
ML (angulus)
⫾
(anglus)
She was treated with surgery 16 mos after eradication of H. pylori.
Final diagnosis: High grade lymphoma( diffuse large cell type ), tumor depth sm, no lymph node metastasis.
IV
39
M
0
⫹
Superficial
sm, n(⫺)
WG3
⫾
1
⫺
Improved
WG1
3
⫺
Improved
WG1
5
⫺
Improved
WG1
9
⫺
Improved
WG1
12
⫺
Improved
WG1
15
⫺
Improved
WG1
19
⫺
Improved
WG1
23
⫺
Improved
WG1
25
⫺
Improved
WG1
V
45
F
0
⫹
Superficial
sm, n(⫺)
WG4
⫹
3
⫺
Improved
WG4
⫹
5
⫺
Improved
WG2
9
⫺
Improved
WG1
12
⫺
Improved
WG1
16
⫺
Superficial
WG4
18
sm, n(⫺)
21
⫺
Superficial
WG4
⫹
VI
57
M
0
⫹
Superficial
sm, n(⫺)
WG4
⫹
4
⫺
Improved
WG1
8
⫺
Improved
WG1
12
⫺
Improved
WG1
VII
49
F
0
⫹
Superficial
sm, n(⫺)
WG4
⫹
2
⫺
Improved
WG2
6
⫺
Improved
WG1
11
⫺
Improved
WG1
VIII
59
M
0
⫹
Superficial
sm, n(⫺)
WG5
⫹
0
WG4
2⫹
3
⫺
Improved
WG4
⫹
4
⫺
UI-IIs, n(⫺)
6
⫺
Improved
WG1
9
⫺
Improved
WG2
IX
41
M
0
⫹
Superficial
sm, n(⫺)
WG5
⫹
3
⫺
Improved
WG1
5
Improved
normal, n(⫺)
8
⫺
Improved
WG1
I
48
M
p53
PCNA
⫺
⫾
⫺
⫹
⫹
⫺
⫾
2⫹
⫹
⫺
⫾
⫾
⫺
3⫹
2⫹
⫺
2⫹
2⫹
⫾
⫹
⫾
⫺
⫺
2⫹
2⫹
2⫹
⫺
2⫹
(continued)
Bcl-2, p53, and PCNA in Gastric MALT Lymphoma/Ohashi et al.
2217
TABLE 8
(continued)
Case
Age (yrs)
Gender
Time after
eradication of H.P.
(mos)
H.P.
Macroscopic appearance
0
⫹
Superficial
2
⫹
Improved
3
Improved
6
⫹
Improved
10
⫺
Improved
13
⫺
Improved
19
⫺
Improved
She received reeradication therapy of H. pylori 6 mos after the start of treatment.
XI
52
F
0
⫹
Superficial
1
⫺
Improved
3
6
⫹
Improved
14
⫹
No change
19
⫺
Improved
She received reeradication therapy of H. pylori 15 mos after the start of treatment.
X
52
F
EUS appearance
tumor depth, n
sm, n(⫺)
Histology
Bcl-2
p53
PCNA
WG5
WG1
⫾
⫹
⫹
⫹
⫹
⫹
⫺
⫹
⫹
sm, n(⫺)
WG1
WG1
WG1
WG1
sm, n(⫺)
WG4
WG4
sm, n(⫺)
WG1
WG2
WG1
PCNA: proliferating cell nuclear antigen; MALT: mucosa-associated lymphoid tissue; EUS: endoscopic ultrasound; H.P.: H. pylori infection diagnosed by urease test, histology, and culture; sm: submucosa; mp:
muscularis propria; UI-IIs: peptic ulcer scar with fibrosis extendig into submucosa; WG: histologic grading for diagnosis of MALT lymphoma by Wotherspoon et al.2
FIGURE 1.
Initial gastric musoca-associated lymphoid tissue (MALT) lymphoma (Case III): (A) MALT lymphoma
Wotherspoon Grade 4 (WG4), (B) Bcl2⫹, (C) p53⫹, (D) proliferating cell nuclear antigen (PCNA)–.
not to have lymph node involvement, and to have
lower tumor stage associated with a more favorable
outcome compared with the patients with high grade
MALT components.6,7 Immnunohistochemical staining for Bcl-2 protein (a marker of impaired apoptosis),
p53 protein (a marker of p53 mutation), and PCNA (a
proliferation marker) was done to elucidate the biologic features of the tumors. Bcl-2 protein was expressed with high frequency by low grade MALT lymphoma. Thus, inhibition of apoptosis via Bcl-2 protein
expression appears to be involved in oncogenesis in
the case of low grade MALT lymphoma. Strong expression of p53 was more common in the high grade
MALT tumors, which suggested that p53 mutation
may be related to histologic transformation of low
grade MALT lymphoma to high grade lymphoma, as
previously reported.8,9 PCNA protein expression
showed a significant difference between low grade
and high grade patients. There were a few patients
with low grade MALT lymphoma that invaded beyond
2218
CANCER May 15, 2000 / Volume 88 / Number 10
FIGURE 2. IIa ⫹ IIc-like gastric tumor
(Case III) after successful eradication of
H. pylori: (E) high grade lymphoma of the
diffuse large cell type, (F) Bcl-2⫾, (G)
p53⫾, (H) proliferating cell nuclear antigen (PCNA) 2⫹.
the musclaris propria. It was interesting that these
patients were negative for H. pylori.10
This study, in agreement with other reports, confirmed the favorable clinical outcome of low grade
gastric MALT lymphoma, which shows an indolent
natural history and prolonged confinement to the site
of origin. Investigation of the patients with relatively
long term follow-up and spontaneous regression revealed that low grade MALT lymphoma remained superficial for a long time and showed gradual progression macroscopically and histologically before
invading into deeper tissues. Most of these tumors
were Bcl-2⫹/p53⫺⬃⫾/PCNA⫺⬃⫹. There were a few
patients whose low grade MALT lymphomas regressed
after the disappearance of H. pylori and their tumors
were sm/superficial/Bcl-2⫹/p53⫺/PCNA⫺⬃⫹. On
the other hand, one patient developed low grade
MALT lymphoma after the disappearance of H. pylori.
This tumor was ulcerated/sm/Bcl-2⫺/p53⫹/PCNA 3⫹
at the time of surgery.
As Stole and Eidt have reported, it is not yet
known whether only early stage of MALT lymphoma
responds to H. pylori eradication or whether more
advanced lesions will also respond, and the information regarding the clinical and prognostic significance
of eradication therapy is limited. By properly selecting
patients for this form of therapy, better results can be
achieved. Assuming that a long-lasting cure can be
attained by eradication of H. pylori, it is important to
take proper measures to select patients who will benefit from this new approach. Thus, prediction of the
regression of gastric MALT lymphoma after eradication of H. pylori is necessary.11
We found complete regression in 9 of our 11 patients treated with an antibacterial regimen against H.
pylori. According to our results, the prognosis of gastric MALT lymphoma depends on stage, histologic
grade, and immunohistochemical features. Advanced
tumor stage (EII) or tumors with a transition to high
grade malignancy did not respond to cure of H. pylori
infection.
Our prospective study supports the concept that
H. pylori positive low grade MALT lymphoma (superficial/sm/Bcl-2⫹/p53⫺⬃⫹/PCNA⫺⬃⫹) tends to disappear after the cure of H. pylori infection. For this
reason, endoscopic examination, histologic grading,
immunohistochemical analysis, defining the depth of
invasion and lymph node involvement, detailed staging by endoscopic ultrasonography, ultrasonographic
examination, and systemic computed tomography
should be used in the selection of patients for treatment of low grade gastric MALT lymphoma by eradication of H. pylori.
Our results give further support to the recommendation of Issacson and Spencer that eradication of H.
pylori is harmless and inexpensive and should be the
first-line treatment for localized gastric MALT lymphoma, especially H. pylori positive/superficial/
sm/low grade/Bcl-2⫹/p53⫺⬃⫹/PCNA⫺⬃⫹ tumors.
Long term results are still unknown, so these patients
should be closely followed. If no response is observed
Bcl-2, p53, and PCNA in Gastric MALT Lymphoma/Ohashi et al.
by the next assessment, they probably should be referred for surgery and/or chemotherapy.
Further studies, including gene analysis and long
term follow-up, will help to clarify the contribution of
Bcl-2, p53, and PCNA to the biologic and clinical behavior of MALT lymphoma. It is also necessary for us
to remember the high incidence of other neoplasms in
patients with gastric MALT lymphoma.12,13 Periodic
follow-up endoscopy, endoscopic ultrasonograpy, and
systemic computed tomography must be performed.
5.
CONCLUSIONS
8.
Gastric MALT lymphoma with (H. pylori positive/
superficial/sm/low grade/Bcl-2⫹/p53⫺⬃⫹/PCNA⬃⫹)
pattern will disappear after patients are cured of H.
pylori infection. Periodic follow-up endoscopy, endoscopic ultrasonography, and systemic computed tomography must be performed.
9.
6.
7.
10.
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