Endometrial carcinoma is the most common female genital tract malignancy prevalent in developed countries such as the USA (Jemal et al., 2010). In Egypt, endometrial cancer accounted for 2.6% of the total female neoplasms (Salim et al., 2009). It was diagnosed in 38% of Egyptian women presenting with perimenopausal bleeding (Zaki et al., 2011). Endometrioid endometrial carcinoma (EECA) accounts for more than three-fourths of endometrial cancers and is thought to develop following a continuum of premalignant lesions, ranging from endometrial hyperplasia without atypia, to hyperplasia with atypia and finally to well-differentiated carcinoma (Boruban et al., 2008; Monte et al., 2010). On the basis of light microscopic appearance and clinical behavior, endometrial cancers have long been classified into major categories (type I and II) (Mutter, 2002; Boruban et al., 2008). Accurate diagnosis of premalignant lesions in routine endometrial biopsies has a great clinical value in patient management. Unfortunately, several recent studies have shown that cytological atypia, which is a predominant criterion for the diagnosis of premalignant lesions (atypical endometrial hyperplasia), has poor reproducibility (Mutter, 2002; Sarmadi et al., 2009). Therefore, solving these problems needs new insights into the morphology of the biologically defined premalignant lesion of the endometrium (Sarmadi et al., 2009). Recent molecular diagnostic methods have provided new ancillary tools for premalignant lesion diagnosis. EECA has a variety of genetic alternations, including microsatellite instability and mutations of phosphotensin gene (PTEN), k-ras, and β-catenin genes (Liu, 2007; Bansal et al., 2009). In addition, these molecular genetic alternations have been described in atypical endometrial hyperplasia (Bansal et al., 2009). Currently, PTEN is the most frequently altered gene in EECA, which is located on chromosome 10 (Samarnthai et al., 2010). The PTEN gene has both lipid and protein phosphate activity, and the combination of the losses of PTEN lipid and protein phosphate activity can cause an aberrant cell growth and an escape from apoptosis, as well as abnormal cell spreading and migration (Lacey et al., 2008; Samarnthai et al., 2010). Mutation of PTEN is a common event in a wide range of human tumors such as glioblastoma (Sano et al., 1999), ovary (Obata et al., 1998), prostate (Giri and Ittmann, 1999) breast (Perren et al., 1999), thyroid (Gimm et al., 2000), and endometrium (Monte et al., 2010; Samarnthai et al., 2010). PTEN mutations were detected in 45.7–83% of endometrial adenocarcinomas; this is the highest known frequency of PTEN mutations in any primary tumor analyzed (Bansal et al., 2009). In this tumor, PTEN mutations were confined to the endometrioid subtype, which accounts for nearly 80% of endometrial cancers (Abd El-Maqsoud and El-Gelany, 2009). PTEN mutations are involved early in endometrial carcinogenesis. In endometrial hyperplasias with or without atypia, which are the precursors of endometrioid carcinoma, its mutation has been detected in 19–55% of the cases (Kapucuoglu et al., 2007; Bansal et al., 2009). PTEN-null glands (i.e. loss of PTEN expression) are shown in a diffuse pattern in EECA, but may also be detected in morphologically normal endometrial tissue, which suggests that PTEN alternation occurs in the earliest phase of endometrial carcinogenesis (Kapucuoglu et al., 2007; Lacey et al., 2008). The hypothesis that loss of PTEN expression could be assessed by immunohistochemical method has led to the suggestion that PTEN immunostaining may be a new and effective tool for the screening of malignant and premalignant endometrial lesions (Sarmadi et al., 2009).
Transport of glucose across the plasma membrane is the first rate-limiting step for glucose metabolism and is mediated by facilitative glucose transporter proteins (GLUTs). The GLUTs differ in their tissue distribution and each transporter protein possesses different affinities for glucose (Thorens and Mueckler, 2010; Krzeslak et al., 2012).
GLUT-1 is broadly expressed in the body tissues and is involved in glucose uptake in the basic state (Macheda et al., 2005). Elevated level of GLUT-1 has been shown in almost all human cancers, including brain, breast, head and neck, bladder, renal, colorectal, lung, and ovarian cancers (Macheda et al., 2005; Krzeslak et al., 2012). Some studies have demonstrated that the level of GLUT-1 expression correlates with specific tumor characteristics. Comparatively higher levels of expression are seen in cancers of higher grade and proliferative index and in cancers of lower degree of differentiation. GLUT-1 expression has been associated with increased malignant potential, invasiveness, and poor prognosis in lung, colorectal, gastric, and ovarian cancers (Kawamura et al., 2001; Sakashita et al., 2001; Kalir et al., 2002). The effect of inhibition of these GLUTs on tumor growth and invasiveness may be of therapeutic value (Wahl et al., 2010).
Our current study aims to determine the variability in PTEN and GLUT-1 expression patterns in proliferative endometrium, endometrial hyperplasia, and endometrioid adenocarcinoma.
Materials and methods
A total of 60 archived formalin-fixed and paraffin-embedded specimens were obtained for this study from the Pathology Department, Faculty of Medicine, Zagazig University. Specimens included 10 cases with proliferative endometrium; 17 cases with endometrial hyperplasia without atypia (15 cases were simple and two cases were complex); eight cases with atypical endometrial hyperplasia; and 25 cases with endometrioid adenocarcinoma specimens (16 cases were grade I, six cases were grade II, and three cases were grade III). Endometrial samples were obtained either by curettage or biopsy specimens. The hyperplasia specimens were evaluated according to WHO classification (Silverberg et al., 2003). Regarding the endometrioid adenocarcinoma cases, grading was assessed according to the International Federation of Gynecology and Obstetrics criteria (Zaino et al., 1995).
This study was done under local ithics approval.
Thick sections of 4 µm were transferred to adhesive slides from representative formalin-fixed, paraffin-embedded blocks. The sections were deparaffinized in xylene and dehydrated through a series of graded alcohols. Antigen retrieval was performed in a microwave oven for 10 min. To block endogenous peroxidase activity, the sections were incubated with 0.3% hydrogen peroxide in methanol for 30 min after cooling to room temperature. The monoclonal antibodies for PTEN (clone 28H6 dilution 1/100; Lab vision, Fremont, California, USA) and the rabbit polyclonal anti-GLUT-1 (1 : 200; Dako Cytomation, Glostrup, Denmark) were added. A biotinylated secondary antibody was applied to sections for 30 min at room temperature. After incubation, the reaction product was visualized using diaminobenzidine. Finally, the sections were counterstained with Mayer’s hematoxylin.
Positive and negative control
Negative control sections were treated with PBS instead of primary antibody. Endometrial stromal cell sections were used as internal positive control for PTEN staining, whereas positive staining of red blood cells was used as internal positive control for GLUT-1 staining.
Data were represented as number and percentage. The differences were compared for statistical significance by χ2-test.
Difference was considered significant at P-value less than 0.05. The statistical analysis was performed using SPSS 16.0 for Windows (SPSS Inc., Chicago, Illinois, USA).
The stained slides were examined by two pathologists (S.A., T.I.) blindly and independently without knowing the original histologic diagnosis. Brown staining in the cytoplasm was accepted as PTEN immunoreactivity. PTEN expression was classified as three grades: (a) negative expression (complete loss) if none were stained positive; (b) 1+ partial loss, if less than 50% were stained positive; and (c) 2+ expression present, if more than 50% were stained positive (Cirpan et al., 2006; Erkanli et al., 2006). GLUT-1-positive staining showed linear membranous staining, particularly at cell–cell borders. GLUT-1 expression was graded into four groups according to the percentage of the positively stained cells: (a) negative; (b) 1+ rare if estimated 1–5% of detected cells were positive; (c) 2+ focal if confluent foci of positive cells were separated by a significant non-stained area; and (d) 3+diffuse if most of the cells were positive. The negative and 1+ were categorized as low expression and 2+ and 3+ were scored as overexpression (Wang et al., 2000; Ashton-Sager et al., 2006). The staining results were then correlated with the original histologic diagnoses and data were tabulated.
Complete loss of PTEN immunoreactivity was found in none of the 10 cases with proliferative endometrium; one of the 17 (5.9%) cases with endometrial hyperplasia without atypia; five of the eight (62.5%) cases with atypical hyperplasia; and 16 of the 25 (64%) cases with endometrioid adenocarcinoma. Partial loss of PTEN expression was observed in two (20%) of the 10 cases with proliferative endometrium samples; four (three simple hyperplasia and one complex hyperplasia without atypia) of the 17 (23.5%) cases with endometrial hyperplasia without atypia; one of the eight (12.5%) cases with atypical hyperplasia; and four of the 25 (16%) cases with endometrioid adenocarcinoma. PTEN expression in more than 50% of glands was observed in eight (80%) of the 10 cases with proliferative endometrium samples; 12 (11 simple hyperplasia and one complex hyperplasia without atypia) of the 17 (70.6%) cases with endometrial hyperplasia without atypia; two of the eight (25%) cases with atypical hyperplasia; and five of the 25 (20%) cases with endometrioid adenocarcinoma. There was a highly significant statistical difference among the four groups regarding PTEN immunostaining (P<0.001). The frequency of PTEN loss of expression in endometrioid adenocarcinoma was significantly higher than that in proliferative endometrium (P<0.001) and also endometrial hyperplasia without atypia (P=0.001). Regarding the frequency of PTEN loss of expression in atypical hyperplasia, it was significantly higher than that in proliferative endometrium and endometrial hyperplasia without atypia (P=0.012 and P<0.001), respectively. However, there was no significant difference between PTEN expression in endometrioid adenocarcinoma and atypical hyperplasia (P=0.94) (Table 1, Figs 1, 2, 3, 4, and 5).
In endometrioid adenocarcinomas, a progressive reduction in the number of PTEN-positive glands was observed, with higher grades. Of the 16 grade I cases (25%), four showed more than 50% positive glands, three (18.75) were in the less than 50% range, and nine (56.25%) showed complete PTEN loss. Of the six grade II cases, one (16.67%) showed more than 50% positive glands, one (16.67%) was in the less than 50% range, and four (66.66%) showed complete PTEN loss. All three grade III cases (100%) showed complete loss of PTEN staining, but the differences were nonsignificant (P=0.7) (Table 2, Figs 4 and 5).
GLUT-1 expression was undetectable in the 10 cases with proliferative endometrium. Hyperplasia without atypia exhibited a low level of expression. High level of GLUT-1 protein was present in six of the eight (75%) cases with atypical hyperplasia and 23 of the 25 (92%) cases with endometrioid adenocarcinoma. The differences between the groups were highly significant (P<0.001) (Table 3, Figs 6, 7, 8, 9, and 10). The frequency of GLUT-1 expression in endometrioid adenocarcinoma was significantly higher than that in proliferative endometrium (P<0.001) and endometrial hyperplasia without atypia (P<0.001). Regarding the frequency of GLUT-1 expression in atypical hyperplasia, it was significantly higher than that in proliferative endometrium and endometrial hyperplasia without atypia (P=0.0015 and P<0.001), respectively. However, the difference was not significant between atypical hyperplasia and endometrioid adenocarcinoma (P=0.2) (Table 3).
With regard to the grades of endometrioid adenocarcinoma, the frequency of GLUT-1 expression progressively increased with higher grades, where 14/16, 87.5% grade I cases; 6/6, 100% grade II cases; and 3/3, 100% grade III cases showed overexpression of GLUT-1 protein, but the differences were nonsignificant (P=0.5) (Table 4, Figs 9 and 10).
There was a highly significant inverse association (P<0.001) between the expression of the two markers (PTEN and GLUT-1) among the studied groups (Table 5).
Endometrial carcinoma is the fifth most common cancer of women worldwide (Tantbirojn et al., 2008). On the basis of clinicopathologic observations, there are two types of endometrial carcinoma: type I usually arising in the background of endometrial hyperplasia, and type 2 which is unrelated to estrogen (Boruban et al., 2008).
Endometrial hyperplasia is classified by the WHO classification criteria into four groups: simple hyperplasia, simple hyperplasia with atypia, complex hyperplasia, and complex hyperplasia with atypia (Silverberg et al., 2003). The overall risk of progression of hyperplasia to cancer is 5–10%, but different types have different progression risks (Mutter, 2002). Currently, there is a lack of criteria that could accurately predict the disease outcome and there is need for a new classification composed of three groups: benign endometrial hyperplasia, endometrial intraepithelial neoplasm (EIN), and endometrial carcinoma (Mutter, 2002; Baak and Mutter, 2005; Baak et al., 2005). Benign hyperplasia is caused by an abnormal hormonal state, whereas EIN is monoclonal hyperplasia at the beginning and becomes a precancerous lesion at advanced stage (Mutter, 2002). The pathogenesis of endometrial carcinoma and its precursor lesion is complex and involves many molecular disturbances. The most frequently altered gene in endometrial tumors of endometrioid histology is PTEN inactivation, and several studies have found that PTEN inactivation is correlated with clonal growth patterns detected in endometrial hyperplasia and carcinoma (Athanassiadou et al., 2007; Erkanli et al., 2006). PTEN is a tumor-suppressor gene; the suppression of carcinogenesis is associated with a negative effect on the PIP3-Akt/PI3K/mTOR signaling pathway, and mutations of this gene is associated with neoplasia (Hay and Sonenberg, 2004; Bilbao et al., 2006). There is growing evidence of a complex interplay between the AKT/PI3K/mTOR pathway and hypoxia (Liu et al., 2006; Shackelford et al., 2009; Yan et al., 2009). In a hypoxic cancer microenvironment, hypoxia-inducible factor-1α regulates tumor cell metabolism and metastasis by the upregulation of GLUT-1, which is involved in delivering glucose into these tumor cells (Brahimi-Horn and Pouysségur, 2007). The expression of GLUT-1 is absent in most types of the normal epithelial cells, and the overexpression is commonly found in a wide spectrum of human malignancies, such as colon, esophagus, thyroid, lung, ovary, and breast cancers (Alò et al., 2001; Ashton-Sager et al., 2006). Furthermore, investigators believe that the expression of GLUT-1 is a potential marker for malignant transformation (Noguchi et al., 2000).
In this study, none of the 10 cases with proliferative endometrium showed loss of PTEN expression; this result was similar to that reported by Abd El-Maqsoud and El-Gelany (2009); Sarmadi et al. (2009); and Rao et al. (2011), and different from that reported by Xiong et al. (2010) and Lee et al. (2012), who recorded PTEN loss in 20% cases of proliferative endometrium. We also found that PTEN expression in proliferative endometrium was significantly higher than that in atypical hyperplasia and endometrioid adenocarcinoma; this agrees with previous studies (Sarmadi et al., 2009; Xiong et al., 2010).
In the present study, loss of PTEN immunoreactivity (PTEN-negative and heterogenous cases) was noticed in 5/17, 29.4% cases of endometrial hyperplasia, whereas it was 6/8, 75% cases of atypical hyperplasia and there was a highly significant difference in PTEN expression between these subtypes of hyperplasia. A finding that agrees with Kapucuoglu et al. (2007); Abd El-Maqsoud and El-Gelany (2009); Sarmadi et al. (2009); and Lee et al. (2012), whose studies reported a significantly lower PTEN scores in atypical hyperplasia compared with endometrial hyperplasia, and incompatible with Kimura et al. (2004) and Xiong et al. (2010), who showed no significant differences among subtypes of hyperplasia. In our study, in the cases of atypical hyperplasia, we found loss of PTEN protein expression in 75% cases; this result was comparable to that reported by Xiong et al. (2010) and Lee et al. (2012), who detected altered PTEN immunoreactivity in 63 and 71% cases of atypical hyperplasia, respectively, and incompatible with that reported by An et al. (2002) and Abd El-Maqsoud and El-Gelany (2009), who detected no PTEN immunoreactivity in 30 and 25% of atypical hyperplasia cases, respectively; this difference may be attributed to using different scoring systems or cutoff values.
In the present study, we detected a significantly higher PTEN expression in endometrial hyperplasia than in EECA, whereas no significant difference was observed between atypical hyperplasia and EECA. These results are similar to results reported by Kapucuoglu et al. (2007); Abd El-Maqsoud and El-Gelany (2009); Sarmadi et al. (2009); Xiong et al. (2010); Rao et al. (2011); and Lee et al. (2012), suggesting that atypical hyperplasia is the precursor of endometrioid adenocarcinoma, which harbors PTEN gene mutations or deletions, and indicating that PTEN inactivation is an early event in endometrial carcinogenesis; this finding agrees with previous molecular studies (Bussaglia et al., 2000).
In our study, loss of PTEN immunoreactivity was 80% in EECA comparable to the recorded results of Xiong et al. (2010) and Lee et al. (2012), and this agrees with the reported data shown in prior DNA studies (Kappes et al., 2001).
In our study, there is a significant statistical difference in PTEN immunoreactivity among proliferative endometrium, endometrial hyperplasia, and endometrial carcinoma groups (P<0.001); this is consistent with the results reported by Tantbirojn, et al. (2008).
With regard to the grade of EECA, progressive reduction in PTEN immunoreactivity was noted with higher tumor grades similar to the results reported by Rao et al., 2011. However nonsignificant, this agrees with the results reported by An et al. (2002), who reported slightly more altered PTEN expressions in grades 1 and 2 endometrioid carcinomas compared with grade 3; however, this difference was not statistically significant. Other studies reported the same findings but with a significant negative correlation (Kapucuoglu et al., 2007; Abd El-Maqsoud and El-Gelany, 2009). Konopka et al. (2002) reported that, in well-differentiated endometrial carcinomas G1, the frequency of PTEN mutations was only half of that found in less differentiated carcinomas G2, suggesting a higher PTEN expression in well-differentiated tumors compared with less differentiated tumors. As suggested by Konopka et al. (2002), defects in PTEN gene may be associated with loss of the ability of endometrial cells to differentiate, thus increasing its malignancy. On the contrary, Kimura et al. (2004), reported higher PTEN expression in grade 3 tumors than in grade 1 and 2 tumors. They suggested that PTEN protein might have been induced to inhibit the aggressive growth of poorly differentiated carcinomas, whereas in well-differentiated cancers PTEN might have been expressed at a lower level.
In this study, we compared the expression of GLUT-1 in proliferative endometrium, hyperplasia without atypia, atypical hyperplasia, and endometrioid adenocarcinoma that was statistically significant among these groups. It was demonstrated that detection of GLUT-1 in proliferative endometrium and hyperplasia without atypia was negative or low, whereas GLUT-1 in atypical hyperplasia and endometrioid adenocarcinoma was overexpressed. This expression pattern is in agreement with previous studies (Wang et al., 2000; Liu et al., 2001; Ashton-Sager et al., 2006; Horrée et al., 2007; Jia et al., 2008). We found that the differences in GLUT-1 expression in atypical hyperplasia and endometrioid adenocarcinoma was nonsignificant (P=0.2), comparable to the results reported by Xiong et al. (2010).
In our study, there was a step-wise increase in GLUT-1 as the tumor type becomes more poorly differentiated, correlating with the increased need for glucose in the tumor cells. This agrees with immunoblot analysis in previous studies (Goldman et al., 2006; Krzeslak et al., 2012).
Other studies demonstrated that immunoexpression of GLUT-1 is associated with increasing grade of malignancy in bladder and breast carcinomas (Reis et al., 2011; Jang et al., 2012).
Regarding the association between PTEN and GLUT-1 expression, in this study, we found that there was a statistically significant negative association between the immunoexpression of PTEN and GLUT-1 in the different groups (P<0.001), these findings support the molecular pathway of PTEN and GLUT-1 upregulation mentioned in some studies (Brahimi-Horn and Pouysségur, 2007; Shackelford et al., 2009; Yan et al., 2009).
Wahl et al. (2010) found that GLUT-1 was expressed strongly in mutant PTEN type I endometrial carcinoma cells and when treated with the glucose analog (2-DG) induced apoptotic cell death. They suggested that distinct alterations in the phosphatidylinositol 3′-kinase (PI3K) pathway upstream may identify endometrial carcinoma patients who may benefit from adjuvant treatment with glucose analogs.
Another study tested the hypothesis that PTEN expression might affect the surface expression of GLUT-1 in thyroid cancer and found that, whereas the PTEN-positive cases were negative for GLUT-1 expression, the PTEN-negative cases showed intense expression of GLUT-1 at the cell surface (Morani et al., 2012).
Lack of PTEN expression and GLUT-1 overexpression may be early events in the tumorigenesis of endometrioid adenocarcinoma. The combination of PTEN-negative/GLUT-1-positive results may be useful in distinguishing benign hyperplasia from EIN and endometrioid adenocarcinoma. The hypothesis that PTEN expression in endometrial hyperplasias can be used as a potential target for preventive treatment may be effective but needs further research. Moreover, studies designed to determine the effect of inhibition of GLUTs on tumor growth and invasiveness may be of therapeutic value.
Conflicts of interest
There are no conflicts of interest.
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