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ORIGINAL ARTICLE
Year : 2021  |  Volume : 17  |  Issue : 1  |  Page : 164-169

Role of WT1, B-cell lymphoma 2, Ki-67 (Mib1), and Her2/Neu as diagnostic and prognostic immunomarkers in ovarian serous and endometroid carcinoma


1 Department of Pathology, Diamond Harbour Government Medical College, Diamond Harbour, West Bengal, India
2 Department of Pathology, Mission of Mercy Hospital, Durgapur, West Bengal, India
3 Department of Pathology, Bankura Sammilani Medical College, Bankura, West Bengal, India

Date of Submission03-May-2019
Date of Decision10-Aug-2019
Date of Acceptance23-Oct-2019
Date of Web Publication15-Mar-2021

Correspondence Address:
Santosh Kumar Mondal
“Subarnabhumi Complex,” Kamini III, Flat A302, 36 Gorakshabashi Road, Dum Dum, Kolkata - 700 028, West Bengal
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_311_19

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 > Abstract 


Background: Ovarian cancer is the fifth common cause of death due to cancer in women. It constitutes 3% of all cancers in females and 15%–20% of genital malignancy. Most of the ovarian cancers are serous type followed by the endometrioid type. Sometimes, glands of these two carcinomas are indistinguishable histologically. It also becomes difficult to differentiate these two types when they are poorly differentiated.
Aims: The aim of this study was to find differences in immunomarker expressions between serous and endometrioid carcinomas and the association of their staining patterns with other clinicopathological prognostic factors.
Materials and Methods: Immunohistochemical staining for WT1, B-cell lymphoma 2 (Bcl2), Ki67 (MIB1), and Her2/Neu were done in paraffin-embedded tissues of histologically diagnosed 38 cases of ovarian serous and endometrioid carcinomas and staining patterns were correlated with other clinicopathological prognostic factors.
Results: Of these 38 cases (21 serous and 17 endometrioid), 24 cases were in Stage I/II and 14 cases Stage III/IV. On the other hand, 16 cases were in low grade, 12 cases intermediate grade, and 10 cases high grade. Twenty of 21 serous carcinomas were strongly positive for WT1, whereas most of the endometrioid carcinomas were negative. Ki67 (MIB1) labeling index and Her2/Neu were higher in both higher grade and stages. On the contrary, the intensity of Bcl2 staining was lower in higher grades and stages lesions.
Conclusions: The use of WT1 may be useful in resolving diagnostic dilemma between serous and endometrioid carcinoma, especially in difficult cases. Ki67, Bcl2, and Her2/Neu may be used as prognostic markers.

Keywords: Endometrioid type, immunohistochemistry, ovarian carcinoma, serous type


How to cite this article:
Mondal SK, Basak B, Bhattacharya S, Panda UK. Role of WT1, B-cell lymphoma 2, Ki-67 (Mib1), and Her2/Neu as diagnostic and prognostic immunomarkers in ovarian serous and endometroid carcinoma. J Can Res Ther 2021;17:164-9

How to cite this URL:
Mondal SK, Basak B, Bhattacharya S, Panda UK. Role of WT1, B-cell lymphoma 2, Ki-67 (Mib1), and Her2/Neu as diagnostic and prognostic immunomarkers in ovarian serous and endometroid carcinoma. J Can Res Ther [serial online] 2021 [cited 2021 Apr 11];17:164-9. Available from: https://www.cancerjournal.net/text.asp?2021/17/1/164/311068




 > Introduction Top


Tumors of the ovaries are of great concern because it accounts for 3% of all cancers in females and is the fifth-most common cause of death due to cancers in women.[1] Ovarian malignancy, which may be primary (80%) or secondary (20%), constitutes about 15%–20% of genital malignancy. Among the primary tumors, 80% are epithelial tumors, which mostly consist of serous, mucinous, and endometrioid types.[1] Serous neoplasm accounts for 20%–50% of all ovarian tumors and among them 20%–25% are malignant.[2] It is the most common malignant ovarian tumor and consists of total 45% of all malignant ovarian tumors.[1],[3] On the other hand, endometrioid carcinoma accounts for approximately 20% of all ovarian cancers and it is the second-most common malignant tumor of the ovary.[1] The histologic features of poorly differentiated endometrioid carcinoma sometimes merge almost imperceptibly with those of poorly differentiated serous carcinoma, making the histologic diagnosis difficult.[2],[3],[4] Same problem arises when there is the presence of well-formed glands in both cases. Different studies have been done regarding the immunomarkers in ovarian carcinoma which have definite diagnostic and prognostic value.

The prognosis of ovarian tumors depends on different factors. According to the different study, it is the stage followed by grades are the two most important prognostic factors. Many authors pointed out the role of different immunomarkers such as Ki67, B-cell lymphoma 2 (Bcl2), and HER2/neu in the ovarian tumors. Some authors also pointed out that as a group, endometrioid carcinoma has a prognosis twice as good as that of serous carcinoma.

Ovarian serous carcinomas demonstrate diffuse strong WT1 nuclear expression, whereas it is not seen in endometrioid type tumors.[5],[6],[7],[8] It has found that nuclear WT1 protein expression can identify misclassified high-grade endometrioid carcinomas, and these tumors should be reassigned to serous histotype. Some studies showed WT1 expression is associated with a poor prognosis of serous carcinomas. A different study found that WT1 expression is a favorable prognostic marker for high-grade serous tumors.

Bcl2, encoded by the BCl2 gene, is the founding member of the Bcl2 family of regulator proteins that regulate cell death (apoptosis). Bcl2 is an anti-apoptotic protein.[1] The study found that Bcl2 expression correlates significantly with such that decreasing survival parallels the decreased expression in ovarian tumor cells.[9],[10] However, a different study contradicts the above finding, showing statistically significant higher expression of Bcl2 in high-grade compared with low-grade ovarian serous carcinoma.[11] In another study, it has been found that positive Bcl2 staining was associated with endometrioid tumor subtype and a favorable tumor grade distribution, but not with the survival status.[12]

Immunohistochemical detection of proliferating cells is an alternative way to determine the proliferative potential of a tumor, and the expression of the Ki67 antigen has become a widely used marker. Antigen KI67 is a nuclear protein that is associated with and may be necessary for cellular proliferation. Furthermore, it is associated with ribosomal RNA transcription. Inactivation of antigen KI67 leads to inhibition of ribosomal RNA synthesis. This antigen is expressed during all active phases of the cell cycle (G1, S, G2, and mitosis), and the monoclonal Ki67 antibody (MIB1) reacts with the nuclear Ki67 antigen expressed in cycling cells. High expression of Ki67/MIB1 has been found to indicate a poor prognosis in several cancers, including ovarian cancer.[13] Different studies show that expression of MIB1 associated with aggressive behavior of ovarian carcinoma.[14]

Her2/Neu is encoded by ERBB2, a known proto-oncogene located at the long arm of human chromosome 17 (17q12). Her2/Neu is amplified in adenocarcinoma of the ovary.[1] In a study, it was found that disease-free, and overall survival is not different significantly in Her2/Neu over expression versus normal Her2/Neu expression.[15] In a different study, a high survival rate was found in patients without Her2/Neu in endometrioid tumor.[15] Another study found statistically significant higher expression of HER2/neu in high-grade compared with low-grade ovarian serous carcinoma.[15]


 > Materials and Methods Top


The prospective study was carried out during the period from April 2017 to March 2019. A total of 38 histologically diagnosed cases of serous carcinoma (21 cases) and endometrioid carcinoma (17 cases) were included in our study. All the relevant history regarding clinical presentation, clinical examination, imaging study, cytological examination, and operative findings were recorded.

The International Federation of Gynecology and Obstetrics (FIGO) staging was followed for the selected cases of serous carcinoma of the ovary and endometrioid carcinoma. Histologic grading for serous carcinoma was performed by system proposed by Shimizu et al. grading of endometrioid carcinoma was done by the FIGO Grading Scheme.

Immunohistochemistry procedure in brief

Immunostaining was done on the representative paraffin-embedded tissue sections by standard procedure supplied by the manufacturer. In brief, 4–5 μ sections taken on poly-lysine coated slides, deparaffinized, and rehydrated. Antigen retrieval was done by pressure cooking method using citrate buffer. We used prediluted-ready to use primary antibody for WT 1 (mouse monoclonal antibody, clone 6F-H2), Bcl2 (rabbit monoclonal antibody, clone E17), Her2/Neu (rabbit monoclonal antibody, clone EP3) and Ki 67 (rabbit monoclonal antibody, clone SP6) supplied by Cellmarque (Sigma-Aldrich) company. The primary antibodies against WT1, Ki67 (MIB1), Bcl2 and HER2/Neu were applied after proper endogenous peroxidase and protein block. Diaminobenzidine was used as chromogen and hematoxylin as counterstain.

Immunohistochemistry result analysis and scoring

In case of WT1 staining, the number of tumor cells with nuclear staining was recorded and reported as percentage staining. For the scoring of immunomarkers, the intensity of these markers was noted among the tumor cells. The intensity of WT1 was classified as 0 (No staining), 1+ (Faint staining or intensity), 2+ (Mild-to-moderate intensity), and 3+ (Strong intensity). The Ki67 (MIB1) labeling index was defined as percentage of immunoreactive tumor cells out of the total number of tumor cells in most intense staining areas. The Bcl2 staining intensity was graded as 0 (No staining), 1+ (Weak intensity) and 2+ (Strong intensity). HER2/Neu staining intensity was classified as 0 (no staining), 1+ (Faint staining/intensity), 2+ (mild-to-moderate intensity), and 3+ (Strong intensity). Only the 3+ staining intensity was regarded as positive or overexpression in case of HER2/Neu immunostaining unlike WT1 or Bcl2 immunostaining.

Statistical analysis was done using an appropriate statistical test by SPSS (version 25.0) software (IBM, Bangalore, Karnataka, India). After getting all the data, it was analyzed by the SPSS by applying Chi-square test, unpaired t-test.


 > Results Top


Grading and staging of the selected cases: in this study, nine patients out of 21 (42.9%) serous carcinoma were bilateral, whereas three out of 17 (17.6%) endometrioid carcinomas were bilateral. The mean age of serous and endometrioid carcinoma was 47.3 years (standard deviation [SD] 9.2) and 53.2 years (SD 9.5), respectively. Of the 21 cases of serous carcinomas, eight cases (38.1%) were in Grade 1, six cases (28.6%) in Grade 2 and seven cases were in Grade 3. Among the 17 endometrioid carcinomas, eight cases (47.1%) were in Grade 1, six cases (35.3%) in Grade 2, and three cases (17.6%) were in Grade 3. Nine out of 21 (42.9%) serous carcinoma and five out of 17 (29.4%) endometrial carcinomas presented as advanced stages (Stage III and Stage IV) disease. No significant correlations were found between the age, stages, and bilaterality. Furthermore, no significant correlation was found between diameter of largest tumor with the stages and grades of the tumors.

Result of WT1 immunomarker staining: total 20 out of 21 (95.2%) serous carcinoma, irrespective of their age, grades, and stages were positive for WT1 staining. Among them, 15 cases (71.4%) showed 3+ positivity [Figure 1]. The remaining five cases (23.8%) showed 2+ positivity. One of the 21 serous tumors was negative for WT1 [Table 1]. In contrast, 14 out of 17 endometrioid carcinomas (82.3%) were negative for WT1 staining [Figure 2]a and [Figure 2]B. Two cases (11.8%) showed 1+ positivity and one case (5.9%) showed 2+ positivity [Table 1]. None of the 17 endometrioid carcinomas showed 3+ positivity. The differences of the staining pattern are statistically significant (P < 0.001) between serous and endometrioid carcinoma like other studies. No significant relationship found between stage and grades of tumors and WT1 staining pattern.
Figure 1: (a) Low-grade serous carcinoma (papillary type) of ovary (H and E, ×100). (b) WT 1 nuclear staining in low-grade serous carcinoma of ovary showing 3+ positivity (×100). (c) High-grade serous carcinoma of ovary (H and E, ×100). (d) WT 1 nuclear staining in high-grade serous carcinoma of ovary showing 3+ positivity (×100)

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Table 1: Expression of WT 1, Bcl 2, Her 2/neu and Ki-67 immunomarkers in serous and endometroid carcinoma of ovary (n=38)

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Figure 2: (a) High-grade endometrioid carcinoma of ovary (H and E, ×100). (b) WT 1 nuclear staining in high-grade endometrioid carcinoma of ovary showing negative staining (×100). (c) Low-grade endometrioid carcinoma (H and E, ×100). (d) Cytoplasmic staining for Bcl2 in low-grade endometrioid carcinoma showing, 2+ positivity (×100)

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Result of Bcl2 immunomarker staining: we found 10 o 16 Grade 1 tumors showed 2+ intensity for Bcl2. Five cases showed 1+ intensity and one case was negative for Bcl2. In 12 intermediate-grade tumors, five cases showed 2+ intensity, five cases showed 1+ intensity, and two cases were negative for Bcl2 [Figure 2]c and [Figure 2]d. In 10 high-grade tumors, only one case showed 2+ intensity, three cases showed 1+ intensity, and six cases were negative for Bcl2 [Table 1]. This pattern of Bcl2 expression is statistically significant between the low-grade and high-grade lesions (P = 0.016). High-grade lesions showed decreased expression of Bcl2 in contrast to the low-grade lesions.

In 14 cases of the 24 early-stage carcinoma (Stage I/II) Bcl2 showed 2+ positivity, nine cases showed 1+ intensity and one case was negative for Bcl2. In contrast, eight cases of the 14 advanced stages diseases (Stage III/IV) were negative for Bcl2. Five cases showed 1+ intensity and one case showed 2+ intensity. The intensity of Bcl2 staining was significantly lower in advanced stages lesions than the early stages lesions (P < 0.001). However, we found no statistically significant differences between the types of tumors and Bcl2 staining pattern.

Results of Ki67 immunomarker staining: The mean Ki67 index in low-grade lesions was 9.89% (SD: 3.50) [Figure 3]c and [Figure 3]d. In intermediate-and high grades lesions, it was 20.39% (SD 8.12) and 41.17 (SD: 7.01), respectively [Table 1]. The difference is statistically significant between low- and high-grades lesions (P = 0.010) and also between low-and intermediate grades lesions (P = 0.001). However, no significant difference of mean Ki67 index was found between intermediate-and high-grades lesions.
Figure 3: (a) Low-grade serous carcinoma (papillary type) of ovary (H and E, ×100). (b) HER2/Neu immunomarker showing 3+ positivity in tumor cells (×100). (c) Ki 67 positivity (nuclear) in endometrioid carcinoma (×100). (d) Ki 67 positivity (nuclear) in high-grade serous carcinoma (×100)

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The mean Ki67 index in the early stages (Stage I/II) was 13.78% (SD 8.10). In cases of advanced diseases (Stage III/IV), it was 34.69% (SD 11.52). However, the difference between the mean Ki67 index was not statistically significant between early and advanced stages diseases (P = 0.135). No significant difference in mean Ki67 index was found between serous and endometrioid carcinomas.

Results of HER2/neu immunomarker staining: in this study, a total of 10 patients out of 38 patients (26.32%) showed HER2/neu overexpression [Table 1]. In low grades, it was 12.5% (two out of 16), intermediate grade 33.33% (four out of 12), and in case of high-grade lesions, it was 40% (four out of 10) [Figure 3]a and [Figure 3]b. The difference is not statistically significant between grades (a total of 10 patients out of 38 patients (26.32%) showed HER2/Neu overexpression). In early stages lesions, it was 16.67% (four of 24), and in advanced lesions, it was 42.86% (six out of 14). The difference is not significant between the stages (P = 0.070). No significant difference was found between serous and endometrioid carcinomas in HER2/Neu overexpression.


 > Discussion Top


In most developing countries, ovarian carcinoma is one of the leading malignancies of the female genital tract. The majority of cases are diagnosed at advanced Stage (III or IV) and the overall prognosis is poor. In our study, 20 out of 21 (95.2%) serous carcinoma, irrespective of their age, grades, and stages were positive for WT1 staining. In contrast, 14 out of 17 endometrioid carcinomas (82.3%) were negative for WT1 staining. Acs et al. examined the expression of WT1 and p53 by immunohistochemistry in 68 cases of ovarian carcinomas (28 serous, 11 endometrioid, 18 clear cell, and 11 mucinous).[16] The difference in WT1 expression was highly significant between serous and other types of tumors.

The study done by Köbel et al. included 500 ovarian tumors of different types. Immunostaining for WT1 and Ki67, along with the other 19 immunomarkers was done.[17] More than 75% of serous carcinoma was positive for WT1.In contrast, <10% endometrioid carcinoma showed positivity for WT1. Hsiao et al. described the dual use of a single Wilms' tumor 1 immunohistochemistry in the evaluation of ovarian tumors and vascular endothelial cells.[8]

Hwang et al. found positive WT1 staining of serous carcinoma in 93% cases, whereas all of the endometrioid carcinomas were negative. The reasons for these discrepancies in the staining percentages are unclear. However, this finding is unlikely to be due to the technical issue as we performed strict quality control for the immunohistochemical study.

We could not find any relation between WT1 expression and stages and grades of the ovarian tumors. In contrast, the study by Netinatsunthorn et al. suggests that expression of WT1 gene may be indicative of an unfavorable prognosis in patients with advanced serous epithelial ovarian carcinoma.[18] However, only the advanced stages serous carcinomas were included in that study.[18] Another study by Yamamoto et al. found that a high WT1 immunoreactivity was associated with higher grade ovarian serous carcinoma and poorer clinical outcome. Recently, Rekhi et al. showed that both Napsin A and WT1 immunomarkers are very useful for differentiating clear-cell carcinoma of ovary from high-grade serous carcinoma.[5]

The findings of Bcl2 staining in our study are in concordance with that of the study of the Anderson et al.[19] Chan et al. proposed that decreased Bcl2 expression with tumor progression resulted from the dysregulation of Bcl2 normally required to maintain the physiological function and integrity of the normal ovarian surface epithelium. Similarly, other studies have reported an inverse relationship between epithelial Bcl2 expression and tumor grade. Baeke-Landt et al. found only 39% of stage III epithelial ovarian carcinomas displayed immunoreactivity to Bcl2in more than 5% of the tumor cells. They did not compare these levels to Bcl2 expression in normal ovarian tissue, but they concluded that Bcl2 expression was inversely related to tumor aggressiveness. None of the above-mentioned studies found any significant correlation between Bcl2 expression and types of tumors. The study by Henriksen R et al. also showed a similar result. In contrast, O'Neill et al. showed statistically significant higher Bcl2 expression in higher grades lesions.[11] The causes remain obscure. May be due to the fact that, they only included the serous carcinomas in their study.

The exact causes of decreasing Bcl2 expression in our study in the higher grades and stages lesions are not well understood. This may be due to the cause that the Bcl2 expressed here is abnormal or mutant variant of Bcl2, which did not react properly with the primary antibody against Bcl2.[10],[11] Besides, the expression of anti-apoptotic protein Bcl2 also depends on the other members of the Bcl2 family.[12]

The findings of Ki67 index are in accordance with other studies. In a study comprises of 68 ovarian carcinomas (26 early stage and 42 advanced stage), Aune et al. found a statistically higher Ki67 index in advanced stage and higher grades lesion in compared to early stage and low grades lesions.[20] They found no significant differences between Ki67 index with that of serous and nonserous carcinoma. These findings are in concordance with our study as well as other studies.[10],[11],[13],[14]

In their study of 50 ovarian tumors, Choudhury et al. found a significantly higher Ki67 index in advance stages lesions.[21] However, there was no relation between mean Ki67 index and grades of tumors.[21] No correlation found in mean Ki67 index with serous versus nonserous histology in their study.[21] The low Ki67 immunoreaction in borderline tumors suggests that increased expression occurs later in the development of carcinoma. In the present study, we found that the proliferation markers Ki67/MIB1was positively correlated with histological malignancy grades.[10],[11],[13]

The percentage of patients with ovarian cancer having HER2/Neu overexpression ranged between 5.9% (Felip et al.) and 40% (Leng et al.). This wide range of prevalence may be explained by variation in the assessment of HER2/neu activation by immunohistochemical or other methods. These methods differ in significant details, including primary antibodies, frozen versus paraffin-embedded tissue, detection techniques, and criteria for interpretation.[15],[16]

Works by Slamon et al. as well as Berchuck et al. have demonstrated that HER2/neu is overexpressed in approximately one-third of ovarian cancers in comparison to normal ovarian epithelium. Berchuck et al. and Felip et al. conducted the studied in advanced-stage epithelial ovarian carcinoma, found that the patients who had overexpression of this protein also had more chance to have persistent disease at second-look laparotomy and had drastically reduced median survival, in comparison to those patients who had normal tumor HER2/neu expression. Among the Asian countries, reports on HER2/nue overexpression were between 25% and 32% (Yang et al. and Seki et al.).

Heublein et al. found Her2/Neu amplification in 7.8% cases of ovarian epithelial tumors.[22] Lenj et al. found statistically significant higher HER2/neu expression in advanced stages of ovarian tumor. However, the relation between HER2/Neu and grades were not significant. They found overexpression of the marker as a poorer prognostic factor. Tuefferd et al. found overexpression of HER2/Neu in 6.6% of 320 ovarian tumors and no prognostic value of HER2/Neu was found. In our study, a total of 10 patients out of 38 patients (26.32%) showed HER2/Neu overexpression. However, statistically no significance was found in relation to grade, stage, or serous versus endometrioid carcinoma.

The role of HER2/Neu in epithelial ovarian carcinomas is still unclear. Several studies support a potential role on survival, while others consider it as not being related to prognosis.[23] The existing reports on efficacy of anti-HER2/Neu treatment in ovarian cancer patients are few and not encouraging, mainly because the response rate was rather low.[11],[15]


 > Conclusions and Take-Home Message Top


The use of WT1 may be useful in resolving diagnostic dilemma between serous and endometrioid carcinoma, especially in difficult cases. Because WT 1 is positive in most of the serous carcinoma while in endometrioid carcinoma, it is most likely to be negative. Ki67, Bcl2, and Her2/Neu may be used as prognostic markers. Higher grade and higher stage tumors have higher percentage of Ki 67 positivity. Higher expression of Bcl2 correlates significantly with decreasing survival. Her 2/Neu expression also correlated with poor prognosis.

Financial support and sponsorship

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Conflicts of interest

There are no conflicts of interest.



 
 > References Top

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Kumar V, Abbas AK, Fausto N, Aster JC. Pathologic Basis of Disease. 8th ed. Philadelphia, Pennsylvania: Elsevier Inc.; 2010.  Back to cited text no. 1
    
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Rekhi B, Deodhar KK, Menon S, Maheshwari A, Bajpai J, Ghosh J, et al. Napsin A and WT 1 are useful immunohistochemical markers for differentiating clear cell carcinoma ovary from high-grade serous carcinoma. APMIS 2018;126:45-55.  Back to cited text no. 5
    
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Al-Hussaini M, Stockman A, Foster H, McCluggage WG. WT-1 assists in distinguishing ovarian from uterine serous carcinoma and in distinguishing between serous and endometrioid ovarian carcinoma. Histopathology 2004;44:109-15.  Back to cited text no. 6
    
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Espinosa I, Gallardo A, D'Angelo E, Mozos A, Lerma E, Prat J. Simultaneous carcinomas of the breast and ovary: Utility of pax-8, WT-1, and GATA3 for distinguishing independent primary tumors from metastases. Int J Gynecol Pathol 2015;34:257-65.  Back to cited text no. 7
    
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Hsiao YH, Siddiqui S, Man YG. Dual use of a single Wilms' tumor 1 immunohistochemistry in evaluation of ovarian tumors: A preliminary study of 20 cases. J Cancer 2010;1:93-7.  Back to cited text no. 8
    
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Mishra SK, Crasta JA. An immunohistochemical comparison of P53 and bcl-2 as apoptotic and MIB1 as proliferative markers in low-grade and high-grade ovarian serous carcinomas. Int J Gynecol Cancer 2010;20:537-41.  Back to cited text no. 9
    
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Kalogeraki A, Tamiolakis D, Matalliotaki C, Karvela-Kalogeraki I, Karvelas-Kalogerakis M, Segredakis J, et al. The prognostic significance of p53, bcl2 and mib1 expressions related with other clinicopathological variables in serous ovarian carcinomas. a clinicopathological study in peritoneal fluids. Rev Med Chir Soc Med Nat Iasi 2015;119:454-60.  Back to cited text no. 10
    
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O'Neill CJ, Deavers MT, Malpica A, Foster H, McCluggage WG. An immunohistochemical comparison between low-grade and high-grade ovarian serous carcinomas: Significantly higher expression of p53, MIB1, BCL2, HER-2/neu, and C-KIT in high-grade neoplasms. Am J Surg Pathol 2005;29:1034-41.  Back to cited text no. 11
    
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Zeren T, Inan S, Vatansever HS, Sayhan S. Significance of apoptosis related proteins on malignant transformation of ovarian tumors: A comparison between bcl-2/Bax ratio and p53 immunoreactivity. Acta Histochem 2014;116:1251-8.  Back to cited text no. 12
    
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Mahadevappa A, Krishna SM, Vimala MG. Diagnostic and prognostic significance of ki-67 immunohistochemical expression in surface epithelial ovarian carcinoma. J Clin Diagn Res 2017;11:EC08-12.  Back to cited text no. 13
    
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Shen XX, Yu L, Bi R, Yang WT. Clinicopathologic study and immunohistochemistry comparison of pax 2, p53 and ki-67 in low- and high-grade ovarian serous carcinomas. Zhonghua Bing Li Xue Za Zhi 2011;40:511-6.  Back to cited text no. 14
    
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Jafri A, Rizvi S. Frequency of her2/Neu protein expression in ovarian epithelial cancers. J Coll Physicians Surg Pak 2017;27:544-6.  Back to cited text no. 15
    
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Köbel M, Kalloger SE, Boyd N, McKinney S, Mehl E, Palmer C, et al. Ovarian carcinoma subtypes are different diseases: Implications for biomarker studies. PLoS Med 2008;5:e232.  Back to cited text no. 17
    
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Aune G, Stunes AK, Tingulstad S, Salvesen O, Syversen U, Torp SH. The proliferation markers ki-67/MIB-1, phosphohistone H3, and survivin may contribute in the identification of aggressive ovarian carcinomas. Int J Clin Exp Pathol 2011;4:444-53.  Back to cited text no. 20
    
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Heublein S, Vrekoussis T, Mayr D, Friese K, Lenhard M, Jeschke U, et al. Her-2/neu expression is a negative prognosticator in ovarian cancer cases that do not express the follicle stimulating hormone receptor (FSHR). J Ovarian Res 2013;6:6.  Back to cited text no. 22
    
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Engelstaedter V, Boda J, Völklein C, Engel J, Jeschke U, Kirchner T, et al. Lack of prognostic relevance of her-2/neu, topoisomerase IIα and EGFR in advanced ovarian carcinoma. Exp Ther Med 2012;3:828-34.  Back to cited text no. 23
    


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