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ORIGINAL ARTICLE
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A histopathological and immunohistochemistry analysis of endometrial lesions among women presenting with abnormal uterine bleeding


1 Department of Pathology, Hamdard Institute of Medical Sciences and Research, Jamia Hamdard, New Delhi, India
2 Department of Obstetrics and Gynecology, Hamdard Institute of Medical Sciences and Research, Jamia Hamdard, New Delhi, India

Date of Submission13-Jul-2020
Date of Decision07-Oct-2020
Date of Acceptance21-Dec-2020
Date of Web Publication05-Aug-2021

Correspondence Address:
Sujata Jetley,
Department of Pathology, Hamdard Institute of Medical Sciences and Research, Jamia Hamdard, Hamdard Nagar, New Delhi - 110 062
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_915_20

 > Abstract 


Objectives: We aimed to histopathologically evaluate the morphological spectrum, apoptotic index (AI), and mitotic index (MI) of endometrial lesions in patients presenting with abnormal uterine bleeding (AUB).
Methods: A cross-sectional study was done over a period of 18 months where a total of 60 newly diagnosed cases of perimenopausal women presenting with AUB were included. All H and E stained pathology slides from the specimens were reviewed for initial histopathological evaluation and diagnosis. Immunohistochemistry for Bcl-2 and Bax was done. The study subjects were divided into two groups: Group 1 included 30 cases of histologically proven proliferative endometrium (PE) and endometrial polyps and Group 2 included 30 cases of hyperplasia, endometrial epithelial neoplasia (EIN)/or carcinoma. For all cases, AI and MI were calculated and compared among the two groups.
Statistical Analysis: Quantitative variables were compared using the Independent t-test/Mann–Whitney test between the two groups and Kruskal–Wallis test for comparison between more than two groups. Qualitative variables were correlated using the Chi-square test. P < 0.05 was considered statistically significant.
Results: In our study of 60 patients of AUB, the mean age was 45.87 years with a parity of 2 or more in most of the patients. Most of the patients in our study had heavy menstrual bleeding (66.67%) with associated complaints of weakness, pallor, and low backache. Out of 60 patients of AUB, Endometrial carcinoma was diagnosed in 13 (21.67%) patients, with the most common histopathological type being Endometrioid carcinoma. There was a significant difference in the AI, MI, and the ratio of AI/MI among various histopathological diagnoses. AI was highest for Endometrial carcinoma and lowest for hyperplasia and polyps. MI was also highest for Endometrial carcinoma and lowest for hyperplasia and polyps. However, the ratio was incongruent as it was highest for hyperplasia without atypia and lowest for PE with endometrial carcinoma being midway. The Bcl-2 expression of relatively benign conditions (Group 1) was significantly higher than Group 2 (Endometrial epithelial neoplasia/carcinoma). Bax intensity showed an almost inverse pattern, being highest in endometrial carcinoma and lower in hyperplasia and polyps with the lowest expression in PE. Even the Bcl-2:Bax ratio was also highest for PE and lowest for endometrial carcinoma with others falling in between them.
Conclusion: It can be concluded that the combination of the proliferative and apoptotic markers and the ratio will help as a tool in aiding the diagnosis of endometrial lesions for patients presenting with AUB.

Keywords: Abnormal uterine bleeding, apoptotic index, Bax, Bcl-2, mitotic index



How to cite this URL:
Walvir NM, Rana S, Jairajpuri ZS, Jetley S, Nigam A. A histopathological and immunohistochemistry analysis of endometrial lesions among women presenting with abnormal uterine bleeding. J Can Res Ther [Epub ahead of print] [cited 2021 Nov 28]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=323174




 > Introduction Top


Abnormal uterine bleeding (AUB) is one of the most frequently encountered gynecologic complaints and the most common cause of hysterectomy in perimenopausal woman. It accounts for >70% of all gynecological consultations in the peri- and post-menopausal age group. The FIGO in 2010, accepted a new classification system which was revised in 2018, for causes of AUB in the reproductive years.[1],[2],[3]

Recently AUB has on an increase and the underlying mechanism has been linked with the proliferation and apoptosis of certain markers. The significance of apoptosis has been widely studied in the normal endometrium and other entities like endometrial carcinoma and endometriosis. Investigators have documented increased apoptosis in AUB, and it is also considered that it may serve as a morphological marker of abnormal endometrial development.[4]

The present study was carried out in the Departments of Pathology and Obstetrics and Gynecology, from December 2017 to May 2019. In the present study, the apoptotic index (AI) and mitotic index (MI) were calculated. Immunohistochemistry (IHC) for Bcl-2 and Bax was done to find the correlation of apoptosis, anti-apoptosis, and mitosis with different histopathological diagnosis in perimenopausal women with AUB.


 > Methods Top


The cross-sectional study was conducted in the Departments of Pathology and Obstetrics and Gynecology, New Delhi from December 2017 to May 2019. Informed consent was taken from the patients and ethical clearance was obtained from the Scientific Committee and the Institutional Ethical Committee.

A total of 60 perimenopausal females (40–50 years) presenting with AUB who underwent endometrial sampling and those who were willing to participate in the study were included. Any patients with abnormal bleeding secondary to myometrial/cervical and vaginal lesions and systemic diseases like coagulation disorders; AUB secondary to disorders of thyroid function and tuberculosis; and who had received hormonal therapy for AUB in the last 3 months, were excluded from the study.

The study subjects were divided into two groups: Group 1 included 30 cases of histologically proven proliferative endometrium (PE) and endometrial polyps and Group 2 included 30 cases of hyperplasia, endometrial epithelial neoplasia (EIN)/or carcinoma.

Demographic data, history, duration, type of abnormal menstrual bleeding, USG findings, and associated clinical symptoms were recorded. All Hematoxylin and Eosin (H and E) stained pathology slides from the specimens were retrieved and uniformly reviewed for initial histopathological evaluation and diagnosis. AI and MI were calculated by counting the number of apoptotic cells or bodies and mitotic figures, respectively per 1000 cells counted in 10 randomly selected high power fields.

IHC for Bcl-2 (mouse monoclonal antibody, clone 124, Dako) and Bax (mouse monoclonal antibody, clone 2D2, Thermoscientific) was done by the biotin-avidin technique with DAB as chromogen. The buffers used were Tris buffer with a high pH of 9.0 for antigen retrieval and Tris-buffered saline with a pH of 7.6 for washing. The percentage of immunopositive cells was determined under light microscopy as assessed at high power. The stained slides were microscopically analyzed by two independent observers. The mean percentage of positive glandular epithelial cells was determined in at least five areas at 400X magnification and assigned to one of the following categories.[5]

  • Percentage of cells stained (P): 0+ (<5%); 1+ (5%–25%); 2+ (>25%–50%); 3+ (>50%–75%); and 4+ (>75%)
  • Immunostaining intensity (I): Score 0 (negative); Score 1+ (weak); Score 2+ (moderate); and Score 3+ (intense)


A semiquantitative evaluation was done using a scoring method. The percentage of positive glandular epithelial cells (P) and the staining intensity (I) were multiplied to produce a weighted score (PXI) for each case.[5] All the findings were entered into data collection forms.

Statistical analysis

Quantitative variables were compared using independent t-test/Mann–Whitney Test between the two groups and Kruskal–Wallis test for comparison between more than two groups. Qualitative variables were correlated using the Chi-square test. P < 0.05 was considered statistically significant.


 > Results Top


In our study of 60 patients of AUB, the mean age was 45.87 years with a parity of 2 or more in most of the patients [Table 1].
Table 1: Age and parity distribution

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The abnormality in the menstruation was noted at 4 fronts: frequency, duration, regularity, and flow volume. Most of the patients in our study had heavy menstrual bleeding (66.67%) with associated complaints of weakness, pallor, and low backache [Table 2]. Although the mean duration of symptoms was comparable among the two groups, the mean endometrial thickness (ET) was significantly more in the hyperplasia/carcinoma group (P < 0.05) [Table 3]a and [Table 3]b.
Table 2: Distribution of clinical symptomatology

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Table 3a: Comparison of symptoms duration and endometrial thickness

Table 3b: Comparison of endometrial thickness among various conditions


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Most of the patients underwent endometrial biopsy (58.33%) for the AUB with few undergoing hysterectomy [Figure 1] and [Figure 2]. Out of 60 patients of AUB, normal PE was seen in 14 (23.33%) patients and endometrial carcinoma was diagnosed in 13 (21.67%) patients, with the most common histopathological type being endometrioid carcinoma [Table 4].
Table 4: Sampling technique and histopathological diagnosis

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Figure 1: Gross photograph of hysterectomy specimen showing a polyp arising from the endometrial Cavity

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Figure 2: Gross photograph of a pan hysterectomy specimen showing a fungating growth near fundus-endometrial carcinoma

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There was a significant difference in the AI, MI, and the ratio of AI/MI among various histopathological diagnoses [Table 5]. AI was highest for endometrial carcinoma and lowest for hyperplasia and polyps. MI was also highest for endometrial carcinoma and lowest for hyperplasia and polyps. However, the ratio was incongruent as it was highest for hyperplasia without atypia and lowest for PE with endometrial carcinoma lying midway.
Table 5: Comparison of apoptotic index, mitotic index, and its ratio

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The Bcl-2 expression of relatively benign conditions (Group 1) was significantly higher than Group 2 (EIN/carcinoma). Bax intensity showed an almost inverse pattern, being highest in endometrial carcinoma and moderate to intense in hyperplasia and polyps with the lowest expression in PE. Even the Bcl-2:Bax ratio was also highest for PE and lowest for endometrial carcinoma with others falling in between them [Table 6]. The representative histopathological images and Immunohistochemistry images of the benign and malignant cases has been shown in [Figure 3],[Figure 4],[Figure 5],[Figure 6],[Figure 7],[Figure 8],[Figure 9],[Figure 10],[Figure 11],[Figure 12],[Figure 13],[Figure 14],[Figure 15],[Figure 16],[Figure 17],[Figure 18],[Figure 19],[Figure 20],[Figure 21],[Figure 22],[Figure 23],[Figure 24],[Figure 25].
Table 6: Immunohistochemistry markers Bcl2 and Bax distribution

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Figure 3: Microphotograph of proliferative endometrium arrow showing glandular mitosis (H and E, ×40)

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Figure 4: Microphotograph of endometrial carcinoma with blue arrows showing apoptotic bodies and black arrow showing mitosis in the glandular epithelium (H and E, ×40)

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Figure 5: Microphotograph of proliferative endometrium showing intense Bcl-2 staining pattern (IHC, ×10)

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Figure 6: Microphotograph of endometrial carcinoma Grade I with squamous morules showing weak glandular Bcl.2 staining and unstained squamous morules (IHC, ×10)

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Figure 7: Microphotograph of hyperplasia without atypia showing moderate Bcl-2 staining (IHC, ×10)

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Figure 8: Microphotograph of proliferative endometrium showing weak Bax staining (IHC, ×10)

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Figure 9: Microphotograph of hyperplasia without atypia showing intense Bax staining (IHC, ×10)

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Figure 10: Microphotograph of endometrial carcinoma Grade III showing intense Bax staining (IHC, ×40)

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Figure 11: Microphotograph showing moderate Bcl.2 staining in endometrial carcinoma

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Figure 12: Microphotograph showing strong Bax in endometrial carcinoma

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Figure 13: Microphotograph showing strong positivity for Bcl-2 in proliferative endometrial glands

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Figure 14: Microphotograph showing positivity for Bcl-2 in proliferative endometrial glands

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Figure 15: Microphotograph showing positivity for Bcl.2 in proliferative endometrial glands

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Figure 16: Microphotograph showing weak positivity for Bax in proliferative endometrial glands

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Figure 17: Microphotograph showing strong positivity for Bcl-2 in disordered proliferative endometrial glands

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Figure 18: Microphotograph showing weak positivity for Bax in disordered proliferative endometrium

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Figure 19: Microphotograph showing glandular and stromal positivity for Bcl-2 In a endometrial polyp

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Figure 20: Microphotograph showing moderate Bcl-2 staining in endometrial simple hyperplasia

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Figure 21: Microphotograph showing strong Bax staining in endometrial simple hyperplasia

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Figure 22: Microphotograph showing Bcl.2 staining in atypical endometrial hyperplasia

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Figure 23: Microphotograph showing strong Bax positivity in simple endometrial hyperplasia

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Figure 24: Microphotograph showing Bcl-2 staining in Grade 2 endometrial carcinoma

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Figure 25: Microphotograph showing Bax staining in simple endometrial hyperplasia

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 > Discussion Top


In the present study, majority of the patients were above 45 years of age. Similar age distribution was seen in other studies by Talukdar et al., and Patil et al., who also reported majority of patients above 40 years of age.[3],[6] The age distribution is due to the occurrence of AUB during the peri-menopausal period.

In our study, a higher incidence of AUB was noticed in multiparous women. No significant difference in the distribution of parity between Group 1 and Group 2 was observed. Many other studies have shown that the incidence of AUB increased along with the parity.[3],[6]

The common deranged AUB parameters observed were increased frequency of menstrual period; increased duration of menses, and heavy flow of blood. Several studies in perimenopausal women with AUB have shown that heavy and prolonged menstrual bleeding was the commonest menstrual pattern.[3],[6]

In majority of patients, the duration was 18–24 months. In contrast, Talukdar et al. reported that majority of patients gave a history of menstrual problem between 3 and 6 months.[3] This duration was much less than what was seen in our study which could be due to the different awareness levels of the patients and the severity of the symptoms.

In our study group of 60 patients, heavy menstrual periods were a presentation in majority of cases. Patil et al. and Cornitescu et al. found that majority of the women presented with menorrhagia.[6],[7]

Sonographic measurement of ET is documented to be a valuable primary tool in evaluating patients with uterine bleeding. In premenopausal women with AUB, analysis of the test performance of Transvaginal ultrasound (TVS) and cut-off levels has produced divergent results.[8]

In the present study, the mean value of ET (mm) on USG in Group 1 was significantly less as compared to that of Group 2. The mean value of ET was lowest in PE and significantly higher in endometrioid adenocarcinoma. Thus, there was a significant difference in ET between different histopathology microscopic diagnoses (P < 0.05). Dreisler et al. reported ET of 4.8 mm (range 0.6–15.0) among premenopausal women, and 2.8 mm (1.2–12.7) in postmenopausal women. In the group with the focal lesion, among premenopausal women, ET was 7.6 mm (range 4.0–9.7) and in postmenopausal women 5.2 mm (2.5–20.0).[8]

For histopathology reporting, the most common sample type was endometrial biopsy in most of the patients followed by hysterectomy, polypectomy, and endometrial aspiration. In our study, in Group 1, 23.33% of the patients had PE, 16.67% of patients had disordered PE, and 10% had endometrial polyp. In Group 2, 21.67% of patients had endometrial carcinoma, 20% had hyperplasia without atypia, and 8.33% of the patients had EIN.

Thirteen cases of endometrial carcinoma were included in Group 2 of the study: 12 (92.31%) cases were of endometrioid carcinoma and 1 case (7.69%) represented clear cell carcinoma. Endometrioid adenocarcinoma is the commonest type of endometrial carcinoma, for which a number of variants have been described.

The World Health Organization Classification of Tumors of Female Reproductive Organs reports that 20%–50% or more of endometrioid adenocarcinomas show squamous differentiation.[9] In the 4 cases, squamous differentiation was noted. The histological picture as characterized by numerous villous fronds with delicate central cores was seen in 61.54% of the patients in this study. A single case of clear cell carcinoma was reported. 46.15% of the endometrial carcinoma patients were classified as Grade I; 38.46% as Grade II; and 15.38% as Grade III.

Patil et al. reported that out of 150 cases, histopathological reports confirmed fibroid in 52 cases, DUB in 49, adenomyosis in 36, and polyp in 11 cases.[6]

Apoptosis or programmed cell death is the intrinsic death program in the cell that regulates various physiological as well as pathological processes.[10] Apoptotic and mitotic indices in endometria of irregular uterine bleeding reflect the actual cell burden that may play a causative role in bringing about the hyperplastic states of the endometrium.[4]

In our study, AI was calculated by counting the number of apoptotic cells/bodies per 1000 cells counted in 10 randomly selected high-power fields. We found a significant increase in the AI from Group 1 to Group 2 patients. The mean value of AI was lowest in PE and was highest in endometrioid adenocarcinoma. Vidyavathi et al. reported that the mean value of AI in endometrial carcinoma was significantly higher and that of disordered PE was significantly lower as compared to other histopathology microscopic diagnoses.[11] Rekha et al. reported that the mean value of AI in simple hyperplasia was higher and that of anovulatory endometrium was lower as compared to other histopathology microscopic diagnosis.[4]

So, in consonance with other studies, we found that AI can significantly reflect the ongoing borderline and malignant picture in the endometrium and may be used as a useful tool to assess the malignant transformation in cases of AUB.

The MI was calculated by counting the number of mitotic figures per 1000 cells counted in 10 randomly selected high-power fields. Similar to the AI, we also found a significant increase in the MI from Group 1 to Group 2 patients. The mean value of MI was lowest in PE and was significantly higher in endometrioid adenocarcinoma.

Vidyavathi et al. found that the mean value of MI in endometrial carcinoma was significantly higher and that of simple hyperplasia was significantly lower as compared to other histopathology microscopic diagnosis.[11]

Because proliferation and apoptosis, both contribute to tumor growth, AI/MI ratio becomes an important parameter. In our study, the ratio between apoptotic and MI was lowest in the normal proliferative epithelium and highest in hyperplasia. Vidyavathi et al.,[11] also reported that AI/MI ratio was lowest in the proliferative phase and highest in simple endometrial hyperplasia. Hence, these studies have shown that in actively proliferating tissues like endometrium, the AI, and the derived AI/MI ratios are better indicators of progression than the use of MI alone.

Today, IHC plays an important role in diagnosing the difficult cases of hyperplasia-atypia-malignant endometrium. It assesses the various steps of apoptosis and mitosis.[12] In our study, we analyzed Bcl-2 and Bax IHC markers and also assessed the Bcl-2:Bax ratio in cyclical endometrium, proliferative phase, and various benign, preneoplastic, and neoplastic endometrial pathologies.

In our study, Bcl-2 showed a significant decreasing trend from Group 1 to Group 2 patients (P < 0.05). The mean value of PxI score (Bcl-2) stain was highest in PE and was lowest in endometrioid adenocarcinoma [Figure 16],[Figure 17],[Figure 18],[Figure 19],[Figure 20],[Figure 21],[Figure 22],[Figure 23],[Figure 24],[Figure 25]. We compared our findings with other studies on pro-apoptotic and anti-apoptotic markers in cyclical endometrium and various non-neoplastic and neoplastic endometrial pathologies. Most of the studies reported an increased positivity for Bcl-2 in the proliferative phase endometrium as compared to other phases of the menstrual cycle.[13],[14] In our study we noted peak glandular positivity for Bcl-2 in cyclical PE, similar to the findings of Vaskivuo et al.[12] We also analyzed 10 cases of disordered PE for Bcl-2 expression. There was no significant difference in the Bcl-2 staining pattern of the proliferative phase endometrium and the disordered PE, both showed strong positivity, although the staining scores were lower in disordered PE. Arjunan et al.,[13] and Laban et al.,[14] demonstrated a gradually increasing intensity of staining for the Bcl-2 protein from normal PE to simple hyperplasia without atypia and complex hyperplasia with atypia (EIN).

In our study, the glandular staining scores for Bcl-2 were low, although Maia et al.[15] demonstrated a strong Bcl-2 expression in endometrial polyps. There was a decline in the glandular Bcl-2 expression in the 13 cases of adenocarcinoma in our study. Similar findings were noted by other workers.[14]

In our study of 13 adenocarcinoma cases, Grade 1 and Grade 2 had high PXI score for Bcl-2 as compared to Grade 3 carcinoma; however, the difference was not statistically significant. Similarly, Vaskivuo also reported high Bcl-2 expression in Grade 1 and Grade 2 but absent Bcl-2 in Grade 3 carcinoma.[12]

Comparing with other studies, we found that the pattern of Bcl-2 expression was more or less similar to our study, showing peak expression of Bcl-2 in the proliferative phase. Although Bcl-2 family proteins play a crucial role in the regulation of the cell proliferation, it might eventually lead to the development of endometrial hyperplasia and possibly neoplasia.[14]

Bax is another member of the Bcl-2 family, but in contrast to Bcl-2, it has an apoptosis-stimulating function. Gene products of the Bcl-2 family can form homo-and heterodimers with each other. The pro-apoptotic action of Bax protein is dependent on the formation of Bax homodimers on the outer mitochondrial membrane.[12]

In our study, the PxI score (Bax) showed a significant increasing trend from Group 1 to Group 2 patients. The mean value of PxI score (Bax) stain was lowest in PE and was highest in endometrioid adenocarcinoma. However, in EIN the PxI score (Bax) showed a decrease which was in contrast to the findings of Vaskivuo et al. who demonstrated an intermediate increase in the intensity of staining of Bax protein in all types of endometrial hyperplasia.[12]

We noted the lowest glandular positivity for Bax in cyclical PE. We also analyzed 10 cases of disordered PE for Bax expression. There was no significant difference in the Bax staining pattern of the proliferative phase endometrium and the disordered PE, both showed weak positivity, although the staining scores were lower in normal PE. In contrast, Kokawa et al.,[10] and Driák et al.[16] found the lowest Bax positivity in hyperplasia and higher Bax positivity in normal PE.

There was a significant increase in the glandular Bax expression in the 13 cases of adenocarcinoma in our study. Similar findings were noted by other workers.[10],[16]

In our study of 13 adenocarcinoma cases, Grade 1 and Grade 2 had low PXI score for Bax as compared to Grade 3 carcinoma; however, the difference was not statistically significant. Vaskivuo et al., on the other hand, reported high Bax expression in Grade 1 and Grade 2 as compared to Grade 3 carcinoma.[12] Porichi et al. also reported a downstream positivity from the well-differentiated type through the moderately and down to the poorly differentiated adenocarcinoma but the difference was statistically nonsignificant.[17]

We also assessed Bcl-2:Bax ratio. It has been proposed that the cellular Bcl-2: Bax ratio is a key factor in the regulation of apoptosis; a high Bcl-2/Bax ratio makes cells resistant to apoptotic stimuli, while a low ratio induces cell death.[12] The molar ratio of Bcl-2 to Bax determines whether apoptosis is induced or inhibited in several tissues.[10]

In our study, the Bcl-2: Bax ratio was higher in Group 1 and lower in Group 2. (P < 0.05) There was a significant difference in the mean value of Bcl-2: Bax ratio between different histopathology microscopic diagnosis (P < 0.05). A significantly lower Bcl-2: Bax ratio in endometrial adenocarcinoma as compared to normal endometrium, disordered PE, and EIN was noted in our study. Similar results were seen by Vaskivuo et al.[12] The decreased expression of Bcl-2 and increased rate of Bax apoptosis in advanced malignancy might reflect the loss of cellular homeostasis and differentiation, and thus accounting for the decreasing ratio from Group 1 to Group 2 patients. In contrast, Driák et al.,[16] and Mirakhor et al.,[18] found a significant increase in the ratio with advanced malignancy.

From the study results, we can state that the combination of the proliferative and apoptotic markers and the ratio will help as a tool in understanding the initiation of endometrial neoplasia and serve as a possible diagnostic and prognostic marker for patients presenting with AUB.

Limitations of the study

Since AUB is a very common disorder among the perimenopausal women, such IHC markers might be costly for the general population. Although they aid in the diagnosis, there always remains a diagnostic dilemma. Second, the sample size for one individual histopathological diagnosis was small and thus future multicentric studies comprising of a bigger population are recommended.


 > Conclusion Top


Histopathological examination remains the gold standard diagnostic tool in the evaluation of AUB which may reveal various endometrial patterns ranging from normal endometrium to malignancy. We found that up to 77% of the women with AUB had an organic cause and only 23% had normal proliferative epithelium. The diagnostic dilemma in histopathology increases with an increasing incidence of AUB, so it must be reported with additional markers: AI, MI, and IHC markers. There is a significant difference in AI, MI, and AI/MI ratio between different histopathology microscopic diagnoses. Among the IHC markers, Bcl-2 and Bcl-2:Bax show a significant decreasing trend, and Bax scores show a significant increasing trend from normal endometrium to hyperplasia to carcinoma among AUB patients.

Thus, it is recommended that clinical examination, routine histopathology, and IHC markers should be judiciously used for an accurate diagnosis in women with AUB.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

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Sharma A, Dogra Y. Trends of AUB in tertiary centre of Shimla hills. J Midlife Health 2013;4:67-8.  Back to cited text no. 1
    
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Munro MG, Critchley HO, Fraser IS. The two FIGO systems for normal and abnormal uterine bleeding symptoms and classification of causes of abnormal uterine bleeding in the reproductive years: 2018 Revisions. Int J Gynecol Obstet 2018;143:393-408.  Back to cited text no. 2
    
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Talukdar B, Mahela S. Abnormal uterine bleeding in perimenopausal women: Correlation with sonographic findings and histopathological examination of hysterectomy specimens. J Midlife Health 2016;7:73-7.  Back to cited text no. 3
    
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Rekha K, Malini A, Xavier R, Baba K. Apoptosis in endometria of dysfuntional uterine bleeding women. Med J Malaysia 2005;60:41-5.  Back to cited text no. 4
    
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Konno R, Yamakawa H, Utsunomiya H, Ito K, Sato S, Yajima A. Expression of survivin and Bcl-2 in the normal human endometrium. Mol Hum Reprod 2000;6:529-34.  Back to cited text no. 5
    
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Patil CS. A study of clinical correlation with histopathological diagnosis of abnormal uterine bleeding. MedPulse 2016;3:697-9.  Back to cited text no. 6
    
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Corniţescu FI, Tănase F, Simionescu C, Iliescu D. Clinical, histopathological and therapeutic considerations in non-neoplastic abnormal uterine bleeding in menopause transition. Rom J Morphol Embryol 2011;52:759-65.  Back to cited text no. 7
    
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Dreisler E, Sorensen SS, Ibsen PH, Lose G. Value of endometrial thickness measurement for diagnosing focal intrauterine pathology in women without abnormal uterine bleeding. Ultrasound Obstet Gynecol 2009;33:344-8.  Back to cited text no. 8
    
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Kurman R, Carcangiu M, Herrington C, Young R. World Health Organisation Classification of Tumors of Female Reproductive Organs. 4th ed. Lyon, France: International Agency for Research on Cancer Press; 2014.  Back to cited text no. 9
    
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Kokawa K, Toshihiko S, Otani T, Nishiyama R, Ishii Y, Yagi S, et al. Apoptotis and the expression of Bax and Bcl2 in hyperplasia and adenocarcinoma of the uterine endometrium. Hum Rep 2001;16:2211-8.  Back to cited text no. 10
    
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Vidyavathi K, Harendra Kumar ML, Narayanaswamy M. Significance of apoptosis in endometrial hyperplasia and carcinoma. J Clin Biomed Sci 2011;1:8-12.  Back to cited text no. 11
    
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Vaskivuo TV, Stenback F, Tapanainen JS. Apoptosis and apoptosis-related 23 factors Bcl-2, Bax, tumor necrosis factor α, NFkB in human edometrial hyperplasia and carcinoma. Cancer 2002;95:1463-71.  Back to cited text no. 12
    
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Arjunan A, Nilavu J, Thiriveni Balajji GS, Prabha V. Expression of Bcl-2 and Ki-67 in cyclical endometrium and in endometrial hyperplasia-an analysis. IOSR J Dental Med Sci 2016;15:43-9.  Back to cited text no. 13
    
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Laban M, Salam Ibrahim AE, Agur E, Ahmed AM. Bcl-2 may play a role in the progression of endometrial hyperplasia and early carcinogenesis, but not linked to further tumorigenesis. J Microsc Ultrastruct 2015;3:19-24.  Back to cited text no. 14
[PUBMED]  [Full text]  
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Maia H Jr., Maltez A, Studart E, Athayde C, Coutinho EM. Ki-67, Bcl-2 and p53 expression in endometrial polyps and in the normal endometrium during the menstrual cycle. BJOG 2004;111:1242-7.  Back to cited text no. 15
    
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Driák D, Dvorská M, Svandová I, Sehnal B, Benková K, Spůrková Z, et al. Changes in expression of some apoptotic markers in different types of human endometrium. Folia Biol (Praha) 2011;57:104-11.  Back to cited text no. 16
    
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Chhieng DC, Ross JS, Ambros RA. Bcl-2 expression and the development of endometrial carcinoma. Mod Pathol 1996;9:402-6.  Back to cited text no. 17
    
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Mirakhor Samani S, Ezazi Bojnordi T, Zarghampour M, Merat S, Fouladi DF. Expression of p53, Bcl-2 and Bax in endometrial carcinoma, endometrial hyperplasia and normal endometrium: A histopathological study. J Obstet Gynaecol 2018;38:999-1004.  Back to cited text no. 18
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10], [Figure 11], [Figure 12], [Figure 13], [Figure 14], [Figure 15], [Figure 16], [Figure 17], [Figure 18], [Figure 19], [Figure 20], [Figure 21], [Figure 22], [Figure 23], [Figure 24], [Figure 25]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]



 

 
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