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Year : 2011  |  Volume : 54  |  Issue : 2  |  Page : 264-268
Immunohistochemical phospho tensin tumor suppressor gene staining patterns in endometrial hyperplasias: A 2-year study

1 Department of Pathology, Kasturba Medical College, Manipal University, Manipal, India
2 Pathologist, Jalandhar, India

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Date of Web Publication27-May-2011


Background: Endometrial carcinoma is a common neoplasm associated with the female genital tract with considerable morbidity.Eendometrial hyperplasias have been widely regarded as precursor lesions. It is of importance to the pathologist to identify the subset of hyperplasias or the associated factor which could be a possible forerunner of malignancy. Phospho tensin gene (PTEN) has gained importance as one of the factors responsible. Aim: To determine the variability in PTEN expression patterns in different types of endometrial hyperplasias. Settings and Design: The study was undertaken on samples received at the Department of Pathology from 2005 to 2007. Materials and Methods: One hundred samples with 76 showing hyperplasias of different types formed the core "study group" with simple hyperplasia without atypia predominating. The rest belonged to the control groups. PTEN intensity and percentage positivity, variability in patterns of glandular and stromal expression, the number and type of PTEN null glands in different types of hyperplasia were evaluated. Statistical analyses used were Fisher's exact test based on Monte Carlo test and chi-square test. Results: Complex hyperplasia was associated with a reduction in number of strongly PTEN positive glands, with an increase in null glands, seen in clusters. Co-existing atypia was associated with the weakest staining and in fewer glands. Conclusions: PTEN expression in endometrial hyperplasias can be used as an early warning of heightened cancer risk and a potential target for preventive treatment. However, extensive research is needed along this line to conclusively establish its effectiveness.

Keywords: Endometrial carcinoma, hyperplasia, phospho tensin tumor suppressor gene expression

How to cite this article:
Rao AC, Arya G, Padma PJ. Immunohistochemical phospho tensin tumor suppressor gene staining patterns in endometrial hyperplasias: A 2-year study. Indian J Pathol Microbiol 2011;54:264-8

How to cite this URL:
Rao AC, Arya G, Padma PJ. Immunohistochemical phospho tensin tumor suppressor gene staining patterns in endometrial hyperplasias: A 2-year study. Indian J Pathol Microbiol [serial online] 2011 [cited 2020 Jun 1];54:264-8. Available from: http://www.ijpmonline.org/text.asp?2011/54/2/264/81588

   Introduction Top

Endometrial carcinoma is a common neoplasm of the female genital tract and is associated with a considerable degree of morbidity; [1] and endometrial hyperplasias have been widely regarded as the associated precursor lesion. It is of importance for the pathologist to identify the subset or factors which could be a possible forerunner of malignancy, especially in hyperplasias. Of the numerous genes involved, the phospho tensin tumor suppressor gene (PTEN) has been identified as the most commonly mutated one in endometrial pre-cancers and cancer. It is being extensively researched upon as an informative marker for delimiting neoplastic and pre-neoplastic glands from normal background endometrial glands. The utility of PTEN expression as a marker for atypical hyperplasias progressing to malignancy could perhaps help provide valuable insight into the category of hyperplasias which can be most definitely classified as "premalignant".

   Materials and Methods Top

A retrospective and prospective study was conducted on 63 endometrial samples and 37 hysterectomy specimens collected from 100 patients, from 2005 to 2007, ranging from 35 to 55 years of age, under investigation for dysfunctional uterine bleeding. Of the total 560 endometrial samples received, PTEN staining was performed on 63 endometrial curettage samples of hyperplasia. PTEN staining was carried out on 7 cases each of normal proliferative and secretory endometrial were taken as positive controls [9],[10],[11] .

Ten cases of endometrioid type of endometrial carcinomas were taken as negative controls as these are traditionally considered PTEN negative. Included in the study group were sections given from areas of endometrium adjacent to carcinomas in 13 specimens, to assess PTEN patterns in atypical complex hyperplasias. Hematoxylin and eosin (H and E) stained slides of all the cases and corresponding PTEN stained sections were studied. The diagnosis of H and E stained slides was categorized as "simple hyperplasia without atypia", "simple hyperplasia with atypia", "complex hyperplasia without atypia" and "complex hyperplasia with atypia". Normal controls were also reviewed and carcinomas were suitably graded. All the slides were stained with commercial monoclonal PTEN 28H6 (Biogenex, Hyderabad, India) antibodies designed for specific localization of PTEN in the nucleus of formalin-fixed, paraffin-embedded sections. PTEN stained sections were suitably graded for percentage of positive glands [2] (<10%, 10-50%, >50%); intensity of staining of glandular epithelial cells (weak, moderate and strong); stromal staining (present or absent) and intensity (weak or strong); null gland number and arrangement (isolated or clustered). Endometrial glands in which less than 10% of epithelial cells were PTEN positive were taken as "null glands".

Statistical analysis of the above cases was carried out using SPSS II software (version 11.0.1 for windows; SPSS, Inc., Chicago, IL, USA). Results were considered statistically significant when P < 0.05. All the analyses were made using Fisher's exact test based on Monte Carlo test and chi-square test.

   Results Top

Within the group of normal endometria, seven cases of proliferative endometrium, four cases of early secretory, two cases of mid secretory and one case of late secretory endometria were taken as positive control. Of the 10 endometrioid carcinomas taken as negative controls, the maximum number of cases belonged to FIGO Grade II and III.

The study group comprised 55 cases of simple hyperplasia without atypia, 8 cases of complex hyperplasia without atypia, and 13 complex hyperplasia cases with atypia. No cases of "simple hyperplasia with atypia" were recorded.

All seven proliferative endometrial controls showed >50% of glands with 3 (42.9%) moderate and 4 (57.1%) strong PTEN positivity in glands [Figure 1]a. The number of PTEN positive glands declined as the secretory phase progressed, with 3 (75%) early and 2 (100%) mid secretory endometria showing >50% glands of moderate to strong intensity. A conspicuous absence of null glands was noted. Both proliferative and secretory endometria showed 100% stromal PTEN positivity, with a gradual decline of intensity from proliferative (57.1% strong) to late secretory phase (100% weak).
Figure 1: (a) Proliferative endometrium: Strong positivity of PTEN in glands and stroma (PTEN, ×200); (b) FIGO Grade 3 Endometrial carcinoma with PTEN negativity (PTEN, ×100)

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In endometrioid carcinomas, a progressive reduction in the number and staining intensity of PTEN positive glands was observed, with higher FIGO grades associated with a weak stromal positivity. Two Grade I cases showed an equal number of positive glands below and above the 50% cut-off, with a staining intensity of moderate (1) to strong (1). Three out of 4 Grade II cases showed >50% positive glands and 1 was in 10-50% range, with weak (2) and moderate (2) intensity. All four Grade III cases had <10% positive glands, with two each showing moderate and weak staining [Figure 1]b. Many null glands were seen in all grades of endometrioid carcinomas, with 9 in 10 cases being seen in clusters.

In the study group of hyperplasias [Table 1], simple hyperplasia without atypia had the maximum number of PTEN positive glands (30.91%: 10-50% glands, 56.36%: >50% glands), with the number reducing as the number of complex hyperplastic glands increased; the least number of PTEN positive glands was seen in complex hyperplasia with atypia (38.5%: <10% and 46.2%: 10-50% positive glands). Intensity of glandular PTEN staining was the strongest in simple hyperplasia (63.64%), [Figure 2]a with rest of the cases showing mostly moderate staining. When PTEN positive glands in simple hyperplasia without atypia and complex hyperplasia without atypia were compared (with a cut-off of 10%), P value of 0.014 was derived which was significant. A comparative analysis of the intensity of staining between simple hyperplasia without atypia and complex hyperplasia with atypia, and complex hyperplasia without and with atypia, gave significant P values of 0.036 and 0.005, respectively.
Figure 2: (a) Simple hyperplasia strong glandular & stromal PTEN positivity; (b) complex hyperplasia with PTEN null glands (PTEN, ×200)

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Table 1: Glandular PTEN positivity and intensity of staining in study group

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Stromal PTEN positivity was seen in all cases, being of strong (63.63% of simple hyperplasia) to weak intensity. Null gland [Figure 2]b number and arrangement were documented, with highest number and clustering noted mostly in complex hyperplasia, predominantly in those with associated atypia (100% showing many null glands, all in clusters). Simple hyperplasia, however, showed the maximum cases with no null glands (15) [Table 2]. A significant P value was obtained on comparing the PTEN staining with null gland number in complex hyperplasia without atypia with simple hyperplasia without atypia (0.044) and complex hyperplasia with atypia (0.038). The arrangement of glands showed that when clustering of null glands was detected, it was often in complex hyperplasias, both with and without atypia, as compared to simple hyperplasia without atypia with a significant P value of .0193.
Table 2: Number and arrangement of PTEN null glands in hyperplasias: in isolation and as clusters

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The data thus obtained were analyzed with comparisons of PTEN parameters between the groups and the pattern of staining was identified. On statistical comparison of the number of null glands between the two control groups and the study group, using Fisher's exact test based on Monte Carlo test, P < 0.001 was obtained, which was found to be highly significant. A comparative analysis of the study using a 50% cut-off for PTEN+ glands between the study and control groups gave a P value of 0.007. The significance of the findings was evaluated to ascertain points of note to help future research, and to distinguish between the study group and the controls.

   Discussion Top

Schroedar, in 1914, first established the relationship of endometrial hyperplasias to abnormal ovarian function. [3],[4] Since then, a lot of progress has been made in every aspect of hyperplasia, from pathogenesis to treatment. Biopsy, however, remains the mainstay in identification of this condition.

Endometrial hyperplasias are divided into two broad categories - hyperplasia with and without cytologic atypia - each being further classified according to glandular complexity and crowding, into simple and complex. [5],[6] Endometrial intraepithelial neoplasia (EIN) describes monoclonal endometrial precancerous lesions associated with a heightened risk of development of carcinoma. [7]

Of current interest are the relationship and the progression of endometrial hyperplasias to carcinoma, made more difficult because of the often experienced diagnostic difficulty in differentiating the two.

Endometrial cancers are currently classified into two major divisions (type 1 and type 2). [8] Type 1 is associated with PTEN mutation, microsatellite instability (MSI) and K-ras mutation. Type 2 is associated with p53 mutation.

PTEN, with a genetic domain on chromosome 10q23, was discovered in 1997 and is known so because of its phosphatase domain and tensin homology. [9],[10],[11] It is a new tumor suppressor, the gatekeeper for endometrium, with its inactivation considered the initiator for carcinogenesis. A possible involvement in embryonic development, cell migration and apoptosis has also been postulated. [9],[10],[11] The suppression of carcinogenesis is associated with a negating effect on the PIP3-Akt signaling pathway. [9],[12],[13] Mutations are common, as observed by an absence of the PTEN protein or by mutation or deletion of DNA coding for the same. [9],[10]

In the endometium, a high expression of PTEN is seen in estrogenic conditions, with a progressive decline with disappearance from the glands during the progesterone period till menstruation, inferring a nonrequirement of PTEN activity. However, there is a high stromal expression throughout the cycle, with the nucleus and cytoplasm showing variable intensity of expression. [12],[14]

Persistent mutant PTEN clones or "null glands" are seen as isolated tubular glands in normal endometrium, [2] and are considered physiological in the premenopausal period. [2],[15] However, over a prolonged period of time, in the presence of unopposed estrogen assault, these may provide the fodder for subsequent progression to malignancy. Compounded is the fact that architecturally, they cannot be distinguished from those expressing PTEN. [2],[12],[15],[16]

The presence of PTEN mutations in endometrial hyperplasias is thought to be a link to an initiating event in endometrial carcinomas of the endometrioid type and may precede the development of cytological atypia.

A lot of interest was evinced by researchers to distinguish the frequency of PTEN mutation in hyperplasia without atypia relative to those with atypia, with contrasting observations regarding the same. [9],[18] Expression in foci of hyperplasias can highlight a stage of disease, hitherto unseen on H and E staining. [15],[16],[19] PTEN immunostaining could thus provide a pathologic tool of importance to seek out precancerous clones in endometrial hyperplasia, signaling a development of malignancy. [20]

The clinical indication for curettage in the study group, similar to that in the study of Mutter et al,[21] was dysfunctional uterine bleeding, with menorrhagia predominating. Most studies have combined all hyperplasias without atypia in a common group. Erkanli et al,[22] had a predominance of simple hyperplasias; Kimura and co-workers [23] and Taranger-Charpin and researchers [24] studied PTEN expression in atypical hyperplasias and carcinomas of various types. In the present study, hyperplasias without atypia were divided into two groups, with correlation with the atypia group and the controls. In our series, the proliferative phase endometria acted as the positive controls, similar to that in other studies; [15],[22],[23],[24] few studies have used stroma as an internal control. [21],[23],[25] The present study concurred with studies conducted by Mutter and coworkers [15],[21] and Taranger-Chapin et al,[24] in exhibiting a differential PTEN expression in various phases of the normal menstrual cycle with the difference of moderate intensity staining of mid secretory endometrial glands. The weak stromal positivity seen correlates well with the result of Kanamori's [25] study. Similar to the series by Mutter, PTEN null glands were conspicuously absent in proliferative endometrii in our study. [21] Using the FIGO grading system in endometrial carcinomas, Piero et al,[26] documented PTEN positivity in less than half the glands, irrespective of grade. However, a reduction in PTEN positive glands along with a marginal increase in null glands with higher grades, was observed with increasing grades of carcinomas in our series and Inaba's series. [27] In contrast, Salvesen et al,[28] documented an almost equivocal number of cases with 50% PTEN positive glands, irrespective of grade, using a 50% cut-off. Numerous PTEN null gland clusters were a consistent feature of Mutter's [21] study, concurring with ours.

In contrast to the observation of Kimura et al, [23] [Table 3] we observed the number of PTEN positive glands and intensity to be much lesser in complex as compared to simple hyperplasia. A weak positivity in atypical glands corresponded with the findings of Mutter, [21] Erkanli, [22] Taranger-Charpin, [24] and their colleagues. Stromal positivity was found to be of stronger intensity in simple hyperplasia in contrast to other studies. [21],[22],[23] Mutter et al,[21] have reported a higher percentage (56.3%) of hyperplasias to be exhibiting null glands, as compared to ours (30%). A finding of significance in the present study was the presence of PTEN null glands in all atypical hyperplasias, with clustering seen higher in complex hyperplasia especially with atypia, correlating with Mutter's [21] study. A comparative analysis of the three groups in our study showed >50% PTEN positive glands in all normal endometria and nearly half of the study group, with a sudden fall in number in the negative controls, as opposed to <50% PTEN positive glands in all groups, with PTEN negative glands increasing toward carcinomas in Erkanli et al.'s [22] study. Glandular staining in the present series was found to correlate well with progression to neoplasia. The highest number of strongly positive PTEN glands was observed in the proliferative endometria. Hyperplasias showed a diverse picture, with no difference existing amongst the subgroups, with all showing moderate to strong positivity in a high number of glands. However, presence of atypia meant a shift toward weaker PTEN positivity and in fewer glands.
Table 3: Percentage glandular PTEN positivity and intensity of staining in hyperplasias in different studies

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PTEN null glands were absent in normal and made their presence felt in the hyperplasias, clustering together with higher complexity of glands, with the number of clusters increasing toward malignancy, an important finding of note. Thus, PTEN null glands could become an important indicator as a forerunner to malignancy.

PTEN staining has its pitfalls. [29] A valid internal control is required, with endometrial stroma and myometrium fitting the role adequately. Few researchers have proposed a cut-off of 10% PTEN loss as positive, since most cases may not have a genetic back up for validation of the negativity. [29]

The pathogenesis of precursors of endometrial carcinomas has always intrigued researchers. At present, research has been oriented toward evaluation of intricate details regarding the progression of endometrial hyperplasias to carcinoma. With the ongoing discovery of new markers, including at the molecular level, a promising future as regards to precancerous endometrial lesions can be expected, in which PTEN could possibly function as an important marker and early diagnostic tool.

   References Top

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29.Soslow RA, Isacson C, Zalondek C. Immunohistology of the Female Genital Tract. In: Dabbs DJ, editor. Diagnostic Immunohistochemistry. 2 nd ed. China: Elsevier; 2006. p. 637-98.  Back to cited text no. 29

Correspondence Address:
Anuradha C. K. Rao
Department of Pathology, Basic sciences block, II floor, Kasturba Medical College, Manipal University, Manipal, Karnataka - 576104
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0377-4929.81588

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