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 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 11  |  Issue : 1  |  Page : 19-24

Expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor type 2/neu in surface epithelial ovarian tumors and its clinicohistopathological correlation


1 Department of Pathology, King George Medical University, Lucknow, Uttar Pradesh, India
2 Department of Obstetric and Gynecology, King George Medical University, Lucknow, Uttar Pradesh, India
3 Department of Surgical Oncology, King George Medical University, Lucknow, Uttar Pradesh, India

Date of Web Publication17-Jan-2018

Correspondence Address:
Dr. Madhu Kumar
Department of Pathology, King George Medical University, Shah Mina Road, Lucknow - 226 003, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/kleuhsj.ijhs_310_16

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  Abstract 


BACKGROUND: Ovarian cancers represent the 4th most frequent type of cancers among females and are the most common cause of death from gynecological cancers in the world.
AIMS AND OBJECTIVES: The aim is to evaluate the expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (HER2/neu) immunohistochemical markers in surface epithelial ovarian tumors and its clinicopathological correlation with CA-125 level, histological type, grading of tumors, and prognosis of ovarian tumors.
MATERIALS AND METHODS: This study included 48 cases of surface epithelial ovarian tumors including serous, mucinous, and adenocarcinoma Not Otherwise Specified (NOS). After grossing and processing, H and E sections were examined and representative 3–4 μm sections taken from blocks for immunohistochemistry which was performed with specific antibodies against ER, PR, and HER2/neu as per standard protocol. Statistical analysis was performed using Chi-square test.
DISCUSSION AND RESULTS: ER expression was higher in malignant, borderline, serous tumors as compared to benign and mucinous tumors. PR expression was higher in borderline, serous tumors as compared to malignant and mucinous tumors. HER2/neu positive cases were higher in malignant, serous as compared to borderline and mucinous tumors.
CONCLUSIONS: ER expression was found to be positive in most of serous tumors, have variable role in prognosis. PR expression showed protective role in survival of patients. Her2/neu was found to be expressed in higher grade and associated with poor prognosis. Together expression of ER and Her2/neu associated with decreased survival rates.

Keywords: Epithelial ovarian tumors, estrogen receptor, human epidermal growth factor receptor type 2 neu, progesterone receptor


How to cite this article:
Verma N, Kumar M, Sagar M, Babu S, Singhai A, Singh N, Dev S, Kumar V. Expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor type 2/neu in surface epithelial ovarian tumors and its clinicohistopathological correlation. Indian J Health Sci Biomed Res 2018;11:19-24

How to cite this URL:
Verma N, Kumar M, Sagar M, Babu S, Singhai A, Singh N, Dev S, Kumar V. Expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor type 2/neu in surface epithelial ovarian tumors and its clinicohistopathological correlation. Indian J Health Sci Biomed Res [serial online] 2018 [cited 2018 Oct 15];11:19-24. Available from: http://www.ijournalhs.org/text.asp?2018/11/1/19/223430




  Introduction Top


Ovarian cancers account for total 3% of all cancers in women and 30% of all cancers of the female genital system. Among cancers of female genital tract, the incidence of ovarian cancer rank below only carcinoma of the cervix and the endometrium.[1] Most ovarian cancers occur sporadically, but 10%–15% has inherited genetic changes that predispose them to ovarian cancers.[2] In recent years, with the development of the molecular biology and immunologic methods, molecules such as steroid receptors, estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor type 2 (HER2/neu) have been tested as potential biomarkers of individualized clinical behavior of cancers.[3] Epidemiological evidence strongly suggests that steroid hormones primarily estrogen and progesterone are implicated in ovarian carcinogenesis.

Aim and objectives

The aim is to evaluate the expression of ER, PR, and HER 2/neu immunohistochemical markers in surface epithelial ovarian tumors and its clinicopathological correlation with CA-125 level, histological type, grading of tumors, and prognosis of ovarian tumors.


  Materials and Methods Top


Present study was conducted in the Department of Pathology, in association with the Department of Surgical Oncology and Gynaecology and Obstetrics, King George's Medical University, from September 2014 to July 2015.

Sample collection

All cases of ovarian tumors received in the past 1 year were included in the study and worked up as they were received.

Inclusion criteria

Surface epithelial stromal tumors of ovary such as benign, borderline and malignant with subtypes serous, mucinous, other tumors (NOS). During the study, most of the patients were receiving pre- and post-operative chemotherapy.

Exclusion criteria

All other histological types such as sex cord-stromal tumors, germ cell tumors and metastatic cancer from nonovarian primary.

Positive control

Normal ovary.

This study included 48 cases, out of them 35 cases are malignant, 3 cases are borderline, and 10 cases are benign. Grossing and processing were done. Sections cut stained with hematoxylin and eosin and blocks collected for immunohistochemistry (IHC) which shall be performed according to heat-induced epitope retrieval method and specific antibodies against ER, PR, and HER 2Neu. The slides were examined at ×400 magnification. Since ER, PR is a nuclear transcription factor and HER2/neu is a membranous transcription factor involved in gene regulation, and hence, nuclear staining was considered as positive in ER, PR, and membranous positivity in HER 2/neu. We also used the patient charts, from which we extracted their history, symptoms, clinical examination, and the imaging findings along with the results and CA-125 level and ascites.

Statistical analysis

The statistical analysis was performed using SPSS (Statistical Package for Social Sciences) Version 15.0 Statistical Analysis Software (IBM SPSS, Chicago, IL, USA). The values were represented in number (%) and using Chi-square test.


  Results Top


Most common age group was 41–50 years and common presenting symptom was pain (79.17%) followed by ascites (62.50%) and palpable lump (52.08%). Gross and microscopy was cystic in mucinous tumors, solid or glandular in others tumors (NOS), and papillary or mixed in serous tumors. Out of 48 cases, 10 cases were benign, 3 were borderline and 35 were malignant [Figure 1]. CA-125 was found to be normal in 21 (43.75%) cases, and abnormal in rest of the 27 cases (56.25%). Normal value of CA-125 was found to be in higher in proportion with benign (90%) and borderline (66.67% tumors) as compared to malignant (33.33%) tumors. Malignant tumors having higher values of CA-125 (71.43%) in 25 cases out of 35 cases. Difference in CA-125 in different histopathological categories was found to be statistically significant (P = 0.002) [Table 1]. CA-125 was found to be higher in cases of adenocarcinoma (NOS) (100%) followed by serous tumors (65.21%) and mucinous tumors (37.5%).
Figure 1: (a) Benign tumor, (b) borderline, (c) serous (d) mucinous tumors of ovary (H and E, ×400)

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Table 1: Comparison of cancer antigen - 125 in different histopathological categories

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ER-positive cases were higher in malignant (77.14%), and borderline tumors (66.67%) as compared to benign tumors (20%). The difference in ER positivity in different histopathological types was found to be statistically significant (P = 0.004). PR positive cases was higher in borderline tumors (100%) as compared to that in malignant tumors (51.43%), but this difference was not found to be statistically significant (P = 0.099). HER2/neu positive cases was higher in malignant (57.14%) as compared to borderline (33.33%) categories and this difference was found to be statistically significant (P = 0.028) [Table 2].
Table 2: Expression of immunohistochemical markers in benign, borderline and malignant tumors

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The comparison of ER, PR, and HER2/neu reactivity in serous and mucinous tumors, [Figure 2] ER positivity was higher for serous (91.3%) as compared to mucinous (25%) and the difference in ER positivity of mucinous and serous was found to be statistically significant (P< 0.001). Although PR positivity with weak intensity was found to be higher for serous (60.87%) as compared to mucinous (25%), but this difference was not found to be statistically significant (P = 0.080). HER2/neu positivity was higher for serous (78.26%) as compared to mucinous (25%) and difference was found to be statistically significant (P = 0.007). Proportion of all positive (ER, PR, and Her2/neu) was almost equal in mucinous (25%) and serous (26.09%), but proportion of all negative (ER, PR, and HER2/neu) was higher in mucinous (37.50%) and the difference was found to be statistically significant (P = 0.016).
Figure 2: Serous tumor displaying (a) estrogen receptor, (b) progesterone receptor nuclear immunoreactivity and (c) human epidermal growth factor receptor type 2 neu membranous immunoreactivity, mucinous tumor displaying (d) estrogen receptor, (e) progesterone receptor nuclear immunoreactivity and (f) HER2/neu shows membranous immunoreactivity (IHC, ×400)

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The comparison of ER, PR, and HER2/neu positivity in other tumors, serous and mucinous tumors [Figure 3], ER-positive cases was higher in other tumors (NOS) (100%), serous tumors (91.3%) as compared to mucinous tumors (25.0%) and this difference was found to be statistically significant (P< 0.001). PR positive cases were higher in serous tumors (60.87%) and tumor (NOS) (50%) types as compared to mucinous tumors (25%). HER2/neu positive cases were higher in serous (69.37%) as compared to other tumor (NOS) (50.0%) and mucinous (25.00%) types, but this difference was found to be statistically significant (P = 0.023) [Table 3].
Figure 3: Comparison of estrogen receptor, progesterone receptor and human epidermal growth factor receptor type 2 positivity in different malignant histopathological types

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Table 3: Comparison of estrogen receptor, progesterone receptor and human epidermal growth factor receptor type 2 positivity in different malignant histopathological types

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ER positivity was found to be 100% of cases in Grade 1, 80% of cases in Grade3, whereas 75% of cases in Grade2. PR positivity was found to be 58% of cases in Grade 3 and Grade 2 and 60% in Grade1. HER2 neu positivity was found to be 100% of cases in Grade1, 75% of cases in Grade 2and 60% of cases in Grade3.

The comparison of ER, PR and her2 neu positivity in FIGO Staging of Tumor, ER-positive cases were found to be maximum in stage IV (100%), stage III (78%) and minimum in stage II (67%). PR positive cases was found to be higher in stage III and II (57.1% and 53.85%, respectively). Her2/neu positive cases were found to be higher in stage I (8.62%) [Table 4].
Table 4: Comparison of estrogen receptor, progesterone receptor and human epidermal growth factor receptor type 2 neu positivity in gynecologists and obstetrics staging of tumor

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According to this study, maximum number of cases that were expired found to be HER2/neu positive (77.78%), ER-positive (66.67%) and maximum number of cases who were survived, found to be ER (85.71%) and PR positive (71.43%). This was found to be statistically significant with PR status.

In the present study, 11 patients received chemotherapy only after the postoperative, 5 (45.45%) expired and 6 (54.55%) were survived, whereas 15 patients received chemotherapy both pre- and post-operative, of them 2 were (13.33%) expired and 13 were (87.87%) survived. Four patients whose outcome was available but no record of chemotherapy was available 2 (50%) of these patients expired, whereas another 2 (50%) survived. Only 5 patients who did not receive any chemotherapy (neither before preoperative nor postoperative), out of them 3 (60%) expired and 2 (40%) were survived.


  Discussion Top


Patient's symptoms profile in our study showed that the most common symptom was pain, ascites and palpable lump. The similar clinical manifestation was mentioned by Robbins and Cotran et al.[4] More than one-third of ovarian cancer patients present with malignant ascites at the time of diagnosis. The onset and progression of ascites are associated with poor prognosis and deterioration in the quality of life as stated by Kipps et al.[5] in our study ascites was found to be >50% of cases.

In our study, CA-125 levels were found to be elevated in maximum number of malignant cases as compared to benign, borderline cases. Zorn et al.[6] have showed that 7.6% of patients with malignant tumors have normal levels. This shows very close similarities with our study find CA-125 level was maximum in malignant tumors [Table 1].

ER-positive cases were higher in malignant (77.14%), and borderline tumors (66.67%) as compared to benign tumors (20%). The difference in ER positivity in different histopathological categories was found to be statistically significant (P = 0.004). PR positive cases was higher in borderline tumors (100%) as compared to that in and malignant tumors (51.43%), but this difference was not found to be statistically significant (P = 0.099). Her neu2 positive cases were higher in malignant (57.14%) as compared to borderline (33.33%) categories, and this difference was found to be statistically significant (P = 0.028) [Table 2].

ER-positive cases were higher in other tumor (NOS) (100%) and serous tumors (91.3%) as compared to Mucinous tumors (25%) and this difference was found to be statistically significant (P< 0.001). PR positive cases were higher in serous tumors (60.87%) and other tumors (NOS) (50.00%) types as compared to mucinous tumors (25%). Her2/neu positive cases were higher in serous (69.37%) as compared to another tumor (NOS) (50%) and Mucinous (25%) types, but this difference was found to be statistically significant.(P = 0.023) [Table 3].

In terms of histomorphological tumor grades and its correlation with IHC, our study found a higher percentage of Grade I and III tumors that expressed ER. PR expression in our study was more frequent in approximately in all grades. An observation that was not supported by Ayadi et al.[7] However, this association of ER/PR expression and grade of tumor was not statistically significant. Her 2/neu was found to be higher in histomorphological Grade I and II.

In the present study, HER2/neu membranous positive cases were higher in malignant, serous and mucinous tumors, Grade I and II. This was found to be statistically significant. In this study, there was no clear-cut correlation between expression of ER, PR, HER2 neu and grade of the malignant tumor. Similar results were obtained by Sylvia et al.[8]

According to our study, ER-positive cases were higher in malignant and borderline as compared to benign cases. ER positivity was found to be maximum in serous and others (NOS) along with strong nuclear positivity in >50% of cells. PR positive intensity of tumor cells was found to be strong in serous tumors, moderate in mucinous tumors and weak in other tumors (NOS), this was approximately concordance with Sylvia et al.,[8] they showed that higher expression of PR positivity in malignant and serous tumors. Thus, PR may also play a carcinogenic role, or rather PR is regulated by estrogen, and therefore, a high PR content in conjunction with high ER expression is likely to be indicative of estrogen-regulated disease.

ER was found to be positive in most of the serous tumors, have a variable role in prognosis. ER expression in tumors with adverse prognostic factors supports the mitogenic role of estrogen in ovarian tumors. PR expressed in almost equal in all histomorphological grades of tumor, higher in malignant and borderline tumors. HER2/neu reactivity was found to be associated with poor prognosis, suggesting their carcinogenic role and help in the differentiation of borderline and malignant tumors.

New convincing data have indicated that estrogen favor neoplastic transformation of the ovarian surface epithelial cells, whereas progesterone offers protection against ovarian cancer development. Her 2/neu is a proto-oncogene encodes a protein belonging to the EGFR tyrosine kinas receptor family. Overexpression of Her 2/neu indicate intracellular signaling pathway involved in cell proliferation, differentiation, migration, and apoptosis. Her 2 positive status is associated with poor prognosis. In recurrent low-grade carcinoma of the ovary, the hormonal therapies had a greater anti-tumor activity in ER+/PR+ patients than in ER+/PR-patient.[9],[10]

FIGO stage is the only universally accepted prognostic factor for patients with ovarian carcinoma; this is a powerful prognostic predictor that most other putative prognostic factors are of little importance compared to the stage. In this study, ER-positive cases were found to be maximum in stage IV (100%), stage III (78%), and minimum in stage II (67%). PR positive cases were found to be higher in stage III and II (57.1% and 53.85%, respectively). Her2/neu positive cases were found to be higher in stage I (8.62%) [Table 4]. In our study, we have shown approximately higher PR expression in all stages and except stage IV were PR negative. There was variable ER expression in stage III and I. Similarly, a few other studies also reported a significant inverse correlation of higher PR concentration in early stage disease.[11],[12]

The expression of Her2 in epithelial ovarian cancer has been less studied. Her2 expression can be determined by IHC, Fluorescent in situ hybridization (FISH), chromogenic (nonfluorescent) in situ hybridization, and enzyme-linked immunosorbent assay among other tests, with reported positivity frequencies of overexpression varying from 1.8% to 76%. In some studies, Her2 overexpression has been associated with advanced stages, poorly differentiated tumors, resistance to chemotherapy and shortened survival.


  Conclusions Top


Together expression of ER and Her2/neu associated with decreased survival rates. These markers may aid in differentiation and prognostication of ovarian tumors. In the present study, results indicate that ER, PR, and HER2/neu status will throw the light for biological behavior and helpful in predicting treatment outcome in ovarian tumors.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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De Toledo Barreta. The role of steroid receptors and HER2 in ovarian Cancer. J Carcinog Mutagen 2014;5:158.  Back to cited text no. 3
    
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Kumar V, Abbas AK, Fausto N, Aster J. In: Robbins, Cotran Pathologic Basis of Disease. 8th ed. Philadelphia Pennsylvania: Elisvier; 2010. p. 1047.  Back to cited text no. 4
    
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Zorn KK, Tian C, McGuire WP, Hoskins WJ, Markman M, Muggia FM, et al. The prognostic value of pretreatment CA 125 in patients with advanced ovarian carcinoma: A Gynecologic Oncology Group Study. Cancer 2009;115:1028-35.  Back to cited text no. 6
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Ayadi L, Chaabouni S, Khabir A, Amouri H, Makni S, Guermazi M, et al. Correlation Between immunohistochemical biomarkers expression and prognosis of ovarian carcinomas in Tunisian patients. World J Oncol. 2010; 1:118-28.  Back to cited text no. 7
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Sylvia MT, Kumar S, Dasari P. The expression of immunohistochemical markers estrogen receptor, progesterone receptor, her-2-neu, p53 and ki-67 in epithelial ovarian tumors and its correlation with clinicopathologic variables. Indian J Pathol Microbiol 2012;55:33-7.  Back to cited text no. 8
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