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2005
The Clinical Significance of p53 Accumulation in
Gastric Carcinoma
Teresa Starzynska, M.D., Ph.D.l
Maciej Markiewski, M.D., Ph.D.2
Wenancjusz Domagala, M.D., Ph.D.2
Krzysztof Marlicr, M.D., Ph.D.’
Janusz Mietkiewski, M.D?
Stephen A. Roberts, Ph.D.4
Peter L. Stern, Ph.D.S
’ Department
of Gastroenterology, Medical
Pomeranian Academy, Szczecin, Poland.
Department of Pathology, Medical Pomeranian
Academy, Szczecin, Poland.
Department of Pathology, General Hospital,
Szczecin-Police, Poland.
Cancer Research Campaign Biomathematics
and Computing Unit, f’aterson Institute for Cancer Research, Christie Hospital (NHS) Trust,
Manchester, United Kingdom.
Cancer Research Carnpaign Department of Immunology, Paterson Institute for Cancer Research, Christie Hospital (NHS) Trust, Manchester, United Kingdom.
Presented in part at ihe 2nd United European
Gastroenterology Week, Barcelona, Spain, July
2, 1993; at the 3rd United Gastroenterology
Week, Oslo, Norway, June 1994; and at the
10th World Congress of Gastroenterology, Los
Angeles, CA, 1994.
Supported by the Cancer Research Campaign of
Great Britain, Polish Foundation of Gastroenterology, Pomeranian Medical Academy, Szczecin,
Poland, and BritisWPolish Joint Research Collaboration Programme.
The authors thank Professor David P. Lane for
the gift of CMI antiserim used in these studies.
Address for reprints: Peter L. Stern, Ph.D., Department of Immunology, Paterson Institute for
Cancer Research, Marichester M20 9BX, U.K.
Received October 27, 1995; revision received
February 5, 1996; accepted February 5, 1996.
0 1996 American Cancer Society
BACKGROUND. Alterations in the expression of p53 tumor suppressor protein is a
frequent event in human cancer but the practical implications of this phenomenon
are yet to be fully exploited. The objective of this study was to determine the value
of p53 accumulation as a marker of tumor progression and prognosis of gastric
carcinoma patients and to evaluate whether this parameter can be properly assessed prior to surgery.
METHODS. The expression of p53 was studied immunohistochemically in 200 gastric carcinomas using paraffin embedded surgical specimens and endoscopic biopsies. The correlation between p53 expression in tumor tissue, selected clinicopathologic variables, and the course of the patients’ disease were analyzed.
RESULTS. Results showed that 42.5% of the gastric carcinomas expressed elevated
levels of p53 protein. P53 accumulation positivity correlated with increasing tumor
stage and size ( P < 0.001 and P = 0.025, respectively). P53 positive tumors had a
higher propensity for lymph node and distant metastases ( P < 0.001). P53 accumulation was also more frequently detected in carcinoma from proximal rather than
distal stomach ( P = 0.027). In patients receiving potentially curative resection
for advanced cancer, p53 accumulation was an independent parameter and the
strongest for poor prognosis (RR = 3.7, P < 0.001). There was complete concordance between immunohistochemical detection of p53 in endoscopic and surgical
material.
CONCLUSIONS. A preoperative assessment of p53 expression in gastric carcinoma
can be helpful to identify patients at high risk of metastatic spread to regional
lymph nodes and independently to identify those with especially poor prognosis. When combined with routine procedures, this simple and inexpensive test
might allow appropriate planning of better treatment strategies. Cancer 1996;
77:2005-12. 0 1996 American Cancer Society.
KEYWORDS: gastric carcinoma, p53 protein, immunohistochemistry, prognosis.
M
utations of the tumor-suppressor p53 gene on chromosome 17p
are a very frequent event in many human cancers but the clinical
usefulness of this phenomenon remains to be defined.’-4 In normal cells
and tissue, p53 protein has a very short half-life and attains such a low
In contrast, the
level that it is not detectable immunohistochemically.s~6
altered forms, present in 30 to 80% of different neoplasms, are more
stable and accumulate to concentrations that can be detected by immunohisto~hernistry.~-”
Thus a simple immunohistochemical procedure
which stratifies malignant tumors into those with and without p53 accumulation can be analyzed for useful correlations with clinical and histopathologic data.
Gastric carcinoma remains an important medical problem. Although
the incidence of the disease is generally declining, it is still the second
Despite progress in diagleading cause of cancer death in the
2006
CANCER May 15,1996 / Volume 77 I Number 10
nostic techniques, in countries other than Japan, the
overall 5-year survival rate is less than 20%."-'4 Surgery
is the treatment of choice for this cancer, but the majority
of patients will suffer a relapse following operation.
Therefore, different treatment modalities, such as gastric
resection with extensive lymphadenectomy and an aggressive chemotherapy, have been investigated.",'"''"
Nevertheless, not all patients benefit from this kind of
treatment. The selection of the most appropriate surgical
and chemotherapeutic approach is clearly central for
maximizing patient disease management. This selection
is currently based primarily on TNM staging. However,
for gastric carcinoma, tumor staging, particularly regional
lymph node status, is very difficult to establish before
surgery and the subsequent histologic examination of resected specimens. Furthermore, TNM classification does
not give a complete separation of good and bad prognosis
for individual patients. New markers which would improve the accuracy of preoperative assessment of gastric
carcinoma stage and its aggressiveness are clearly required.
The clinical significance of p53 accumulation in gastric carcinoma remains a controversial issue. While some
authors have found this alteration to be associated with
advanced stages of the disease and shorter survival time,
others detected no such orr relation."^^' In a previous
study of 55 gastric carcinoma patients, we demonstrated
that the presence of p53 accumulation in tumor tissue
might favor a more aggressive clinical course of the disease." The objective of the present study was to determine, on a large series of patients, the value of p53 overexpression as a marker of tumor progression and prognosis
in this cancer and to evaluate whether this parameter can
be properly assessed prior to surgery.
METHODS
Gastric Carcinoma Patients
Two hundred patients with gastric carcinoma, diagnosed
and treated between 1987 and 1994 at the Departments
of Gastroenterology, Pathology, and the First Department
of Surgery, Pomeranian Medical Academy, Szczecin, Poland were included in this study. All cases had adequate
clinical and pathologic information. Patient's sex, age,
family history of cancer, durations of symptoms, tumor
site, size, stage, and histology, type of treatment performed, and follow-up data were recorded. The median
age of the patients was 59 years (range: 24-90 years) and
67.5% of the patients in the series were male. Sixty one
gastric tumors (30.5%)were located in the antrum or pylorus region, 85 (42.5%) in the body, 43 (21.5%) in the
cardia or fundus, in 4 patients (2%) carcinoma affected
nearly the whole stomach, and in 7 patients (3.5%)cancer
developed in the gastric stump. For further analysis, gastric carcinomas were divided into proximal and distal le-
sions. Stage and histologic type of gastric carcinoma were
assessed from routine examination of paraffin sections
obtained from surgical specimens, stained with hematoxylin and eosin (H & E). Evaluation of tumor stage was
performed according to the criteria of the International
Union Against Cancer (UICC) additionally tumor were
classified as early or advanced according to the criteria
of the Japanese Research Society for Gastric
Histologic typing was assessed according to Lauren's clas~ification.'~A potentially curative resection was performed on 128 patients, 26 underwent noncurative gastric
resection, and 46 underwent palliative surgical procedures or laparatomy. Patients were asked to continue
their clinical care at the Department of Gastroenterology
in Szczecin. Control visits were made every 3 months for
the first 2 years after surgery and then yearly. These visits
included conventional clinical examination, ultrasonography of the abdomen, and gastroscopy. Patients could
come to the clinic independently of the schedule if they
felt unwell. Time of recurrence or metastases, survival
time, and cause of death were recorded.
Tissue Preparation
All of the patients were examined endoscopically before
operation, and a minimum of four tissue specimens were
sampled with routine biopsy forceps. These specimens
were fixed in 80% ethanol and embedded in paraffin.
Surgical material from the same patients was fixed in 10%
neutral formalin and also embedded in paraffin. Surgical
material from all 200 patients was used for immunohistochemical analyses. Additionally, in 90 patients, p53 expression was studied using endoscopic material.
lmmunohistochemistry
Histology of all of the cases was reviewed and representative sections from 2 to 5 different areas of each tumor
were selected for immunohistochemistry. These were deparaffinized in xylene, transferred to 95% ethanol, and
air-dried. The polyclonal rabbit anti-p53 antibody, CM1,
raised against the full length human p53 protein, was
used as a primary antibody. A 3-stage immunoperoxidase
technique was used as previously described." Briefly, the
slides were incubated overnight at 4 "C with polyclonal
anti-p53 antibody and diluted 1/750. The sections were
washed and treated consecutively for 30 minutes with
biotinylated swine anti-rabbit antibody (Dakopatts,
Glostrup, Denmark) diluted 1/400 in TBS and streptavidin
HRP-conjugated reagent (Dako Ltd., U.K.) diluted 1/BOO,
at room temperature. Peroxidase was visualized using
0.05% solution of diaminobenzidine tetrahydrochloride
(Sigma, St. Louis, MO) and 0.1% solution of nickel chloride in TBS containing 0.03% hydrogen peroxide (10 min).
Finally, the slides were lightly stained in haemalum (Mayer's, Merck, Poole, UK). Replacement of the primary anti-
p53 Protein in Gastric Carcinorna/Starzynska et al.
2007
body with normal rabbit serum was used as a negative
control. Colonic carcinoma sections with p53 accumulation were includled in each experiment to ensure that
the procedure was working optimally. Specific nuclear
staining of cells (regardless of proportion) was considered
positive for abnormal p53 expression.
Statistical Analysis
For all 200 patients, p53 expression in gastric carcinoma
was compared with selected clinicopathological variables. These included sex, age, family history of cancer,
duration of symptoms, tumor site, size, depth, histologic
type, and metastatic status at presentation. Comparisons
between p53 expression in tumor tissue and these parameters was performed using the chi-square test and Fisher's exact test. Among 128 patients who undeiwent potentially curative ga:stric resection, 111 were included in the
survival analysis. The median follow up time for these
patients was 33 months (range: 3-85 mos). The disease
free survival time was defined as the time to cancer recurrence. The overall survival time was defined as the time
to cancer related death. Univariate survival analysis was
performed using; the log rank test for a whole group of
patients after potentially curative gastric resection (n =
111; including 19 patients with early tumors) and independently for a subgroup of patients with advanced cancer (n = 92).2R.L'? The variables assessed were: age (550
vs. >50 years), sex, duration of symptoms ( < G vs. >6
mos), tumor site (distal vs. proximal stomach), size ( < 5
vs. >5 cm), depth, histology (intestinal vs. diffuse), regional lymph node status, and p53 expression in cancer
tissue. Multivariate Cox regression was used to determine
which parameters were independently of prognostic iniportance.'"
There were no cancer-related deaths in the 19 patients with early disease; the outcome of these patients
is completely determined by the 1 parameter, therefore
these patients were excluded from multivariate analysis.
A step-up procedure was used to build the model, including only terms that were significant at the 0.05 level. Significance levels quoted are those to remove each of the
terms in the final model from that model. A significance
level of 0.05 was used throughout.
RESULTS
The Expression of p53 in Gastric Tissue
p53 accumulation was detected in 85 out of 200 (42.5%)
gastric carcinomas. Irnmunoreaction was always localized in the nuclieus of neoplastic cells (Fig. 1).A negative
reactivity with anti-p53 antibody was seen in gastric epithelium adjacent to carcinoma, including intestinal metaplasia (11 = 154) and in stroma (n = 200). There was
complete concordance between the final results of immunohistochemical staining among 90 carcinomas stained,
FIGURE 1. lmmunohistochemical detection of p53 accumulation
111 en-
doscopic biopsies is shown. Gastric carcinoma of a well differentiated
intestinal type(a) and a poorly differentiated tubular carcinoma (b) shs3wing
strong nuclear staining (original magnification (a) x180; (b) ~ 4 0 0 ) .
using both endoscopic and surgical material. Thirty-eight
of these tumors showed positive and 52 negative reactivity. However, the intensity and pattern of immuno renction were related to the type of material used. On endoscopic biopsies, p53 staining was always much stronger
and distributed in a greater proportion of the cells. Forty
seven percent and 32% of p53 positive endoscopic biopsies exhibited labelling in more than 95% and betweim 50
and 75% of tumor cells, respectively. In the remaining
21%, p53 accumulation was detected in less than 50% of
the cancer cells, however, no case with less than 10% of
positive cells was seen. By contrast, 29 out of 38 (76%) of
the surgical specimens, scored as p53 positive, exhibited
focal reactivity. In no case were only occasional positive
cells found, although some specimens showed nonreactive areas especially in the centre of the section. The proportions of p53 positive cells and the intensity of staining
could vary between different areas of the same tumor
but the pattern was independent of tumor depth. The
2008
CANCER May 15,1996 / Volume 77 / Number 10
preservation of p53 antigenicity in endoscopic specimens
was probably improved by the rapid fixation offered by
80% alcohol and small biopsy size.
TABLE
p53 Overexpression and Selected Clinicopathologic
Features
The relationships between p53 expression in gastric cancer and selected clinicopathologic variables are summarized in Table 1. There was a highly significant correlation
between the presence of p53 accumulation in neoplastic
tissue and tumor stage. The proportion of p53 positively
reacting carcinomas increased as the stage progressed ( P
< 0.001). Only 15% of the gastric carcinomas from the
patients without metastases were p53 positive compared
with 50% of the tumors which had invaded regional
lymph nodes and 67% of the neoplasms with distant metastases ( P < 0.001). Twenty-two percent, 28%, 37%, and
62% of T1, T2, T3, and T4 carcinomas, respectively, overexpressed p53 ( P < 0.001). Fewer of the tumors classified
as early showed p53 overexpression compared with tumors classified as advanced (19%vs. 45%; P = 0.039). p53
overexpression was detected more frequently in carcinoma from proximal rather than distal stomach (60%and
38%, p53 overexpressing tumors, respectively; P = 0.027).
There was also an association between p53 positivity and
tumor size, with 25% of the small (<2 cm) tumors being
p53 positive compared with 52% (2-5 cm) and 41% (>5
cm) of the larger tumors ( P = 0.025). p53 expression was
unrelated to patient sex, age, family history of cancer,
duration of symptoms, and histologic type.
Parameter
Relationship between p53 Expression and Survival
Of 111 patients who underwent potentially curative surgery, including 19 with early and 92 with advanced gastric
carcinoma, 39 had tumors with p53 accumulation and 72
had carcinoma with undetectable p53 protein. Figure 2
shows the actuarial survival curves of this group, and of
the p53 negative and positive subgroups. In these patients, the presence of p53 accumulation was a marker
of poor prognosis. The overall 5-year survival rates were
20% for patients with carcinoma overexpressing the p53
protein and 70% for patients who had tumors with an
undetectable level of p53 ( P < 0.001). The analogous results for disease free survival time were 28% versus 72%
( P < 0.001).
Results of univariate analyses (Table 2) show that
in addition to p53 accumulation, the prognosis of these
patients was significantly adversely affected by metastatic
spread to the regional lymph nodes ( P < 0.001) and increasing tumor depth ( P < 0.001).There was a weak effect
on the disease free interval with increasing duration of
symptoms ( P = 0.0171, but this was not carried through
to survival. The other indicators were not significantly
associated with survival or disease free interval.
1
Relationship between p53 Expression in Gastric Carcinoma and
Selected Clinicopathologic Features
Number
examined
p53 accumulation
positive
Sex
male
female
135
65
59 (44%)
26 (40%)
NSa
Age
<50
>50
53
147
18 (34%)
67 (46%)
NS
Family history of cancer
Positive
Gastric cancer
Other cancers
Negative
No reply
61
32
29
98
41
23 (38%)
12 (38%)
11 (38%)
39 (40%)
NS
51
54
63
30
25 (49%)
24 (44%)
27 (43%)
7 (23%)
NS
43
146
11
26 (60%)
55 (38%)
4 (36%)
36
77
87
9 (25%)
40 (52%)
36 (41%)
P = 0.025
114
86
49 (43%)
36 (42%)
NS
22
61
41
68
5 (22%)
17 (28%)
15 (37%)
42 (62%)
P < 0,001
Early cancer
Advanced cancer
21
179
4 (19%)
81 (45%)
P = 0.039
Metastases at presentatione
Negative
Only lymph node
Distant
68
80
51
10 (15%)
40 (50%)
34 (67%)
Duration of symptoms (mosIb
0-6
7-12
13-60
3 0
Tumor site
Proximal stomach
Distal stomach
Other'
P = 0.027
Tumor size (cm)
<2
2-5
>5
Histology
Intestinal
Diffuse
Tumor depthd
T1
T2
T3
T4
P < 0.001
NS: not significant.
a Not significant, ,yz test.
Data available from 198 patients.
'Gastric stump or nearly all stomach affected.
From 192 patients.
' From 199 patients.
p53 Protein in Gastric CarcinomalStarzynska et al.
lymph node status achieved statistical significance ( P <
0.001; RR -= 3.8 and P = 0.035, HI< -= 2.4, respectively).
b
a
100
"j
.....
90
.....
.......
70
.\"
.-2
I
CONCLUSIONS
.. . ... .. . .
80
....,,..... .......14172
.
60
40
5
b
,
;
;
'
;
,
,
,
,
v)
30
28139
20
t
10
1
0
0
20
40
2009
60
Time (Months)
80
100
0
.
I
20
.
I
40
.
I
.
60
I
80
.
I
100
Time (Months)
FIGURE 2. Acturial survival curves for p53 negative (broken line) and
positive (solid line) platients after potentially curative resection for gastric
carcinoma are shown: (a) all patients. (b) patients with advanced disease.
The numbers 01 dearhs and patients in each group are given.
Similar results were observed for the 92 patients who
underwent potentially curative surgery for advanced gastric carcinoma. Figure 2b shows survival curves of this
group, and for I he p53 positive and negative subgroups.
I n these patienrs, the presence of p53 accumulation was
a marker of poor prognosis. The overall 5-year survival
rates were 15% for patients with carcinomas overexpressing 1153 protein and 63% for patients who had tumors with undetectable levels of p53 (1' < 0.001). The
analogous results of disease free survival tinie were 23%
versus 65% (I' <: 0.001). The results of univariate analysis
show that the prognosis of these patients was also significantly adversely affected by metastatic spread to regional lymph nodes ( P < 0.001) and increasing tumor
depth ( P < 0.0L2). The other indicators were not significantly associated with survival or disease free interval.
'l'ablc 2 also shows that there were no cancer-related
deaths in the I!>patients with early disease; the outcome
of these patients is completely determined by the 1 parameter thcrefore they were excluded from the multivariate analysis.
I n the multivariate Cox regression analysis (?'able 3)
of overall survival time for the group of patients after
curative sui-gery for advanced carcinoma, the accumulation of p53 was the strongest predictor of poor prognosis
( I > < 0.001; relative risk (RK) = 3.7). The other parameters
which achieved statistical significance were metastases
to the regiona'l lymph nodes ( P = 0.025; HR = 2.5) and
tumor depth ( P - - 0.012; RR = 2.2, for tumors without vs.
with serosal involvement). IJsing cancer recurrence as the
end point, similar results were obtained but only p53 and
There is growing interest i n the supplementation of the
traditional methods used to assess cancer progres:;ion
and predict its course by use of different molecular markers.'9 Recent studies have suggested that the accumulation of p53 protein in neoplastic cells might be such a
marker."" '" However, in contrast t o numerous papers
discussing the clinical significance of this phenomenon,
it has not been determined whether tumor samples obtained during diagnostic procedures constitute sufficient
material to properly assess p.53 status. The problem is
especially important in terms of heterogeneity of p53 accumulation in malignant tumors observed by many authors.l: 2lI.22
We have compared 1153 irnmunostaining on surgical
and endoscopic material and clearly demonstrated that
the presence of p53 accumulation in gastric carcinoma
can be detected using endoscopic biopsy prior to surgery.
We have also shown that this simple test can be helpful
to predict tumor progression. In this study, the accuniulation of p53 protein was seen to occur in early gastric
cancers confined to the mucosa but the proporticin of
tumors exhibiting p53 overexpression increased as the
tumor stage progressed. Thus, 22%, 28%, 37%. and 62%
of T I , T2, T3, and '1.4 tumors, respectively, expressed elevated levels of p53. l'he analysis of our data also revealed
a significant association between p53 accumulation and
metastatic spread. p53 was detected in 15% of gastric
carcinomas without metastases, 50% of tumors which
had invaded regional lymph nodes, and in 67% of neoplasms with distant metastases. A strong relationship between p53 accumulation and metastases, together with
the possibility of its simple preoperative assessment,
might be useful in clinical practice to enhance our ability
to select patients with a high risk of lymph node involvement and plan optimal surgical strategies.
p53 studies on gastric carcinoma have produced conflicting results as to the relationship between p53 expression and tumor stage. In two recent studies of 180 and
149 gastric carcinoma patients, no correlation between
p53 positivity, metastatic spread, and depth of tumor
penetration were seen."'."' By contrast and in agreement
with our results, 4 other studies of 77, 96, 135, and 357
patients, reported a higher propensity for metastasis to
the regional lymph nodes in gastric carcinoma with p53
l~;~lwl..l5
accumu~ation,
I n this study, p53 accumulation
was also correlated with other indicators of poor prognosis for gastric cancer being more frequently detected in
carcinoma from proximal rather than distal stomach and
in larger neoplasms.
The Lauren classification divides gastric carcinoma
2010
CANCER May 15,1996 / Volume 77 I Number 10
TABLE 2
Univariate Log Rank Analyses of Prognostic Factors for 111 Gastric Carcinoma Patients (92 advanced tumors)
Who Underwent Potentially Curative Surgery
Feature
p53 accumulation
% 5-year
70 (63)
20 (15)
76 (69)
22 (17)
sunival
Sex
M
F
Age
0-50
51 t
14/72 (141571
28139 (281351
10157 (10/42]
32/53 (32150)
0119
18152 (18152)
14125 (14125)
10115 (10115)
21152 (21139)
21/59 (21153)
8/20 (8117)
33/90 (33174)
26/71 (26152)
16/40 (16140)
30/74 (30161)
12/37 (12131)
13/33 (13127)
29178 (29165)
0-6 m
>6 cm
10123 (10/21)
32188 (32/711
46 (44)
52 (42)
None
Stomach
Other
17/53 (17144)
7/21 (7117)
7/19 (7115)
58 (50)
61 (55)
59 (48)
Regional lymph node
Metastases
Tumor deplh
Histology
Tumor site
Tumor size
Duration of
symptoms
Family history of
cancer
-ve
t ve
-ve
tve
Ti
T2
T3
T4
Deaths/
patients
Diffuse
Intestinal
Proximal
Distal
0-5 cm
>5 cm
51 (54)
24 (24)
29 (29)
41 127)
56 (51)
n!a
53 (44)
52 (38)
48 (48)
48 (38)
5 i (49)
46 (37)
52 (43)
Parameter
p53 accumulation Present
vs. absent
Lymph node metastases
Positive vs. negative
Tumor depth T2 vs. T3 t T4
Disease free
Relative risk
P value
Relative risk
P value
3.7
<0.001
3.8
<0.001
2.5
2.2
0.025
0.012
2.4
0.035
NS
-
NS: no1significant
into intestinal and diffuse subtypes with different clinical,
histologic, and epidemiologic characteristic^.^^ These differences suggest distinct etiologies and molecular mechanisms of development but in this study and those of
others, p53 accumulation did not correlate with tumor
histo~ogy,17,Z0,?I
However, some authors observed p53
overexpression primarily in gastric carcinomas with tubular structure^.'^^^^
In spite of the vast array of established parameters
disease free
P value
0.96 (0.97)
72 (65)
28 (23)
75 (67)
32 (28)
100
51 (51)
43 (43)
43 (43)
56 (41)
56 (51)
nla
60 (51)
55 (41)
59 (59)
51 (41)
66 (59)
59 (50)
55 (46)
0.12 (0.30)
39 (35)
60 (50)
0.017 (0.059)
0.81 (0.73)
68 (61)
52 (37)
57 (44)
0.56 (0.47)
<0.001 1<0.001)
<0.001 (<O.OOl)
ID0
TABLE 3
Multivariate Analyses of Prognostic Factors for Patients after
Potentially Curative Surgery for Advanced Cancer
SUMVal
% 5-year
P value
<O.OOI (0.012)
0.34 (0.075)
0.23 (0.37)
0.51 (0.61)
0.47 (0.41)
<0.001 (<0.001)
<0.001 (<0.001)
0.003 (0.18)
0.69 (0.25)
0.13 (0.22)
0.76 (0.43)
0.43 (0.37)
0.68 (0.69)
which help to predict outcome of gastric carcinoma patients, individual tumor behavior still can not be accurately determined for the group of patients by TNM staging. Patients who are likely to survive (early carcinomas)
or die (inoperable tumors) within 5 years can be identified. However, for patients with advanced, but operable
gastric carcinoma, who constitute the largest group of
patients with newly diagnosed disease, the likelihood of
survival to 5 years is less certain. It is clearly important
to identify those patients who are most likely to benefit
from aggressive therapy.
Our analysis showed a highly significant association
between the presence of p53 accumulation and reduced
survival time in a group of patients who underwent curative surgery for advanced gastric cancer. The overall and
disease free 5-year survival rates for patients whose tumors accumulated p53 protein and in patients who had
carcinoma with undetectable levels of p53 were 15%versus 63% and 23% versus 65%, respectively. Furthermore,
p53 accumulation was an independent predictor and the
strongest predictor of poor prognosis, followed by metastases to the regional lymph nodes, and serosal involvement. These results are consistent with a previous study
of 76 patients which indicated that p53 accumulation can
p53 Protein in Gastric CarcinomalStanynska et al.
be an independent parameter of poor prognosis.” A significant positive correlation between p53 immunopositivity and shorter survival has been reported but the influence on prognosis for advanced but operable tumors was
not determined.:’s
Investigation of p53 status in early gastric carcinoma
has shown increased incidence of p53 accumulation in
patients with the poorest postoperative course3: and in
those with tumors of a penetrating growth pattern.:’” The
studies and work presented here are consistent with a
role for p53 in expansion and aggressiveness of this malignancy.
In conclusion, this report shows that in gastric carcinoma, the expression of p53 protein in tumor tissue can
be properly assessed prior to surgery, using immunohistochemistiy on a small tissue samples obtained during
endoscopy. Furthermore, we demonstrate that the preoperative assessmcnt of p53 expression in this carcinoma
can be helpful in identifying patients at high risk for metastatic spread, including regional lymph node involvement, and in the discrimination of those patients with
especially poor prognosis. When combined with routine
procedures, this simple and inexpensive test might allow
better planning of appropriate treatment strategies.
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Lane DP. The regulation of p53 function. Inf J C h c e r
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Aj. Activating mutations for transformation by p53 produce
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6. Oren M. The p53 cellular tumor antigen: gene structure,
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Greaves R. lggo H, Lane DP. Activating mutations
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