|Year : 2017 | Volume
| Issue : 4 | Page : 334-338
Association of the hormonal receptor status of endometrial carcinomas with the markers of tumor aggression: A comparison with similar studies in developed nations
Somsubhra Goswami, Arijit Sen, Manash Biswas
Department of Pathology, Armed Forces Medical College, Pune, Maharashtra, India
|Date of Submission||13-Nov-2016|
|Date of Acceptance||12-May-2017|
|Date of Web Publication||4-Sep-2017|
Department of Pathology, Armed Forces Medical College, Solapur Road, Pune - 411 040, Maharashtra
Source of Support: None, Conflict of Interest: None
Background: Endometrial carcinomas (EC) are the most common gynecological malignancy in developed nations, but in developing nations, it follows cervical cancer. Estrogen and progesterone receptor (ER and PR) status is important prognostic indicators in EC. With this in background, we intended to compare the hormonal receptor status of our cases with markers of tumor aggression and compare our results with that of developed nations. Aims: The present retrospective study aims to check the association of ER and PR status of cases of EC with markers of tumor aggression-tumor grade, MIB-1 score (proliferative index), depth of myometrial invasion, and incidence of nodal metastasis and to also compare status of our cases in developing nation with the studies of similar nature in the developed countries. Materials and Methods: The cases diagnosed in this tertiary care center over the past 2 years were evaluated. ER and PR status of cases in this retrospective observational study was performed using immunohistochemistry. The hormonal status of the cases was checked for its association with markers of tumor aggression. Results: A total of 34 cases were evaluated during the period of the study. The age of the cases ranged from 35 to 85 years. Mean age being 60.36 years. Twenty-four out of 34 (70.6%) cases were ER and PR positive. Significant association of positive hormonal status was found with lower histological grade (P = 0.01) and low MIB-1 score (P = 0.0009) while no association of hormonal status was found with depth of myometrial invasion and incidence of nodal metastasis. Conclusion: We conclude that positive ER and PR status is associated with lower histological grade and low MIB-1 score; however, our study in contrast to previous studies done in developed nations did not find any association with depth of myometrial invasion and incidence of nodal metastasis likely due to late access to treatment in our country when the disease had already advanced.
Keywords: Comparison with developed nations, endometrial adenocarcinoma, hormonal receptor status, markers of tumor aggression
|How to cite this article:|
Goswami S, Sen A, Biswas M. Association of the hormonal receptor status of endometrial carcinomas with the markers of tumor aggression: A comparison with similar studies in developed nations. Med J DY Patil Univ 2017;10:334-8
|How to cite this URL:|
Goswami S, Sen A, Biswas M. Association of the hormonal receptor status of endometrial carcinomas with the markers of tumor aggression: A comparison with similar studies in developed nations. Med J DY Patil Univ [serial online] 2017 [cited 2019 Apr 21];10:334-8. Available from: http://www.mjdrdypu.org/text.asp?2017/10/4/334/213938
| Introduction|| |
Endometrial cancer is the most common gynecologic malignancy in developed countries, with an incidence of 12.9/100,000 women and a mortality rate of 2.4/100,000. In developing countries, it is the second most common gynecologic malignancy (cervical cancer is more common), with an incidence of 5.9/100,000 and a mortality rate of 1.7/100,000. The endometrial carcinoma is formed and develops in close relation to the plasma and tissue levels of sex steroidal hormones and their receptors. The connection with the atypical endometrial hyperplasia is recognized, associated with prolonged estrogen stimulation, of endogenous or exogenous origin, not being counterweight by progesterone. This broadly classifies them into type 1 and 2 tumors. Type 1 (80%–85%) carcinoma encompasses endometrioid carcinomas and its variants and has specific  common genetic alterations, namely, microsatellite instability, mutations of PTEN, beta-catenin, PIK3CA, and K-RAS, whereas type 2 endometrial carcinomas (EC) only consist of 10% of tumors and are serous, clear cell and carcinosarcomas. Reporting on a case of endometrial carcinoma by a pathologist includes the histological typing, histological grade in cases of endometrioid carcinomas, evidence of lymphovascular invasion, depth of myometrial invasion, involvement of cervical stroma, incidence of nodal metastasis, and hormonal receptor status. This comprehensive reporting by the pathologist helps the clinician not only to decide upon the right course of treatment as per stage of disease but also based on the risk factors. Hence, an extensive histopathological evaluation becomes mandatory. In the present study, we propose to study the hormonal estrogen and progesterone receptor (ER and PR]) status of the EC and check the association with few markers of tumor aggression such as histological grade, MIB-1 score, depth of myometrial invasion, and incidence of nodal metastasis. Histological grade and MIB-1 score elicits about the aggressive nature of the tumor, whereas the depth of myometrial invasion and incidence of nodal metastasis are a part of the staging of disease and reflects upon the disease progression. No studies on similar lines were found in the review of Indian literature. The present retrospective study aims to:
- Check the association of ER and PR status of cases of EC with markers of tumor aggression-tumor grade, MIB-1 score (proliferative index), depth of myometrial invasion, and incidence of nodal metastasis
- Also compare status of our cases in developing nation with the studies of similar nature in the developed countries.
| Materials and Methods|| |
It was a retrospective study performed at tertiary care center of developing nation. All the cases of endometrial adenocarcinoma diagnosed over the past 2 years from July 1, 2014, to June 30, 2016, were included in the present study. In those cases in which no staging laparotomy specimen was available for complete evaluation, only their endometrial biopsies were included in the study. Being a retrospective study, sanction was taken from the head of the institution. The Institutional Ethics Committee clearance was taken for this study. The age of the patient and her menstrual status were noted from the clinical information sheet received with the sample. All the cases were reviewed for the confirmation of diagnosis, they were typed histologically, and the cases were then graded based on the modified International Federation of Gynecology and Obstetrics grading system: Grade 1 - <5% of nonsquamous or nonmorular solid growth pattern, Grade 2-6%–50% of nonsquamous or nonmorular solid growth pattern, and Grade 3 - >50% of nonsquamous or nonmorular solid growth pattern. If the nuclear atypia is higher for the grade, the lesion is escalated to a higher grade. All cases of endometrial carcinoma are evaluated for ER (Dako monoclonal mouse antibody clone ID5, dilution 1:100, incubation 30 min) and PR (Path-in situ rabbit monoclonal antibody clone EP2 ready to use, incubation 30 min) receptor status. Allred score was used to score the cases for ER and PR. MIB-1 scoring was conducted in all cases (Dako monoclonal mouse antibody clone MIB-1 ready to use, incubation 30 min) by immunohistochemistry. All those cases, in which hysterectomy with staging laparotomy had been performed, were additionally assessed for depth of myometrial invasion and incidence of nodal metastasis. All cases positive for either ER or PR or both were put into one group and those negative for both were placed in the other group. The hormonal receptor status of all the cases was correlated for markers of tumor aggression, namely, histological grade, MIB-1 score (semiquantitative assessment and average score of ten high-power fields), depth of myometrial invasion (morphometric assessment on whole endometrium to serosal thickness sections under low-power view), and incidence of nodal metastasis. All the data are tabulated in SPSS-XL (2013) Version 22.0. Armonk, NY: IBM Corp, and Fischer's exact probability test was used to evaluate the results with P < 0.05 taken as significant.
| Results|| |
A total of 34 cases were studied. Thirty were hysterectomy with staging laparotomy whereas four were only endometrial biopsies. In the latter, no hysterectomy had been done at the center of the study and cases had been lost to follow-up. The age of the cases ranged from 35 to 85 years. Mean age being 60.36 years. The association of hormonal receptor status and age is tabulated in [Table 1]. Twenty-four out of 34 (70.6%) cases were ER/PR positive. The mean age of ER/PR-positive and negative cases was 58.87 and 63.16 years, respectively. [Figure 1] shows the ER/PR status of cases. Seven out of 34 (20.59%) cases were premenopausal while 27/34 (79.41%) were postmenopausal. Thirty-two out of 34 cases were of endometrioid type of endometrial carcinoma as only two cases were of serous papillary. The association of menstrual status with histological type is tabulated in [Table 2]. The association of histological grade with mean age is tabulated in [Table 3]. Sixteen out of 34 (47.05%), 7/34 (20.5%), and 11/34 (32.35%) cases were Grade I, II, and III, respectively. There were seven premenopausal cases, five Grade I and two were Grade II. Two cases of serous papillary carcinoma are included with Grade III for evaluation. The mean of age for the various grades is also tabulated. The mean age of the cases were found to be increasing with increase in histological grade. [Figure 2] depicts three cases with different histological grades. The association of hormonal receptor status with grade of lesion is tabulated in [Table 3]. Low histological grade was found to associated with positive hormonal receptor status. The association was significant with P = 0.01. The association of hormonal receptor status with MIB-1 score of lesion is tabulated in [Table 4]. The association was significant with P = 0.0009. Positive hormonal receptor status was associated with lower MIB-1 score. Both the cases of serous papillary adenocarcinoma were in the hormonal receptor status-negative category with >50% MIB-1 score. [Figure 3] depicts two cases with very low and very high MIB-1 scores (×100). The association of hormonal receptor status with depth of myometrial invasion is tabulated in [Table 5]. Only 30 cases which had undergone hysterectomy were included in the present evaluation. The association was not found to be significant with P = 0.54. [Figure 4] depicts two cases with less than and more than 50% myometrial invasion (×100). The association of hormonal receptor with nodal metastatic status is also tabulated in [Table 5]. Only 30 cases which had undergone hysterectomy with staging laparotomy were included in the present evaluation. The association was not found to be significant with P = 0.19.
|Figure 1: (a) Grade 1 tumor with 8/8 Allred score - estrogen receptor strongly positive, (b) Grade 3 tumor with 0/8 Allred score - estrogen receptor negative, (c) Grade 1 tumor with 8/8 Allred score – progesterone receptor positive, (d) Grade 3 tumor with Allred score 0/8 - progesterone receptor negative|
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|Figure 2: (a) International Federation of Gynecology and Obstetrics Grade 1, H and E, ×400. (b) International Federation of Gynecology and Obstetrics Grade 2, H and E, ×400 (c) International Federation of Gynecology and Obstetrics Grade 3, H and E, ×400|
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|Figure 3: (a) MIB-1 score >90% in a case of serous papillary carcinoma, (b) MIB-1 score <2% in a case of Grade 1 endometrioid carcinoma|
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|Figure 4: (a) Less than 50% myometrial invasion (b) >50% myometrial invasion|
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|Table 5: Association of hormonal receptor status with myometrial invasion in hysterectomy specimens|
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| Discussion|| |
The mean age of our 34 cases evaluated in the present study was 60.36 years. Carcinoma of the endometrium is uncommon before 40 years of age, and peak incidence is seen in 55–65-year-old females. In our study, 70.6% of cases were positive for ER/PR, whereas in previous studies, it has been varied with Srijaipracharoen et al. getting a figure of ER - 59.3% and PR - 65.7%. In an Indian study  of 50 cases, an ER and PR positivity of 68% and 76% was observed. In our study, mean age of hormonal receptor-negative tumors was 63.16 years, which was around 5 years more than those of hormonal receptor-positive tumors, 58.17 years. Previous studies too have found younger patients for PR-positive status. Hormonal receptor-positive tumors were found to be significantly associated with lower histological grades in our study with P = 0.01. Previous studies too have found similar results. Type 1 tumors have been shown to be of lower histological grade and occurring in premenopausal females. The MIB-1 score of <50% was found to be associated with hormonal receptor-positive status with P = 0.0009. Similar results have been found in previous studies too. Increased levels of P53 and Ki67 usually are associated with more aggressive tumors. ER/PR positivity is associated with lower grade of lesion and overexpression of Ki67 with higher grade lesions. In our study of 30 cases in which staging laparotomy had been performed, no association was found between hormonal receptor status and depth of myometrial invasion (P = 0.54). A large multicentric study from a developed nation of 832 cases of endometrial carcinoma by Trovik et al. has established independent correlation of ER/PR-positive status with reduced hazard ratio for myometrial invasion. Similar results were also observed by Stoian et al. and Ferrandina et al. As far as the association of hormonal receptor status with nodal metastatic status is concerned, though the number of cases was small, no significant association was found of hormonal receptor-negative status tumors with propensity for nodal metastasis (P = 0.19). The study by Trovik J et al. had shown loss of ER/PR independently predicted nodal metastasis. A Chinese study  of 200 patients at the Shanghai Cancer Center too showed results similar to the previous study discussed. The difference in the finding is likely due to late access to therapy by patients from our country when the disease has already metastasized to nodes and is advanced. Thus, irrespective of hormonal receptor status of our cases predominantly showed advanced stage of disease in the form of increased depth of myometrial invasion and incidence of nodal metastasis in contrast to most international studies likely due to delayed access to therapy.
| Conclusion|| |
ER/PR positivity was found in 70.6% of cases. Hormone receptor-positive (58.87 years) EC were found to have early mean age of presentation as compared to hormone receptor-negative carcinomas (63.16 years) by 4.29 years. ER/PR positivity was significantly associated with lower histological grade and lower MIB-1 score, mostly <10%. ER/PR-positive and negative tumors both predominantly showed higher stage of disease with >50% myometrial invasion and nodal metastasis likely due to late access to therapy in our part of the world.
We would like to thank the Department of Pathology, Armed Forces Medical College.
Financial support and sponsorship
This study was financially supported by the Department of Pathology, Armed Forces Medical College, by providing tissue blocks and case details.
Conflicts of interest
There are no conflicts of interest.
| References|| |
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011;61:69-90.
Wei JJ, Paintal A, Keh P. Histologic and immunohistochemical analyses of endometrial carcinomas: Experiences from endometrial biopsies in 358 consultation cases. Arch Pathol Lab Med 2013;137:1574-83.
Prat J, Gallardo A, Cuatrecasas M, Catasús L. Endometrial carcinoma: Pathology and genetics. Pathology 2007;39:72-87.
Wang Y, Ma XL, Xi CG, Lin J, Ren CX, Liu CR. Correlation between estrogen receptor status and clinicopathologic parameters in endometrial cancer: A comparative study by immunohistochemistry using different scoring systems. Zhonghua Bing Li Xue Za Zhi 2013;42:509-14.
Srijaipracharoen S, Tangjitgamol S, Tanvanich S, Manusirivithaya S, Khunnarong J, Thavaramara T, et al.
Expression of ER, PR, and Her-2/neu in endometrial cancer: A clinicopathological study. Asian Pac J Cancer Prev 2010;11:215-20.
Kumari PR, Renuka IV, Apuroopa M, Chaganti PD. A study of expression of estrogen and progesterone receptor, in atrophic, hyperplastic and malignant endometrial lesions, with emphasis on relationship with prognostic parameters. Int J Res Med Sci 2015;3:3318-25.
Kounelis S, Kapranos N, Kouri E, Coppola D, Papadaki H, Jones MW. Immunohistochemical profile of endometrial adenocarcinoma: A study of 61 cases and review of the literature. Mod Pathol 2000;13:379-88.
Zidan AA, Hassan AA, Abu Seadah SS, Ibrahim EH, Attiah SM. Selected immunohistochemical prognostic factors in endometrial hyperplasia versus carcinoma. J Am Sci 2015;11:1-9.
Trovik J, Wik E, Werner HM, Krakstad C, Helland H, Vandenput I, et al.
Hormone receptor loss in endometrial carcinoma curettage predicts lymph node metastasis and poor outcome in prospective multicentre trial. Eur J Cancer 2013;49:3431-41.
Stoian SC, Simionescu C, Margaritescu C, Stepan A, Nurciu M. Endometrial carcinomas: Correlation between ER, PR, Ki67 status and histopathological prognostic parameters. Rom J Morphol Embryol 2011;52:631-6.
Ferrandina G, Ranelletti FO, Gallotta V, Martinelli E, Zannoni GF, Gessi M, et al.
Expression of cyclooxygenase-2 (COX-2), receptors for estrogen (ER), and progesterone (PR), p53, ki67, and neu protein in endometrial cancer. Gynecol Oncol 2005;98:383-9.
Yang B, Shan B, Xue X, Wang H, Shan W, Ning C, et al.
Predicting lymph node metastasis in endometrial cancer using serum CA125 combined with immunohistochemical markers PR and Ki67, and a comparison with other prediction models. PLoS One 2016;11:e0155145.
[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]