Preoperative evaluation of P53 and bcl-2 over expression in clinical stage 1 endometrial carcinoma and their correlation with surgico-pathological data and prognosis of patients

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Open Journal of Obstetrics and Gynecology, 2011, 1, 55-63

doi:10.4236/ojog.2011.12012 Published Online June 2011 (http://www.SciRP.org/journal/ojog/ OJOG

Published Online June 2011 in SciRes. http://www.scirp.org/journal/OJOG

Preoperative evaluation of P53 and bcl-2 over expression in

clinical stage 1 endometrial carcinoma and their correlation

with surgico-pathological data and prognosis of patients

Emad A. Fyallah1, Reda A. Hemida1, Kamal I. An war 1, Nada A. Nadia2, Lotfy S. Sherif1, Mohammad T.

Sayed-Ahmed1

1Departments of Obstetrics and Gynecology, Mansoura University, Nile Delta, Egypt;

2Pathology, Faculty of Medicine, Mansoura University, Nile Delta, Egypt.

Email: [email protected]

Received 29 April 2011; revised 26 May 2011; accepted 3 June 2011.

ABSTRACT

Introduction: P53 and bcl-2 over expression was re-

ported to affect the biology and prognosis of patients

endometrial carcinoma. Methods: This prospective

study included 38 patients with histologically con-

firmed endometrial carcinoma and staged clinically

as stage I. Immunohistochemical staining of the tu-

mor specimens obtained by dilatation and curettage

(D&C) with P53 an d bcl-2 mono clonal antibodies was

done. The surgical, pathological and follow up data of

all patients were studied. Results: There were 18

cases (47.4%) with positive P53 over expression. P53

over expression was found to be associated with in-

creasing grade of differentiation, advanced stage, and

non endometrioid type (significant), and increased

depth of myometrial invasion (non-significant). It

was associated with more recurrence rate (22% ver-

sus 15%) and shorter mean survival time (33.9 versus

29.2 months). Bcl-2 expression was present in24 cases

(63.2%) of the studied group. There was significant

decrease in bcl-2expression with poorly differentiated,

advanced stage, increased depth of myometrial inva-

sion, and non-endometrioid type. It was not signifi-

cantly correlated with recurrence rate and mean sur-

vival time. Conclusion: P53 over expression in the

D&C specimens was associated with adverse surgi-

copathological criteria, increased mortality rate, and

shorter survival time in patients with endometrial

carcinoma. A significant decrease in bcl-2 expression

was associated with adverse surgicopathological cri-

teria, but it was not significantly correlated with

prognosis of the patients.

Keywords: Endometrial Carcinoma; Prognosis; P53;

Bcl-2

1. INTRODUCTION

Endometrial carcinoma is the most common malignancy

of the female genital tract accounting for almost half of

all gynecologic cancers in western world. It represents

the fourth most common cancer after breast, lungs and

bowel cancers, and the seventh leading cause of death

from malignancy in women [1].

Mariani et al. [2], reported that in the pretreatment

curettage specimen, the presence of unfavorable level of

P53 and bcl-2 or non endometrioid histological feature

or combination of those, can significantly predict lymph

node status in patients with endometrial carcinoma.

P53 gene mutation was found to affect the biological

features of endometrial carcinoma, as it was found to be

associated with more aggressive histologic subtypes than

endometrioid carcinoma. Strong expression of p53 cor-

relates with advanced stage and high grade of the tumor

and was detected more frequently in endometrial cancer

with lympho-vascular space invasion [3].

Bcl-2 belongs to a family of apoptosis-regulatory

genes which may either promote cell survival or en-

courage cell death [4]. Expression of bcl-2 does not only

contribute to oncogenesis but also to chemotherapy re-

sistance in variety of tumors by inhibiting apoptosis [5].

Bcl-2 expression was found to be increased in grade 1

and 2 endometrioid adenocarcinoma, while in the serous

papillary endometrial cancer showed immuno-nega-

tivity to bcl-2 [6]. Bcl-2 may have an importance in the

progression of endometrial carcinoma [7].

To the best of our knowledge, there are few reported

studies to evaluate the correlation of pre-operative test-

ing of P53 and bcl-2 expression with the surgico-patho-

E. A. Fyallah et al. / Open Journal of Obstetrics and Gynecology 1 (2011) 55-63

logical data and prognosis of patients in clinical stage 1

endometrial carcinoma. We tried to evaluate th is point in

this prospective clinical study.

2. PATIENTS AND METHODS

This prospective clinical study was conducted at the de-

partments of Gynecology and Pathology, Faculty of

Medicine, during the period from April 2005 to October

2008. The study included 38 patients with histologically

confirmed endometrial carcinoma and staged clinically

as stage I.

The routine pre-operative work up of these patients

was done. Dilatation and curettage was done, a part of

the biopsy was prepared in paraffin sections for his-

tologic examination and another part was used for im-

munohistochemical staining with P53 and bcl-2 mono-

clonal antibodies.

P53 immune staining: Immunohistochemical reaction

was carried out for detection of P53 protein over expres-

sion in endometrial tumor tissue using monoclonal

mouse anti-human P53 protein, clone; DO-7, supplied

by DAKO corporation, USA. Positive staining was de-

fined as homogenous pattern of nuclear staining (brow-

nish coloration) that involved more than 5% of the cells.

Bcl-2 immunohistochem ical staining: The primary an-

tibody used was the second generation monoclonal

mouse anti-bcl-2 protein (Biogenex, Cat no. Am 287).

Using the high power field, the immunoreactivity (posi-

tive cases) for bcl-2 was determined by the percentage of

tumor cells showing cytoplasmic (brown) staining that

involved more than 5% of the cells.

After that, patients were subjected to surgical treat-

ment, in which peritoneal cytology, extra-fascial hyster-

ectomy, bilateral salpingo-oophrectomy and pelvic

lymph node sampling were done.

The use of adjuvant radiotherapy was individualized

in the tumor board meetings .Candidates of postopera-

tive radiotherapy were suggested by use of prognostic

factors such as surgical staging, depth of myometrial

invasion, histologic type and tumor grading.

Follow up: Patients were followed up every three

months, by history, physical examinations, and ultra-

sound. MRI was done every 6 months. The surgico- pa-

thological data of all patients were studied. Overall sur-

vival, recurrence rate and duration were estimated.

2.1. Statistical Analysis

Statistical analysis was done by using SPSS (Statistical

package of social science) program version 10, 1999.

The data were parametric by using Kolmogrov-Smirnov

test. The qualitative data were presented in the form of

means, standard deviation and range. Student test was

used for comparison of the two groups. One way ANO-

VA test was used to compare more than two groups.

Man-Whitney test was used to compare the non-para-

metric data. Sensitivity, specificity and accuracy were

calculated. Kaplan-Meier survival analysis was done to

calculate the cumulative survival. Significance was con-

sidered when P value is less than 0.05.

2.2. Ethical Considerations

The research was approved by The Ethical Review

Committee of our Faculty of Medicine. Formal and

written consents were taken from all patients.

3. RESULTS

This study included 38 cases of histologically confirmed

endometrial carcinoma, clinical stage I, during the pe-

riod from April 2005 to October 2008. The mean follow

up duration from the treatment was 21.5 month, (range 6

- 40 months). After surgical staging (according to FIGO

staging 1988), there were 30 cases with stage I, 4 cases

with stage II and 4 cases with stage III.

Pretreatment study of P53 over expression by “Im-

muno-histochemical stain” was done for the studied

group; there were 18 cases (47.4%) with positive P53

over expression.

P53 over expression was found to be associated with

increasing grade of differentiation, advanced stage, and

non endometrioid type (significant), and increased depth

of myometrial invasion (non-significant) as can be con-

cluded fr om Table 1.

The relation between P53 over expression and recur-

rence of the disease in the study group: Although the

recurrence of the disease in patients with negative P53

over expression was 15% (3 of 20 cases), in the po sitive

group it was 22 % (4 of 18 cases) but this d ifference was

not statistically significant (P value 0.576).

The survival time was prolonged in P53 negative pa-

tients, as the mean survival time in p53 negative group

was 33.9 months while it was 29.21 months in p53 posi-

tive group (Table 2).

Figure 1: Kaplan-Meier estimates the influence of

P53 over expression in the recurrence of the studied

group. There was difference in the mean recurrence du-

ration in both groups.

The relation between P53 over expression and mortal-

ity of the studied group is shown in Table 3, the mortal-

ity between P53 po s itive patients was higher 16.6% (3 of

18 cases) in comparison to the mortality between nega-

tive patients, which was 5% (1 of 20 cases) the differ-

ence is significant (P value 0.026).

Figure 2: Kaplan-Meier estimates the influence of

P53 over expression in the mortality duration of the stu-

died group: There was difference in the mean mortality

duration in both groups. It was shorter in positive group.

Bcl-2 expression was studied also, bcl-2 expression

E. A. Fyallah et al. / Open Journal of Obstetrics and Gynecology 1 (2011) 55-63

OJOG

Table 1 . Relationship between P53 over expression and degree of differentiation of the tumor, surgical staging, depth of myometrial

invasion, and histological type in the study group.

P53

Grade

Negative Positive

Total P value

G1 11 (78.6%) 3 (21.4%) 14 (100%)

G2 6 (37.5%) 10 (62.5%) 16 (100%)

G3 3 (37.5%) 5 (62.5%) 8 ( 10 0%)

Total 20 (52.6%) 18 (47.4%) 38 (100%)

0. 037

Stage

Stage I 19 (63.3%) 11 (36.7%) 30 (100%)

Stage II 1 (25.0%) 3 (75.0%) 4 (100%)

Stage III 0 (0%) 4 (100%) 4 (100%)

Total 20 (52.6%) 18 (47.4%) 38 (100%)

0. 013

Myometria l invasion

No invasion 4 (66.7%) 2 (33.3%) 6 (33.3%)

Invasion < 50% 9 (52.9%) 8 (47.1%) 17 (100%)

Invasion > 50% 7 (46.7%) 8 (46.7%) 15 (100%)

Total 20 (52.6%) 18 (47.4%) 38 (100%)

0.709

Histopathologic type

Endometrioid 18 (62.1%) 11 (37.9%) 29 (100%)

Adenosquamous 1 (25.0%) 3 (75.0%) 4 (100%)

Papillary serous 1 (20.0%) 4 (80.0%) 5 ( 1 00 % )

Total 20 (52.6%) 18 (47.4%) 38 (100%)

0. 047

Table 2. The relation between P53 over expression and the mean survival time in the study group.

P53 expression Mean S D* Minimum Maximum P value

Negative

Positive

Overall

33.9

29.21

32.78

2.77

2.79

2.25

28.46

23.73

28.36

39.34

34.68

37.2

0.461

P value: 0.461 (non significant); S D*: St andard deviation.

Table 3. The relation between P53 over expression and mortality of the study group.

P53 expression Number of cases Number of died cases P value

Negative

Positive

Total

1 (5%)

3 (16.6%)

4 (100%)

0.026

P value: 0.026 ( significant).

E. A. Fyallah et al. / Open Journal of Obstetrics and Gynecology 1 (2011) 55-63

Figure 1. Kaplan-Meier estimates of the influence of P53 over expression in the re-

currence of the studied group: As seen in this figure, the faint line represents the posi-

tive group while the dark line represents the negative group.

Figure 2. Kaplan-Meier estimates of the influence of P53 over expression in the mor-

tality duration of the studied group: As seen from this figure, the faint line represents

the positive group while the dark line represents the negative group. There was differ-

ence in the mean mortality duration in both groups. It was shorter in positive group.

E. A. Fyallah et al. / Open Journal of Obstetrics and Gynecology 1 (2011) 55-63

OJOG

Table 4. The relation between bcl-2 expression and the degree of differentiation, surgical staging, depth of myometrial invasion and

histological type in the studied group.

Bcl-2

Grade Negative Positive Total P value

G1 2 (14.2%) 12 (14.2%) 14 (100%)

G2 6 (37.5%) 10 (62.5%) 16 (100%)

G3 6 (75.0%) 2 (25.0%) 8 (100%)

Total 14 (36.8%) 24 (63.2%) 38 (100%)

0.006

Stage

Stage I 9 (30.0%) 21 (70.0%) 30 (100%)

Stage II 2 (50%) 2 (50%) 4 (100%)

Stage III 3 (75%) 1 (25%) 4 (100%)

Total 14 (36.8%) 14 (36.8%) 38 (100%)

0.018

Myometria l invasion

No invasion 1 (16.7%) 5 (83.3%) 6 (100%)

Invasion <50% 5 (29.4%) 12 (70.6%) 17 (100%)

Invasion >50% 8 (53.3%) 7 (46.7%) 15 (100%)

Total 14 (46.7%) 7 (46.7%) 38 (100%)

0.083

Histopathological type

Endometroid 9 (31%) 20 (69%) 29 (100%)

Adenosquamous 1 (25%) 3 (75%) 4 (100%)

Papillary 4 (80%) 1 (20%) 5 (100%)

Total 14 (36.8%) 24 (63.2%) 38 (100%)

0.070

was present in 24 cases (63.2%) of the studied group.

Table 4, Shows the relation between bcl-2 expression

and the degree of differentiation, surgical staging, depth

of myometrial invasion and histologic type in the studied

group. There was significant decrease in bcl-2 expres-

sion with poorly differentiated, advanced stage, in-

creased depth of myometrial invasion, and non-endo-

metrioid type.

Ta ble 5 : Show the relation between bcl-2 expression

and the recurrence of the disease in studied group. There

was no significant relation between bcl-2 over expres-

sion and recurren ce of the disease in th e stud ied group (P

value 0.627).

Figure 3: Kaplan-Meier estimates the influence of

bcl-2 expression on the recurrence duration of the stud-

ied group: There was no significant difference in the

mean recurrence duration in both groups, the mean re-

currence duration for the negative group was 34 months

and for the positive group about 32 months.

Table 6: shows the relation between bcl-2 gene ex-

pression and the mortality in the studied group. As can

be seen from the table, there was no significant differ-

ence in the mortality rate between bcl-2 positive and

negative cases. (P value 0.615).

Figure 4: Kaplan-Meier estimates the influence of

bcl-2 expression on the mortality dur ation of the studied

group. There was no significant difference in the mean

recurrence duration in both groups, the mean mortality

duration for the negative group was 34 months and for

the positive group about 33.5 months.

4. DISCUSSION

Endometrial carcinoma is the most common malignancy

of the female genital tract accounting for almost half of

all gynecologic cancers in western world [1].

The aim of this randomized trial was to evaluate of

P53 and bcl-2 expression in clinical stage 1 endometrial

carcinoma and their correlation with surgico-pathologi-

cal data and prognosis of patients.

In this study P53 and bcl-2 expression were investi-

gated immunohisto-chemically in 38 patient with clinical

stage-1 endometrial carcinoma. After surgical staging,

stage I represented 79% of our studied group. This result

was comparable to that obtained by Creasman et al. [8].

In this work P53 over expression was detected in 18

cases (47.4%) of our studied group .This finding was

E. A. Fyallah et al. / Open Journal of Obstetrics and Gynecology 1 (2011) 55-63

similar to that obtained by Pilka et al. [9].

In this study, P53 expression was increased with the

grade of malignancy (Table 1), which was statistically

significant (P 0.03). This was in accordance with the

observations reported by other authors [10,11].There

was also a positive correlation between P53 gene muta-

tion and stage of endometrial carcinoma (Ta ble 1 ). So,

P53 gene expression increased significantly in advanced

stages (P value 0.01). This report was in agree with that

of Veralucia et al. [12], but did not agree with other au-

thors [13,14].

In our study p53 gene over expression increased with

increased depth of myometrial invasion but it was not

statistically significant as noticed in Table 1, this finding

was in agree with that of other authors [14,15]. On the

other hand, Cerchi et al. [16] and Pilka et al. [9], found a

Table 5. The relation between bcl-2 expression and recurrence of the disease in the studied patients.

Bcl-2 Total number Recurrence No recurrence Percent

Negative

Positive

Overall

85.7%

79.2%

81.6%

P value: 0.627 (Non significant). Chi square: 0.076

Figure 3. Kaplan-Meier estimates of the influence of bcl-2 expression on the recurrence duration of

the studied group: As seen from this figure, the faint line represents the positive group while the dark

line represents the negative group. There was no significant difference in the mean recurrence dura-

tion in both groups, the mean recurrence duration for the negative group was 34 months and for the

positive group about 32 months.

E. A. Fyallah et al. / Open Journal of Obstetrics and Gynecology 1 (2011) 55-63 61

Table 6. The relation between bcl-2 expression and mortality.

Bcl-2 expre ssion Number Number of died cases P value

Negative

Positive

Over all

2 (14.2%)

2 (8.3%)

4(10.5%)

0.541

P value: 0.615 (Non significant).

Figure 4. Kaplan-Meier estimates the influence of bcl-2 over expression on the mortality duration of

the studied group: As seen from this figure, the faint line represents the positive group while the dark

line represents the negative group. There was no significant difference in the mean recurrence dura-

tion in both groups, the mean mortality duration for the negative group was 34 months and for the

positive group about 33.5 months.

significant positive correlation between P53 over ex-

pression and depth of myometrial invasion.

There was significant correlation between P53 gene

mutation and histologic type of the tumor (Table 1). In

endometrioid type, it was 37.9%, while in papillary se-

rous type it was 80% (P value 0.047). These findings

were in agree with that of other authors [1 3,15].

In our study there were 3 cases (3 of 20) of recurrence

in the P53 negative gr oup (15%) and 4 cases in P53 pos-

itive group (4 of 18) (22.2%) this difference was not

statistically significant (P value 0.57) .These results were

in agree with Marcia et al. [14].On the other hand, Pilka

et al. [9] and Appel [11], found that a significant correla-

tion between P53 gene mutation and recurrence of the

disease. The difference between these studies and our

study may be due to shorter follow up time and smaller

sample size in our study.

The mean survival time for P53 negative patients was

38.15 months and for the P53 positive patients was

31.68 months. So, P53 over expression in our study was

associated with increased mortality rate and shorter sur-

vival time in patients with endometrial carcinoma .These

results were supported by findings of other authors [7,

11].

Bcl-2 expression in endometrial carcinoma:

In this study bcl-2 expression was investigated in 38

cases of histologically documented endometrial carci-

noma. It was found that bcl-2 was expressed in the cyto-

E. A. Fyallah et al. / Open Journal of Obstetrics and Gynecology 1 (2011) 55-63

plasm of tumor cells in 24 cases (63.2%). Nearly the

same results obtained by Erkanli et al. [15] and Appel et

al. [11].

There were negative correlation between bcl-2 ex-

pression and the grade of the tumor. These findings were

in agree with Halperin et al. [17]. There were also a sig-

nificant negative correlation between bcl-2 expression

and the stage of endometrial carcinoma (Table 2). These

findings were in agree with other authors [7,9].

Regarding the depth of myometrial invasion in our

study (Table 2), there were negative correlation between

bcl-2 over expression and the depth of myometrial inva-

sion, but the difference was not statistically significant

(P value 0.08). These findings were in agree with Marcia

et al. [14] and Appel et al. [11]. On the other hand, other

authors [7,9], reported a significant immuno-negativity

with increasing the depth of myometrial invasion.

Regarding the correlation between bcl-2 expression

and the histologic type of endometrial carcinoma in our

study (Table 2), there was high expression of bcl-2 in

endometrioid type than non-endometrioid typ es, this was

not statistically significant (P value 0.07). These findings

were in agree with that of Geisler et al. [18].

In the current study there was no significant correla-

tion between bcl-2 expression and recurrence or survival

of the patients with endometrial carcinoma (Ta b le s 6 &

7). These findings were supported by the findings ob-

tained by other authors [11,14,19].

5. CONCLUSIONS

P53 over expression in the D&C specimens was associ-

ated with adverse surgico-pathological criteria, increased

mortality rate, and shorter survival time in patients with

endometrial carcinoma.

A significant decrease in bcl-2 expression was associ-

ated with adverse surgico-pathological criteria, but it

was not significantly correlated with prognosis of the

patients.

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