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From the Molecular Gastroenterology & Pancreatic Cancer Research
Unit*
and the Department of
Pathology,
The Department of Veterans Affairs
Medical Center, Kansas City, Missouri; and the Department of
Medicine,
University of Kansas Medical
Center, Kansas City, Kansas
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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2 and
Pearson/Spearman’s rho correlation coefficient with regression
analyses, there was an inverse correlation between the AI and
Cdc2/Cdk1 or cyclin B1 in MALT and MALT lymphoma tissues. There was no
correlation between AI and PCNA labeling in any of the tissues. These
results suggest that Cdc2/Cdk1 and cyclin B1 expression may be actively
associated in the modulation of cellular death by apoptosis, as
well as cellular proliferation and transformation during the evolution
of H. pylori-associated gastritis to MALT lymphoma.
Subclassification of high labeling score (
40) for Cdc2/Cdk1 and
cyclin B1 and low labeling index (<0.6) for apoptotic cells in
H. pylori-associated MALT may help in identifying a
population of patients with an increased risk of developing MALT
lymphoma.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Self-immolation or programmed cell death, apoptosis, is crucial for the overall health of an organism and essential for both the development and function of an effective immune repertoire.12-16 The development of neoplastic growth can be considered a perturbation in the balance of cellular proliferation, differentiation, and apoptosis.14-16 Cells that have been exposed to toxic agents or infected with harmful viruses and/or bacteria can escape apoptosis and gradually undergo transformation as a result of the malfunction of certain genes.12,14 Recent studies on the molecular mechanism of apoptosis indicate several cell cycle regulatory genes including cyclin-dependent kinase (Cdc2/cdk1) and cyclin B1 may be directly involved in this process.17-22 Normally the complex events of the cell cycle are regulated by cell cycle specific cyclin-dependent kinases (CDKs), which become activated as the result of phosphorylation along with interaction with cyclins. The Cdc2-cyclin B1 complex controls the G2-M phase transition in eukaryotes by promoting breakdown of nuclear membrane, chromatin condensation, and microtubule spindle formation, allowing for ordered DNA replication and repair. Unscheduled up- or down-regulation of these cell cycle regulatory genes during the cell cycle can help cells overcome the death sentence, and Cdc2-cyclin B1 complex may play a crucial role in the induction of tumorigenesis. The significance and extent of apoptosis and disturbance of cell cycle regulatory proteins in the genesis of H. pylori-associated MALT to MALT lymphoma is unknown. To determine the association between cell cycle regulatory proteins, specially Cdc2 and cyclin B1, and apoptotic cell death during the progression of MALT lymphoma and to identify protein marker(s) that may help in recognition of the population that is at increased risk of developing MALT lymphoma, we examined the extent of apoptosis, cell proliferation, and Cdc2 and cyclin B1 expression in lymphoid cells in H. pylori-associated chronic gastritis, gastric MALT, and MALT lymphoma.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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After obtaining informed consent, gastric mucosal biopsies were prospectively obtained during esophagogastroduodenoscopy (EGD) with large biopsy forceps. The gastric biopsies were placed in 10% buffered formalin for routine hematoxylin and eosin (H&E), immunohistochemistry, and apoptotic studies. Determination of the presence of H. pylori was based on the results of gastric mucosal biopsies stained with H&E as well as a modified Giemsa stain. H. pylori colonization was considered to be present if one or more of the Giemsa-stained gastric biopsy specimens demonstrated typical H. pylori structures. The density of H. pylori was determined in Giemsa-stained sections according to the upgraded Sydney grading system.23 Criteria for normal control patients included a completely normal endoscopic appearance of the stomach, the absence of H. pylori on at least six Giemsa-stained gastric surveillance biopsies, and normal histology.
H. pylori-positive patients were defined in this study as having chronic H. pylori gastritis if they were found to have a mild to moderate mononuclear cell infiltrate in the lamina propria according to the updated Sydney grading system.23 Lymphoid aggregates could be present, but not lymphoid follicles or lympho-epithelial lesions. If a lymphoid aggregate was noted, all available serial sections were closely scrutinized to exclude the presence of a germinal center.
The diagnosis of MALT required a confidence of diagnosis of lymphoma score of 3 to 4 according to Wotherspoon et al.24 Features of MALT included the presence of a moderate to severe dense lymphocytic infiltrate in the lamina propria, one or more germinal centers, none to rare lympho-epithelial lesions, no Dutcher bodies, and the absence of monoclonality on Southern blot gene rearrangement testing in conjunction with a benign clinical, endoscopic, radiological, and laboratory investigation.
The diagnosis of low-grade MALT lymphoma was made on the basis of histology, requiring a confidence of diagnosis of lymphoma score of 5 according to Wotherspoon et al.24 Histological components of gastric MALT lymphoma included 1) clusters of centrocyte-like cells, both intraepithelially and intralumenally, invading mucosal epithelium and forming lympho-epithelial lesions; 2) reactive lymphoid follicles within the mucosa and submucosa exhibiting variable obliteration of the mantle zone and infiltration of germinal center by centrocyte-like cells; and 3) a dense subepithelial plasma cell infiltrate.25-29 Low- and high-grade MALT B cell lymphomas were distinguished based on criteria described by Isaacson.25,26 Confirmation of malignancy required demonstration of B cell immunoglobulin heavy chain monoclonality.25 The institution’s Human Subjects Committee approved the study.
Chemicals
PCNA, Cdc2, and cyclin B1 antibodies were purchased from NeoMarkers, Inc. (Fremont, CA) and Santa Cruz Biotechnology, Inc. (Santa Cruz, CA). DNA fragmentation detection kit (TdT FragEL) was purchased from Oncogene Research Products (Cambridge, MA). Immunohistochemical kits were purchased from Zymed Laboratories, Inc. (San Francisco, CA). All other materials were of the highest commercially available grade.
Immunohistochemistry
The immunohistochemical staining was carried out according to manufacturer’s recommendations (Zymed) and our previous modified method.30 Briefly, paraffin-embedded 10-µm tissue sections were dewaxed in xylene and rehydrated in 1x PBS through different concentrations of ethanol. To block endogenous peroxidase activity, slides were incubated in 3% hydrogen peroxide (3% v/v) in methanol for 5 minutes at room temperature. The slides were then incubated in citrate buffer (Zymed) in a microwave oven at high power for 5 minutes and allowed to cool for 15 minutes. After washing the slides in water followed by 1x PBS for 5 minutes, sections were incubated in ready to use tissue blocker for 15 minutes at room temperature. Tissue blocker was replaced with primary antibodies or preimmune IgG as negative controls and incubated overnight at 4°C. Antibodies used included a mouse monoclonal antibody at a 1:300 dilution for Cdc2 (NeoMarkers); a mouse monoclonal antibody at a 1:200 dilution for cyclin B1 purchased from, and a ready-to-use monoclonal antibody for PCNA (Zymed). After incubation with primary antibodies, slides were rinsed with 1x PBS (3x 5 minutes) and incubated for 10 minutes at room temperature in biotinylated rabbit-anti-goat IgG (Zymed). After rinsing with PBS (3x 5 minutes), sections were incubated in peroxidase-conjugated linker for 10 minutes at room temperature. Antibodies were detected by incubation with 3,3'-diaminobenzidine tetrahydrochloride solution, provided by Zymed with their kit, for a period of time sufficient to yield dark brown color, usually 5 minutes. Sections were counterstained with hematoxylin for microscopic examination. Lymphoid cells were identified by CD20 immunohistochemical analysis.
Determination of PCNA Labeling Index (LI) and the Expression of Cdc2 and Cyclin B1
The LI of PCNA, Cdc2, and cyclin B1 were determined in the
different portions (eg, superficial and deep regions of lamina propria,
intraepithelial lymphocytes, and germinal center, mantle zone, and
marginal zone of MALT) of paraffin-embedded gastric biopsy tissue
sections of H. pylori-negative normal and H.
pylori-positive chronic gastritis, MALT, and MALT lymphoma
patients as depicted in Figure 1
. To
determine the LI, the immunostained sections were first scanned under
low magnification (100x) field to locate the hot spots (areas with
maximal Cdc2- or cyclin B1-immunopositive lymphoid cells) in different
portions of immunostained sections. The LI of PCNA, Cdc2, and cyclin B1
in a 400x field was then scored by determining the average count of
the number of lymphoid cells with positively staining nuclei and/or
cytoplasm at five hot spots in lamina propria, organized mucosal
lymphoid tissue (ie, germinal center, mantle zone, marginal zone), and
intraepithelial lymphocytes of the immunostained sections. A minimum of
five sections from each patient was examined to accurately determine
the LI of these proteins. All slides were scored blindly three times by
observers without knowledge of the patient’s clinical and/or
histological findings.
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Apoptosis was visualized using TdT FragEL DNA fragmentation detection kit (Oncogene Research Products). The staining procedures were modified based on the manufacturer’s recommendations. Briefly, after routine deparaffinization, rehydration, and washing in 1x PBS, pH 7.4, tissues were digested with proteinase K (20 mg/ml in 1x PBS) for 20 minutes at room temperature and washed. After incubation in equilibration buffer for 10 minutes, sections were treated with terminal deoxynucleotidyltransferase (TdT) enzyme at 37°C for 1 hour. After the TdT treatment and histochemical staining, slides were counterstained with methyl green to identify the normal and apoptotic cells. A specimen known to be positive for apoptotic cells was used as a positive control. Distilled water was substituted for TdT for use as a negative control.
Determination of Apoptotic Index (AI)
All slides were scored blindly three times without knowledge of
the patient’s clinical and/or histological findings. The AI was
determined in the paraffin-embedded gastric biopsy tissue sections of
H. pylori-negative normal and H. pylori-positive
chronic gastritis, MALT and MALT lymphoma patients (Figure 1)
. To
determine AI in normal and diseased sections, TUNEL-immunostained
sections were first scanned under low power magnification (100x) to
locate the apoptotic hot spots (areas with maximal TUNEL-positive
lymphoid cells) within lamina propria, organized mucosal lymphoid
tissue (ie, germinal center, mantle zone, marginal zone), and
intraepithelial lymphocytes. The AI at 400x field was then scored by
counting the number of TUNEL-positive cells. At least five hot spots in
a section were selected to determine the average count. A minimum
of 500 cell nuclei from each slide was counted. Positively staining
cells with the morphological characteristics of apoptosis were
identified using standard criteria, including chromatin condensation,
nucleolar disintegration, and formation of crescentic caps of condensed
chromatin at the nuclear periphery. Data were expressed as a mean
percentage of total cell numbers. Photographs of cells were taken using
a Zeiss photomicroscope.
Colocalization of PCNA, Cdc2, Cyclin B1, and Apoptosis in Serial Sections
To define associations, PCNA, Cdc2, cyclin B1, and apoptotic cells were immunodetected using immunohistochemistry and TUNEL assay in step-serial sections of each biopsy sample of normal, chronic gastritis, MALT, and MALT lymphoma patients. The LI of PCNA, Cdc2, cyclin B1, and AI were determined in the same areas of the serial sections stained with different antibodies and/or TUNEL assay. The numbers of lymphoid cells with immunostaining nuclei and/or cytoplasm were determined at three hot spots. Data were expressed as a mean percentage of total cell numbers.
Statistical Analysis
Statistical analyses were performed using
2, Pearson, Spearman’s rho correlation
coefficient, regression analysis, and Student’s t-test. For
all statistical analyses, the SPSS system and Sigma Stat for personal
computer were used, with significance defined as P <
0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Immunohistochemistry of PCNA was performed in normal
(n = 5), H. pylori-associated chronic
gastritis (n = 7), gastric MALT
(n = 12), and B cell low-grade gastric MALT
lymphoma (n = 12). Examples of
PCNA-immunostained positive lymphoid cells are shown in Figure 2A
and the PCNA LI are summarized in
Figure 3
and Table 1
. The LI of PCNA-positive lymphoid cells
was significantly (P < 0.05, paired two-tailed
Student’s t-test) elevated during the transition of chronic
gastritis to MALT and MALT lymphoma. PCNA LI was increased 3.3- and
2.7-fold in MALT and MALT lymphoma, respectively, relative to chronic
gastritis. In MALT, the PCNA LI was significantly
(P < 0.01, paired two-tailed Student’s
t-test) higher in germinal center than mantle zone and
marginal zone (Table 1)
. No hot spots were found in paraffin sections
of normal tissue.
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Immunohistochemical studies demonstrated the presence of Cdc2 and
cyclin B1 proteins in the lymphocytes of normal, chronic gastritis,
MALT, and MALT lymphoma patients (Figures 2B, 2C, and 3)
. The LI of
Cdc2 and cyclin B1 were significantly higher (P
< 0.05, paired two-tailed Student’s t-test) in MALT
lymphoma compared to H. pylori-associated chronic gastritis
and MALT tissues (Figure 3)
. The mean Cdc2 LI was 2.1% (median 2.2, SD
1.13) in H. pylori-associated chronic gastritis, 5.1%
(median 5.0, SD 1.5) in MALT, and 7.0% (median 7.0, SD 1.8) in MALT
lymphoma. The mean cyclin B1 LI was 2.1% (median 1.5, SD 1.3), 3.7%
(median 3.0, SD 1.5), and 6.3% (median 6.0, SD 1.3) in H.
pylori gastritis, MALT, and MALT lymphoma, respectively.
These two proteins exhibited regional differences in the
immunohistochemistry of MALT (Figure 3, B and C
, and Table 1
) and MALT
lymphoma (data not shown). The comparative analysis of the labeling
scores of Cdc2 and cyclin B1 indicated that the mean LI of Cdc2 was
17.1% (median 15.5, SD 7.3), 5.6% (median 1.05, SD 3.3), and 3.4%
(median 2.0, SD 3.7) in germinal center, mantle, and marginal zone,
respectively, and the cyclin B1 LI was 11.1% (median 12.5, SD 5.6) in
germinal center, 3.1% (median 2.5, SD 1.2) in mantle zone, and 1.9%
(median 1.2, SD 1.6) in marginal zone. A significantly higher labeling
score (P < 0.01, paired two-tailed Student’s
t-test) for these proteins was found in the germinal center
relative to mantle and marginal zone of MALT (Table 1)
. The
overexpression of Cdc2 and cyclin B1 protein was also observed in the
gastric glands surrounded by neoplastic and/or non-neoplastic lymphoid
cells. No hot spots were found in paraffin sections of normal tissue.
Although mean labeling scores of PCNA, Cdc2, cyclin B1, and apoptosis
exhibited significant differences in gastritis, MALT, and MALT
lymphoma, several specimens of gastritis and MALT had overlapping
scores of PCNA, Cdc2, and cyclin B1 LI, and apoptosis as those
noted in MALT lymphoma samples. The highest common overlapping value
for Cdc2 and cyclin B1 is 4.3 in both chronic gastritis and MALT
specimens. Accordingly, the cutoff values for Cdc2 and cyclin B1 scores
were considered as 4.0 (Figure 3)
for subclassification of
patients.
Apoptotic Index (AI) in H. pylori-Associated Chronic Gastritis, MALT, and MALT Lymphoma
Positive staining of apoptosis in lymphoid cells was observed in
formalin-fixed, paraffin-embedded sections of chronic gastritis,
MALT, and MALT lymphoma patients with AI ranging from 0.2 to 0.65%
(median 0.4, SD 0.3), 0.8 to 3.0% (median 1.3, SD 0.9), and 0.4 to
0.85% (median 0.6, SD 0.4), respectively. The statistical analysis
indicated that the apoptotic index in MALT was markedly higher
(P < 0.05, paired two-tailed Student’s
t-test) compared to chronic gastritis and MALT lymphoma
(Figure 3)
. No significant difference in AI was noted between MALT
lymphoma and chronic gastritis (Figure 3)
. In MALT, apoptosis was
significantly higher (P < 0.01, paired
two-tailed Student’s t-test) in germinal center, as
compared to mantle and marginal zone (Table 1)
. In several specimens of
H. pylori-associated chronic gastritis and MALT, the
apoptotic index had overlapping scores with those detected in MALT
lymphoma. The highest overlapping value for apoptosis is 0.65%
in both chronic gastritis and MALT specimens. Thus, the cutoff values
for the apoptosis score was considered as <0.6% (Figure 3)
for
subclassification of patients.
Correlation between AI and PCNA, Cdc2, and Cyclin B1 Labeling Index
To examine the association between the induction of
apoptosis and the expression of PCNA, Cdc2, and cyclin B1 in H.
pylori-associated chronic gastritis, MALT, and MALT lymphoma, the
labeling scores in colocalized areas of serial sections were examined
using ,2
Pearson, and Spearman’s rho
correlation coefficient with regression analysis. The
immunohistochemical colocalization analysis and correlation
coefficient, on plots of AI versus the Cdc2 or cyclin B1 on
a per-case basis, showed a significant inverse correlation between AI
and these two proteins in both MALT and MALT lymphoma patients (Figures 2, 4, and 5)
. No significant
correlation between AI and PCNA LI was found (data not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The low labeling scores for Cdc2 and/or cyclin B1 in some areas of MALT
and MALT lymphoma sections (Figure 5)
lacking apoptotic cell death
suggest that deficiency of these proteins may not always induce mitotic
catastrophe or apoptosis in lymphoid cells. Other factors may also be
important in regulation of apoptosis. High apoptotic score was always
encountered in the MALT and in the deep portion where lymphoid cells
are generally activated in response of specific foreign substances
and/or pathogens and undergo several successive rounds of cell division
over a period of several days.38
Therefore, these studies
suggest that the status of the lymphoid cell (ie, resting or activated
lymphocyte) may be one crucial factor for induction of apoptosis.
While analyzing the expression of Cdc2 and cyclin B1 and apoptosis in individual patients, we observed a gradual augmentation of Cdc2- and cyclin B1-positive lymphoid cells, and inhibition of apoptosis, in H. pylori-associated MALT and MALT lymphoma. Moreover, variable distributions of cyclin B1- and Cdc2-positive lymphoid cells were observed in both MALT and MALT lymphoma in these same patients. Taken together, these studies indicate that in the initial stage of this lymphoproliferative disease, the deletion of unwanted and/or defective lymphocytes, might involve down-regulation of Cdc2 and/or cyclin B1 genes. As the disease progresses, up-regulation of these genes may ensure the survival of the defective repertoire. These defective lymphocytes may gradually acquire multiple genetic anomalies, which then eventually transform MALT into MALT lymphoma.
The diagnosis of low-grade B cell lymphoma in gastric biopsies is
usually straightforward.28
Doubtful cases are confirmed by
scoring of histological appearances24
and/or by
determining B cell monoclonality using polymerase chain reaction (PCR),
Southern blot, or immunohistochemical methods.28,39
However, recent studies have raised a question about the specificity of
PCR monoclonality as a method of determining the clonality of malignant
cells.40
Accordingly, identification of pure MALT and
early cases of MALT lymphoma based on PCR technique is
inappropriate.40
The present immunohistochemical studies
(Figure 3)
suggest that the high labeling score (4.0) of Cdc2 and
cyclin B1 in conjugation with a low labeling index (<0.6) of apoptotic
cells in H. pylori-associated MALT may help identify a
population that is primed to develop MALT lymphoma.
In summary, our findings indicate that Cdc2 and cyclin B1 may play an important role in the modulation of cellular death, proliferation, and transformation during the evolution of chronic gastritis to MALT lymphoma. Moreover, the labeling scores of Cdc2 and cyclin B1 may be used as one potential parameter for identifying the population at increased risk of developing MALT lymphoma.
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Acknowledgements |
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Footnotes |
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Supported by a Department of Veterans Affairs Merit Review Grant and the Midwest Biomedical Research Foundation (Kansas City, MO).
S. K. B. and A. P. W. made equal contributions in this study.
Accepted for publication September 4, 1999.
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correlation
coefficient, and regression analysis for the correlation of apoptotic
labeling index (AI) with
Cdc2 or cyclin B1 labeling scores. A: Plot of Cdc2 labeling
index against AI per MALT patient. B: Plot of cyclin B1
labeling index against apoptotic LI per MALT patient. C:
Plot of Cdc2 labeling index against AI per MALT lymphoma patient.
D:. Plot of cyclin B1 labeling index against apoptotic LI
per MALT lymphoma patient. Note that 36 labeling spots were analyzed
from either MALT or MALT lymphoma patients.