Comparative immunohistochemical characteristics of expression of estrogen receptors-alpha, progesterone receptors, p16, p53, Ki-67 and caspase 3 in invasive endometrial adenocarcinoma and normal proliferative endometrium
DOI:
https://doi.org/10.14739/2310-1237.2016.1.72165Keywords:
Endometrial Neoplasms, Estrogen Receptor alpha, Progesterone Receptors, Tumor Suppressor Protein p53, Cyclin-Dependent Kinase Inhibitor p16, Ki-67 Antigen, Caspase 3Abstract
Endometrial cancer occupies the sixth place among newly diagnosed neoplasms in women. In late stage it has unpredictable prognosis. Immunohistichemical studies of the tumor are very important for prognosis of tumor course.
The aim. To characterize the expression of the estrogen receptors-alpha, progesterone receptors, p53, p16, ki-67 and caspase 3 in the invasive endometrioid endometrial adenocarcinoma compared with the normal proliferative endometrium.
Materials and methods. The uteruses of 56 women with the verified diagnosis of endometrial cancer (stage pT1-4MxNx) and biopsies of 30 women with normal proliferetive endometrium were analyzed. For this purpose, immunohistochemical and morphometrical studies were used.
Results: It was established that level of expression of estrogen receptors-alpha was significantly lower in tumor glands and stroma compared with normal proliferative endometrium: the median was 6.0 (5.0; 7.0) points for tumor glands and 7.0 (6.0; 8.0) points for glands of normal proliferative endometrium(р<0,05); for stromal compartment medians were 5.0 (4.0; 6.0) points and 7.0 (6.0; 7.0), respectively (р<0.05). The level of expression of progesterone receptors showed the similar pattern and also was significantly lower in tumor glands and stroma compared with normal tissue. Medians were 7.0 (6.0; 8.0) points for tumor glands and 8.0 (7.0; 8.0) points for normal proliferative endometrium (р<0.05). Medians of expression of progesterone receptors in stroma were 6.0 (4.0; 6.0) points for tumor and 7.0 (7.0; 7.0) for normal endometrial tissue (р<0.05). The distinctive feature of endometrial adenocarcinoma was significantly higher ratio of expression of estrogen receptors-alpha and progesterone receptors in tumor glands and stroma (medians were 1.17 and 1.33, respectively) compared with normal proliferative endometrium (medians for glands and stroma were the same and equaled 1.00). Also it was shown that levels of expression of Ki-67 (the median was 2.0 points), p53 (the median – 11.50%), p16 (the median – 57.08 CUOD) were statistically significantly higher and caspase 3 expression level was statistically significantly lower (the median – 48.54 CUOD) in cells of adenocarcinoma of endometrium compared with normal proliferative endometrium, where the medians for these markers were as follows: the median for Ki-67 was 1.0 point, p53 – 3.00%, p16 – 33.46 CUOD and caspase 3 – 65.02 CUOD. In the stromal component of tumor medians of expression of p16 and caspase 3 were 3.22 and 43.87 CUOD. This was statistically significantly lower than in normal endometrial tissue (the median for p16 – 10.33 CUOD and for caspase 3 – 53.50 CUOD, respectively).
Conclusions. Invasive endometrioid adenocarcinoma of the endometrium loses the sensitivity of tumor glandular and stromal cells to harmonizing regulatory signals of estrogen and progesterone in comparison with normal proliferative endometrium. Endometrioid adenocarcinoma has increased expression levels of p53 and p16, elevated level of proliferation and a reduced level of apoptosis of tumor cells compared to cells of normal endometrium.
References
Stewart, B. W., & Wild, Ch. P. (2014). World cancer report 2014: IARC. Geneva: WHO Press.
Ferlay, J., Soerjomataram, I., Dikshit, R., Eser, S., Mathers C., Rebelo, M., et al. (2015). Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. International Journal of Cancer, 136(5), 359–386. doi: 10.1002/ijc.29210.
Colombo, N., Creutzberg, C., Amant, F., Bosse, T., González-Martín, A., Ledermann, J., et al. (2016). ESMO-ESGO-ESTRO Consensus Conference on Endometrial Cancer. Diagnosis, Treatment and Follow-up. International Journal of Gynecologic Cancer, 26(1), 1–30. doi: 10.1097/IGC.0000000000000609.
Yutaka, Ueda, Takayuki, Enomoto, Toshihiro, Kimura, Takashi, Miyatake, Kiyoshi, Yoshino, Masami, Fujita, & Tadashi, Kimura. (2013). Syvorotochnye markery dlya rannego vyyavleniya ginekologicheskogo raka [Serological markers foe early detection of gynecological cancer]. Reproduktivnaya e´ndokrinologiya, 6(14), 73–80. [in Ukrainian].
Levchenko, N. E., Laktionov, K. P., Taipov, M. A., Titova, M. S., & Shevchenko, V. E. (2013). Molekulyarnye markery raka e´ndometriya (Obzor literatury) [Molecular markers of endometrial cancer (review of literature)]. Opukholi zhenskoj reproduktivnoj sistemy, 3–4, 86–89. [in Russian].
Engelsen, I. B., Akslen, L. A., & Salvesen, H. B. (2015). Biologic markers in endometrial cancer treatment. APMIS, 117(10), 693–707. doi: 10.1111/j.1600-0463.2009.02467.x.
Zidan, A. A., Hassan, A. A., Seadah, Sh. Sh. A., Ibrahim, E. H., & Attiah, S. M. (2015). Selected immunohistochemical prognostic factors in endometrial hyperplasia versus carcinoma. Journal of American Science, 11(4), 14–22.
Bender, D., Buekers, T., & Leslie, K.K. (2011). Hormone receptors and endometrial cancer. Proceedings in Obstetrics and Gynecology, 2(1), 1–25.
Makhina, E. V., Pichigina, A. K., Koldysheva, E. V., Molodykh, O. P., & Lushnikova, E. L. (2014). Diagnosticheskaya i prognosticheskaya znachimost' ocenki proliferativnoj aktivnosti kletochnykh populyacij e´ndometriya pri giperplasticheskikh i neoplasticheskikh processakh (obzor literatury) [Diagnostic and prognostic value of assessment of endometrial cell proliferative activity in hyperplastic and neoplastic processes (Review)]. Fundamental'nye issledovaniya, 10, 420–427. [in Russian].
Chernyshova, A. L., Kolomiec, L. A., Bochkareva, N. V.,& Krickaya, N. G. (2010). Immunogistokhimicheskie kriterii prognoza pri rake e´ndometriya (obzor literatury) [Immunohistochemichal prognostic kriterias in endometrial cancer (Review)]. Sibirskij onkologicheskij zhurnal, 1(37), 79–84. [in Russian].
Zakharceva, L. M., Vorob'eva, L. I., & Manzhura, E. P. (2001). Morfologicheskie i immunogistokhimicheskie kriterii prognoza pri rake e´ndometriya (Obzor literatury) [Morphological and immunohistochemichal prognostic kriterias in endometrial cancer (Review)]. Onkologiya,3(4), 252–256. [in Ukrainian].
Tumanskij, V. A., & Baudarbekova, M. M. (2009). Issledovanie receptorov e´strogenov i progesterona pri zhelezistoj giperplazii, atipichnoj giperplazii i adenokarcinome e´ndometriya [Research of the estrogen-receptors and progesterone-receptors in cases of simple hyperplasia, atypical hyperplasia and adenocarcinoma of endometrium]. Patologіia, 6(2), 111–113. [in Ukrainian].
Stanescu, A. D., Nistor, I., Poteca, A. G., Ditescu, D., & Comanescu, М. (2014). Prognostic biomarkers in endometrial adenocarcinoma. Romanian Journal of Morphology and Embryology, 55(4), 1339–1344.
Dabbs D. J. (Ed.) (2010). Diagnostic Immunohistochemistry. Philadelphia: Saunders/Elsevier.
Allred, D. C., Harvey, J. M., Berardo, M., & Clark, G. M. (1998). Prognostic and predictive factors in breast cancer by immunohistochemical analysis. Modern Pathology, 11, 155–168.
Risberg, B., Karlsson, K., Abeler, V., Lagrelius, A., Davidson, B., & Karlsson, M. G. (2002). Dissociated expression of Bcl-2 and Ki-67 in endometrial lesions: diagnostic and histogenetic implications. International Journal of Gynecological Pathology, 21(2), 155–160. doi: 10.1097/00004347-200204000-00008.
Buchynska, L. G., & Nesina, I. P. (2006). Expression of the cell cycle regulators p53, p21WAF1/CIP1 and p16INK4A in human endometrial adenocarcinoma. Experimental Oncology, 28(2), 152–155.
Tumanskyi, V. O., Yevsieiev, A. V., Kovalenko, I. S., Zubko, M. D., & Zaporizkyi derzhavnyi medychnyi universytet (patentee) (2015) Patent Ukrainy na korysnu model №99314 Ukrayina, MPK (2015) G01N 21/00, G06K 9/00. Sposib fototsyfrovoi morfometrii imunohistokhimichnykh preparativ №u 2014 14 103 [Ukraine patent for utility model №99314 Ukraine, IPC (2015) G01N 21/00, G06K 9/00. Method of photo digital morphometrical study of immunohistochemical micropreparations]. Biuleten, 10. [in Ukrainian].
Rasband, W. S., & Image J, U. S. (1997–2016). National Institutes of Health. Bethesda, Maryland. – Retrieved from http://imagej.nih.gov/ij/
Dvorakova, E., Chmelarova, M., Laco, J., & Spacek J. (2013). Methylation analysis of tumor suppressor genes in endometroid carcinoma of endometrium using MS-MLPA. Biomedical papers of the Medical Faculty of the University Palacky. Olomouc, Czechoslovakia, 157, 298–303.
Kreizman-Shefer, H., Pricop, J., Goldman, S., Elmalah, I., & Shalev, E. (2014). Distribution of estrogen and progesterone receptors isoforms in endometrial cancer. Diagnostic Pathology, 77, Retrieved from http://diagnosticpathology.biomedcentral.com/articles/10.1186/1746-1596-9-77. doi: 10.1186/1746-1596-9-77.
Baudarbekova, M. M. (2011). Osoblyvosti imunohistokhimichnoho profiliu invazyvnykh adenokartsynom endometriia [Features of immunohistochemical profile of invasive endometrial adenocarcinomas]. Patolohiia, 8(3), 62–64. [in Ukrainian].
Han, G., Sidhu, D., Duggan, M. A., Arseneau, J., Cesari, M., Clement, P. B., et al. (2013). Reproducibility of histological cell type in high-grade endometrial carcinoma. Modern Pathology, 26, 1594–1604. doi:10.1038/modpathol.2013.102.
Milde-Langosch, K., Bamberger, A. M., Goemann, C., Rössing, E., Rieck, G., Kelp, B., & Löning, T. (2001). Expression of cell-cycle regulatory proteins in endometrial carcinomas: correlations with hormone receptor status and clinicopathologic parameters. Journal of Cancer Research and Clinical Oncology, 127, 537–44. doi: 10.007/s004320100256.
Guo, Z. L., Guo, Z. L., Chen, K., Wang, X. Q., & Hu, W. (2011). Expression and relationship of Ezh2, Runx3 and caspase-3 in endometrial adenocarcinoma. Zhonghua Bing Li Xue Za Zhi, 40(6), 387–391.
Downloads
How to Cite
Issue
Section
License
Authors who publish with this journal agree to the following terms:- Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution License that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.
- Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgement of its initial publication in this journal.
- Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (SeeThe Effect of Open Access).
