Proliferative lesions of the endometrium are a heterogenous group of lesions with variable pathological, clinical, epidemiological, and genetic properties (Hayes et al., 2006). These lesions are either benign or malignant; the most common benign lesions are endometrial hyperplasia and the most common malignant lesions are endometrial carcinoma, the fifth most common cancer worldwide in women (Tantbirojn et al., 2008) Fig. 1.
There are two main types of endometrial carcinoma, type I or endometrioid type and type II or nonendometrioid type, exhibiting different molecular alterations, consistent with a dualistic model of endometrial tumorgenesis (Reid Nicholson et al., 2006). The phenotype of endometrial carcinoma is determined during carcinogenesis. Type I carcinomas inactivate phosphatase and tensin (PTEN) very early before any histological change (latent precancer). Nongenetic hormonal selection factors modulate the risk of cancer through their action on preclinical latent clones, which may undergo involution or expansion. Additional mutations are accelerated by a microsatellite instability phenotype and define stepwise progression events to endometrial intraepithelial neoplasia and then adenocarcinoma. Serous (type II) tumors are first seen as a short-lived preinvasive stage called serous endometrial intraepithelial carcinoma (Liobet et al., 2009). Both survivin and cyclooxygenase-2 are overexpressed, and they seem to be early events in the occurrence of endometrial carcinoma (Erkanli et al., 2007).
The PTEN homolog, which is deleted on the chromosome 10 tumor suppressor gene, plays important roles in cell survival and apoptosis because it inhibits cell cycle progression by downregulating cyclin D1 and activates proapoptotic molecules through dependent and independent pathways (Tsugawa et al., 2002).
Mutter et al. (2009) proposed that the use of PTEN immunostaining in a clinical setting may be informative in identifying premalignant lesions that are likely to progress to carcinoma.
Survivin called Baculoviral inhibitor of apoptosis repeat-containing 5 is a member of the inhibitor of the apoptosis family of antiapoptotic proteins. Survivin protein is expressed highly in most human tumors and fetal tissue, but is completely absent in terminally differentiated cells. This therefore makes survivin an ideal target for cancer therapy (Zhang et al., 2005). Survivin is a relevant prognostic and predictive factor as well as a promising molecular target to improve the effectiveness of radiotherapy (Capalbo et al., 2007).
There is a relationship between the percentages of survivin-stained cells and the patients’ characteristics, including clinical stage, histological grade, presence of invasion in more than half of the myometrium, clinical outcome, and survival rate (Takai et al. 2002).
Survivin overexpression might be one of the important mechanisms in the development of endometrioid adenocarcinoma along with lost or decreased activity of PTEN, and is increased in correlation with higher grades in endometrioid adenocarcinoma (Erkanli et al., 2006).
The aim of this study was to investigate the expression of PTEN and survivin in different proliferative endometrial lesions and to study their correlation with classical prognostic factors.
Materials and methods
This study was carried out on 50 cases selected to cover a wide range of different proliferative endometrial lesions. Five-micrometer-thick sections were obtained from the paraffin blocks of the specimens and one section from each specimen was stained with hematoxylin and eosin for histopathological reevaluation and two other sections were mounted on positive charged slides and subjected to immunostaining for PTEN and survivin (mouse monoclonal antibody).
Clinical assessment of cases
Clinical data recorded for each case included age and the type of biopsy in different cases.
Histological assessment of cases
Hematoxylin and eosin-stained paraffin sections were examined microscopically to reevaluate the histopathologic data and the (International Federation of Gynecology and Obestetrics) staging system for carcinoma of corpus uteri.
Two unstained positively charged slides (Biogenix, Memphis, TN, USA) were prepared from each paraffin block for immunostaining with the PTEN monoclonal antibody and the survivin monoclonal antibody.
For the PTEN-positive control, positive control was in the form of normal prostatic tissue and for survivin, sections from prostatic carcinoma were used. As a negative control for both markers, a tumor tissue was processed in the above sequence but the primary antibody was excluded; instead, a phosphate buffer solution was added.
Evaluation of immunostaining
PTEN and survivin immunostaining was assessed quantitatively using the image cytometry Cell Analysis System (CAS 200, Becton-Dickinson, Oxford, UK). Both PTEN and survivin give a brown staining PTEN immunoreactivity was detected in the nucleus, with stromal reaction while survivin detected in the nucleus and/or cytoplasm. To evaluate PTEN expression in the various samples, we applied a scoring method. Scores consist of the sum of the staining intensity (0=negative, 1=weak, 2=intermediate, and 3=strong staining) and the percentile of positive cells (0=0%, 1=1–25%, 2=26–50%, 3≥50%) (Boruban et al., 2008).
The evaluation of survivin expression was carried out using another scoring method. A mean percentage of positive tumor cells was determined by the examination of (300) cells in at least five areas at ×400 magnification. Cells were assigned to one of the five following categories: (a) 0, less than 5%, (b) 1, 5–25%, (c) 2, 26–50%, (d) 3, 51–75%, or (e) 4, more than 75%. Samples with scores of less than 1 were considered as negative (Baak and Mutter, 2005).
Statistical analysis in the present study was conducted using the mean, standard error, unpaired student t-test, the Kruskal–Wallis test, linear correlation coefficient, and χ2 by SPSS version 10 (Chicago, USA).
The present study included 50 cases of different proliferative endometrial lesions. The histopathologic types are summarized in Table 1.
The age of different groups ranged from 25 up to 83 years: the benign cases between 25 and 55 years of age, and the malignant cases between 43 and 83 years of age.
Type of biopsy in different cases
Fourteen cases of the benign group had been subjected to an endometrial biopsy, whereas the rest of the benign cases and all malignant cases had been subjected to a total abdominal hysterectomy, some with pelvic lymph nodes (LNs) and some with omental biopsies (OB) and/or peritoneal wash(PW) (Table 2).
Measured grossly in cases of hysterectomy, most cases of endometrioid carcinoma (EC) and malignant mixed mullerian tumors (MMMT) had endometrial thickness of more than 1 cm (14 and four cases, respectively) and most cases of EH had endometrial thickness of less than 1 cm (eight cases). There was a significant difference in the endometrial thickness between the benign and the malignant group (P=0.019).
Sections from all cases stained by hematoxylin and eosin were reexamined and cases of endometrial hyperplasia and carcinoma were subclassified as shown in Tables 3 and 4, respectively.
Seven cases of endometrial carcinoma were grade III and seven cases were grade II. Five cases of EC were grade I, six cases were grade II, and four cases were grade III. However, all cases of MMMT were grade III. There was no significant difference in the grades of malignant cases (P=0.060), as shown in Table 5.
Most of the endometrial carcinomas (13 out of 19 cases) and half of the cases of MMMT (three cases) showed invasion into more than half of the myometrium. There was no significant difference between the extent of myometrial invasion in EC and MMMT (P=0.412).
Pelvic lymph nodes, omental biopsies, and peritoneal wash in malignant lesions
Ten of the malignant cases (out of 25) had a positive LN. Five of the cases had positive OBs and five cases had a positive PW out of the total (25) specimens. There were no significant differences between malignant deposits in LN, OB, and PW among the different malignant cases (P=0.682).
F-results of immunostaining
All cases of disordered proliferative (DP) endometrium (five cases), all endometrial polyps (EP) (three cases), and all the different variants of endometrial hyperplasia studied (17 cases) showed positive PTEN immunostaining ranging from mild to strong reactivity. In terms of endometrial adenocarcinomas, only six cases of endometrial adenocarcinoma out of 19 showed a weak PTEN expression (+), whereas the rest of the cases were negative. Among six cases of MMMT, mild (+) PTEN immunoreactivity was observed in only two cases versus four negative cases. In contrast, four DP cases showed negative survivin reactivity, only one showed weak positivity (+), whereas two out of three cases of EPs were negatively stained for survivin; the last one showed a weak expression (+). However, cases of simple and complex endometrial hyperplasia without atypia showed positive survivin (seven out of 11 cases) (% 63.64), whereas all cases of endometrial hyperplasia with atypia (six cases) were positive. All studied variants of endometrial adenocarcinoma showed positive survivin reactivity ranging from moderate-to-high expression. All cases of MMMT showed moderate-to-high survivin expression.
There were highly significant differences in both PTEN and survivin expression among different endometrial lesions (P=0.001). These findings are summarized in Tables 6 and 7.
PTEN and survivin expressions in different variants of EH are summarized in Table 8.
PTEN and survivin expressions in different grades of endometrial carcinoma are summarized in Table 9.
Comparison between both PTEN and survivin expression in endometrial carcinoma and MMMT is summarized in Tables 10–12.
There was no significant difference between PTEN and survivin expression in both groups: PTEN (P=0.507) and survivin (P=0.535).
Differences between PTEN and survivin expression in both benign and malignant lesions are illustrated in Tables 13 and 14. There were highly significant and significant differences between PTEN (P=0.001) and survivin (P=0.021) expression in both benign and malignant groups.
Correlations between PTEN and survivin expression in different variants of the lesions studied are summarized in Table 15. There was an inverse relationship between PTEN and survivin immunoreactivity.
Proliferative lesions of the endometrium are a heterogenous group of lesions with variable pathological, clinical, epidemiological, and genetic properties (Hayes et al., 2006). These lesions are either benign or malignant; the most common benign lesions are endometrial hyperplasias and the most common malignant lesions are endometrial carcinomas.
In the present study, the age range in DP, EP, and EH was 25–45 years, whereas in EC and MMMT the age range was 35–83 years. There was a highly significant difference in age in the different groups (P=0.000). Bokhman (1983) found that endometrial adenocarcinoma rarely occurs before the age of 40 years, but the incidence increases markedly between the ages of 45 and 65 years, following which it plateaus. The median age at presentation is 63 years; 90% of the cases are found in women past menopause and only 1% are found in women below 40 years of age.
Endometrial thickness less than 1 cm was found in DP, EP, and some cases of EH, whereas endometrial thickness more than 1 cm was most commonly found in cases of ACH, EC, and MMMT. There was significantly increased endometrial thickness in the malignant groups than in the benign groups (P=0.019). In the present study, the majority of the endometrial carcinoma were grade III (13 out of 25 cases). There was no statistically significant difference in the grades of endometrial carcinoma (P=0.060).
In the present study, preexisting atypical complex hyperplasia was found in 10 out of 25 cases of malignant endometrial lesions, and this was statistically significant (P=0.021). These findings are in agreement with those of Baak et al. (2005), who reported that most of their patients with preexisting atypical complex hyperplasia subsequently developed endometrial carcinoma. Sarmadi et al. (2009) stated that on the basis of clinicopathologic observations, there are two types of endometrial carcinoma: type I usually arising against the background of endometrial hyperplasia and type 2, which is unrelated to estrogen. In contrast, Lotfallah et al. (2005) found that 90% of their cases of simple and complex hyperplasia regressed spontaneously.
In the present study, PTEN positivity was detected in all benign lesions. Simple and complex EH without atypia showed moderate-to-strong PTEN immunoreactivity; however, simple and complex EH with atypia showed mild to strong PTEN immunoreactivity. No significant difference was found between the two groups (P=0.640). The highest PTEN immunoreactivity as well as homogeneity was detected in DP endometrium (+3), EPs (+3), and all cases of endometrial hyperplasia without atypia, in which PTEN expression was 45.46%. However, endometrial hyperplasia with atypia had less homogenous patterns, in which a few scattered PTEN-negative hyperplastic glands are interspersed among PTEN-positive hyperplastic glands. These findings are in agreement with those of Levine et al. (1998), Geyer et al. (2009), and Liu (2001), who found that PTEN immunoreactivity was heterogeneous in most patients with atypical complex hyperplasia. This heterogeneity was attributed by Kanamori et al. (2001) to the fact that PTEN-negative glands may have a somatic PTEN mutation because endometrium has a certain degree of somatic PTEN instability and mentioned that several studies have found that PTEN inactivation is correlated with the clonal growth pattern detected in endometrial hyperplasia and carcinoma. Lacey et al. (2008) explained loss of PTEN expression in the negative glands as the beginning of the earliest stages of endometrial tumorigenesis. These previous studies support the findings of the present study not only in the heterogeneous PTEN expression in ACH but also in the obvious decline in PTEN expression in malignant endometrial cases.
In the present study, PTEN expression in different variants of EC showed decreased expression to negativity (13 out of 19 cases were negative). There was no significant difference between PTEN expression among the different cases of endometrial adenocarcinoma (P=0.311) and no significant difference among the different grades of endometrial carcinoma (P=0.166). Also, MMMT cases showed weak to negative PTEN expression, with no significant difference between MMMT and EC (P=0.507). In contrast, PTEN expression showed a highly significant increase in benign more than in malignant endometrial lesions (P=0.001). In agreement with this, Mutter et al. (2000) found that PTEN expression was completely absent in 97% of EC of their cases. Orbo et al. (2003) reported loss of PTEN protein expression in 55% of specimens in patients with subsequent EC. However, Kapucuoglu et al. (2007) found complete loss of PTEN in 20% of ACH and PTEN immunoreactivity was present in all normal proliferative endometrium and all hyperplasia without atypia and in 48% of EC. Allison et al. (2008) reported PTEN expression in 52% of EC. Lacey et al. (2008) reported that loss of PTEN expression begins in the earliest stages of endometrial tumorigenesis, under conditions of excess estrogen exposure. This may explain the frequent detection of preexisting endometrial hyperplasia, particularly with atypia in cases of endometrial carcinoma. Tantbirojn et al. (2008) mentioned that PTEN damage accumulates in the transition from premalignant to malignant disease. This may explain the gradual decline in PTEN expression from benign to atypical hyperplasia and more severe decline in malignant cases. Moreover, Boruban et al. (2008) observed that PTEN is a major gene involved in the pathogenesis of endometrioid endometrial adenocarcinoma, so that altered PTEN function is partly responsible for the etiology of the majority of the EC. Thus, decreased PTEN expression is a marker of the earliest endometrial precancers. Also, Sarmadi et al. (2009) found that the intensity of the PTEN reaction was significantly higher in the group with proliferative endometrium than hyperplastic endometrium and EC. In contrast, Pallares et al. (2005) reported that PTEN expression had low sensitivity and specificity as a marker for progression from EH to carcinoma.
In the present study, there was a stromal reaction of PTEN in some cases of endometrial carcinomas and this finding is in agreement with that of Cristofano and Pandolfi (2000), who concluded that stromal cells were stained with PTEN, similar to normal endometrium, and then PTEN staining in stromal cells was used as a positive control in each case. The degree of staining of stromal cells in endometrial carcinoma was evaluated.
In the present study, survivin negativity was found in most of the benign endometrial lesions with weak expression and gradual increased expression towards atypical endometrial hyperplasia with moderate to strong immunoreactivity. In endometrial carcinoma and malignant mixed mullerian tumors showed significant increase in surviving expression.
In the present study, four cases of EH without atypia showed negative survivin expression and five cases showed weak expression, whereas all cases of EH with atypia showed moderate-to-strong positivity. There was a significant difference between the two groups (P=0.008).
In the present study, all cases of EC showed moderate-to-strong survivin expression, whereas all cases of serous adenocarcinoma and clear cell carcinoma showed strong expression. No significant difference was detected (P=0.742).
In the present study, most of the cases of grades I, II (10 out of 25), and III showed strong positivity for survivin (12 out of 25) and there was a highly significant difference between survivin expression in different grades of endometrial carcinoma (P=0.001).
No previous studies in the literatures included a comparison of either PTEN or survivin expression in different variants or grades of malignant endometrial lesions.
In the present study, most of the EC cases showed moderate (10.53%)-to-strong (89.47%) survivin expression. Also, most of the MMMT cases showed moderate (33.33%)-to-strong (66.67%) survivin expression. There was no significant difference between survivin expression in EC and MMMT (P=0.535).
In the present study, 15 cases of benign lesions out of 25 were positive for survivin and all cases of malignant lesions were positive. There was a significant difference between survivin expression in both benign and malignant lesions.
These finding are in agreement with those of Takai et al. (2002), who analyzed the relationship between the percentages of survivin-stained cells and the patients’ characteristics, including clinical stage, histological grade, and presence of invasion to more than half of the myometrium. There was abundant survivin immunoreactivity in the nucleus and/or the cytoplasm of the endometrial carcinoma cells. Scoring on the basis of the percentage of positive cells indicated that survivin expression was significantly associated with the proliferating cell nuclear antigen-labeling index, clinical stage, histological grade, and the presence of invasion to more than half of the myometrium.
Higher levels of survivin and protein expression were observed in endometrial adenocarcinomas than in atypical or normal endometrium. Shin et al. (2001) performed immunohistochemical staining of their specimens and found that 83.3% of the endometrial adenocarcinoma samples, 55% of the atypical endometrial samples, and 25% of the normal endometrial samples were positive for survivin protein. Inhibition of survivin by RNA interference reduces cell proliferation and induces apoptosis by downregulating cyclin D1 and phosphorylated retinoblastoma protein and activating caspase-3 and caspase-8. The authors also found that the mitogen-activated protein kinase (MAPK) pathway was the signal transduction pathway upstream of survivin. Epidermal growth factor and transforming growth factor-α upregulated survivin protein expression by activating the MAPK pathway in endometrial cancer cells. Also, Ai et al. (2006) reported that survivin is an attractive target for endometrial cancer treatment. Growth factors could regulate survivin expression by activating the MAPK pathway. Survivin may participate in the onset and progression of endometrial carcinoma by inhibiting apoptosis and promoting proliferation. Survivin expression is correlated with the malignant degree and the prognosis of a tumor (Ai et al., 2006). Nabilsi et al. (2005) suggested that survivin is overexpressed in high-grade endometrial tumors and this finding was in agreement with the present results, which showed increased positivity with tumor grade.
In the present study, there was a highly significant difference between PTEN and survivin expression in different variants of EH and different grades of EC (P=0.000). Also, there was a highly significant difference between PTEN and survivin expression in EC and MMMT (P=0.001).
From the present results, it is clear that there is an inverse relationship between PTEN and survivin, in which PTEN expression increased in benign lesions and decreased to lost in malignant lesions, whereas survivin expression decreased to lost in benign lesions and increased in malignant lesions; thus, there was a significant difference between PTEN and survivin expression in different endometrial lesions (P=0.026). Pallares et al. (2005) concluded that increased survivin expression was frequent in ECs and may be dependent on signal transducer and activator of transcription-3 and PI3 K/AKT activation. Because PTEN abnormalities are very frequent in ECs, the results from their study indicated that PTEN may interfere with the process of apoptosis and cell proliferation by promoting survivin expression. Changes in the percentage of the present results from those of the previous studies again indicate that both PTEN and survivin are monoclonal in nature and the number of cases in the present study are relatively small (50 cases) in comparison with the large number of cases in different studies. Survivin is not a specific marker of EC but may reflect an important mechanism in tumor progression of the endometrium. (Lehner et al., 2002). Erkanli et al. (2006) concluded that survivin overexpression might be one of the important mechanisms in the development of endometrioid adenocarcinoma along with lost or decreased activity of PTEN.
From the present study, it can be concluded that loss of PTEN expression is a potential marker for predicting the subsequent risk of endometrial carcinoma. Thus, PTEN may be a useful immunohistochemical biomarker of mutations of the PTEN suppressor gene. We believe that women with atypical endometrial hyperplasia and early-onset endometrial carcinoma should be evaluated for PTEN expression in their endometrial biopsies. Such an analysis could have therapeutic implications, given that inhibitors of the PTEN mutation pathway are being studied in patients with advanced endometrial cancer. In terms of survivin, we conclude that the apoptotic inhibiting gene survivin plays an important role in the endometrial carcinogenesis and its increased expression is associated with increased severity and worse prognosis of endometrial cancer. Thus, it may be useful as a prognostic factor as well as a therapeutic target in the plan of treatment for endometrial cancer.
Conflicts of interest
There are no conflicts of interest.
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Zhihong A, Lianhua Y, Xianrong Z, Ying Z, Dongmei Z, Yinhua Y, Youji F. Inhibition of survivin reduces cell proliferation and induces apoptosis in human endometrial cancer. 2006;107:746–756