Prognostic significance of the immunohistochemical status of the endometrium as markers of therapy for endometrial hyperplasia

Abstract

BACKGROUND: In patients of reproductive age with endometrial hyperplasia without atypia, hormonal treatment, and prognosis of response remain relevant issues.

AIM: To increase the effectiveness of hormonal therapy for endometrial hyperplasia in patients of reproductive age with abnormal uterine bleeding, considering the receptivity, and proliferative activity of the endometrium.

MATERIALS AND METHODS: A total of 179 patients of reproductive age with abnormal uterine bleeding and endometrial hyperplasia were examined. After the removal of the endometrial tissue, hormonal therapy was performed for 6 months: 101 patients received dydrogesterone 20 mg/day, and 78 patients received norethisterone acetate 10 mg/day. The expression levels of estrogen receptor-α (Erα), progesterone receptor (PR), and Ki67 in the endometrial tissue were determined by immunohistochemistry at baseline and 3 months after the treatment. The comparison group consisted of 18 women without gynecological pathology. Variation statistics methods were used to process the data, the differences between the indicators groups of patients were considered significant at p <0.05.

RESULTS: Before treatment, the expression levels of ERα, PR in both compartments, and Ki-67 in the glands were lower (p < 0.05) in the endometrial hyperplasia group than in the control group. Remission was achieved in 77 (76.24%) (dydrogesterone) and 62 (79.49%) (norethisterone acetate) patients. Initially, the expression level of ERα in the glands and stroma of endometrial hyperplasia was lower (p <0.05) than that in the comparison group; the resistant group had a lower (p <0.05) response to treatment. The expression of PR in the resistant group was lower (p <0.05) than that in the comparison group and remission group. The expression level of Ki67 in the response group was lower than that in the comparison group (p <0.05), and the expression in the stroma was lower than that in the resistant group (p <0.05). After treatment in both compartments, the expression levels of ERα and PR were lower in the resistant group than in the comparison group and response group (p <0.05). A logistic regression equation was obtained with a set of predictors: ERα (glands) + PR (glands and stroma) + Ki-67 (stroma) with a potential response to therapy of 93%.

CONCLUSIONS: The specified predictive model is promising. The therapy was effective in 93% of cases.

Keywords

endometrial hyperplasia / abnormal uterine bleeding / immunohistochemistry / estrogen receptors / progesterone receptors / dydrogesterone / norethisterone acetate

References

[1] Cree IA, White VA, Indave BI, Lokuhetty D. Revising the WHO classification: female genital tract tumours. Histopathology. 2020;76(1):151–156. doi: 10.1111/his.13977

[2] Cree I.A., White V.A., Indave B.I., Lokuhetty D. Revising the WHO classification: female genital tract tumours // Histopathology. 2020. Vol. 76, N 1. P. 151–156. doi: 10.1111/his.13977

[3] Dore M, Filoche S, Danielson K, Henry C. Efficacy of the LNG-IUS for treatment of endometrial hyperplasia and early stage endometrial cancer: can biomarkers predict response? Gynecol Oncol Rep. 2021;36:100732. doi: 10.1016/j.gore.2021.100732

[4] Dore M., Filoche S., Danielson K., Henry C. Efficacy of the LNG-IUS for treatment of endometrial hyperplasia and early stage endometrial cancer: can biomarkers predict response? // Gynecol Oncol Rep. 2021. Vol. 36. P. 100732. doi: 10.1016/j.gore.2021.100732

[5] Orazov MR, Mikhaleva LM, Orekhov RE, et. al. Prevention of endometrial hyperplasia in women of reproductive age. Gynecology, Obstetrics and Perinatology. 2022;21(1):101–106. (In Russ). doi: 10.20953/1726-1678-2022-1-101-106

[6] Оразов М.Р., Михалева Л.М., Орехов Р.Е., и др. Профилактика гиперплазий эндометрия в репродуктивном периоде // Вопросы гинекологии, акушерства и перинатологии. 2022. Т. 21, № 1. С. 101–106. doi: 10.20953/1726-1678-2022-1-101-106

[7] WHO classification of tumours. Female genital tumours, WHO classification of tumours, Vol. 4. 5th ed. Lyon: IARC Press; 2020.

[8] WHO classification of tumours. Female genital tumours, WHO classification of tumours. Vol. 4. 5th ed. Lyon : IARC Press, 2020.

[9] Chernukha GE, Ivanov IA, Efendieva ZN, et al. Etiological structure and diagnosis of abnormal uterine bleeding. Gynecology. 2018;20(2):14–18. (In Russ). doi: 10.26442/2079-5696_2018.2.14-18

[10] Чернуха Г.Е., Иванов И.А., Эфендиева З.Н., и др. Этиологическая структура и возможности диагностики аномального маточного кровотечения // Гинекология. 2018. Т. 20, № 2. С. 14–18. doi: 10.26442/2079-5696_2018.2.14-18

[11] Lacey JV Jr, Sherman ME, Rush BB, et al. Absolute risk of endometrial carcinoma during 20-year follow-up among women with endometrial hyperplasia. J Clin Oncol. 2010;28(5):788–792. doi: 10.1200/JCO.2009.24.1315

[12] Lacey J.V. Jr, Sherman M.E., Rush B.B., et al. Absolute risk of endometrial carcinoma during 20-year follow-up among women with endometrial hyperplasia // J Clin Oncol. 2010. Vol. 28, N 5. P. 788–792. doi: 10.1200/JCO.2009.24.1315

[13] Chandra V, Kim JJ, Benbrook DM, et. al. Therapeutic options for management of endometrial hyperplasia. J Gynecol Oncol. 2016;27(1):e8. doi: 10.3802/jgo.2016.27.e8

[14] Chandra V., Kim J.J., Benbrook D.M., et al. Therapeutic options for management of endometrial hyperplasia // J Gynecol Oncol. 2016. Vol. 27, N 1. P. e8. doi: 10.3802/jgo.2016.27.e8

[15] Nooh AM, Abdeldayem HM, Girbash EF, et al. Depo-provera versus norethisterone acetate in management of endometrial hyperplasia without atypia. Reprod Sci. 2016;23(4):448–454. doi: 10.1177/1933719115623643

[16] Nooh A.M., Abdeldayem H.M., Girbash E.F., et al. Depo-provera versus norethisterone acetate in management of endometrial hyperplasia without atypia // Reprod Sci. 2016. Vol. 23, N 4. P. 448–454. doi: 10.1177/1933719115623643

[17] Nees LK, Heublein S, Steinmacher S, et al. Endometrial hyperplasia as a risk factor of endometrial cancer. Arch Gynecol Obstet. 2022;306(2):407–421. doi: 10.1007/s00404-021-06380-5

[18] Nees L.K., Heublein S., Steinmacher S., et al. Endometrial hyperplasia as a risk factor of endometrial cancer // Arch Gynecol Obstet. 2022. Vol. 306, N 2. P. 407–421. doi: 10.1007/s00404-021-06380-5

[19] Kappusheva LM, Mikhaleva LM, Golukhov GN, et al. Immunohistochemical evaluation of the efficacy of therapy in female patients of reproductive age with ab-normal uterine bleeding and endometrial hyperplasia. Gynecology, Obstetrics and Perinatology. 2022;21:2:18–24. (In Russ). doi: 10.17116/rosakush20222205122

[20] Каппушева Л.М., Михалёва Л.М., Голухов Г.Н., и др. Иммуногистохимическая оценка эффективности терапии прогестинами пациенток репродуктивного возраста с аномальными маточными кровотечениями и гиперплазией эндометрия без атипии // Вопросы гинекологии, акушерства и перинатологии. 2022. Т. 21, № 2. С. 18–24. doi: 10.20953/1726-1678-2022-2-18-24

[21] Lin CY, Wu RC, Yang LY, et. al. MicroRNAs as predictors of future uterine malignancy in endometrial hyperplasia without atypia. J Pers Med. 2022;12:311. doi: 10.3390/jpm12020311

[22] Lin C.Y., Wu R.C., Yang L.Y., et al. MicroRNAs as predictors of future uterine malignancy in endometrial hyperplasia without atypia // J Pers Med. 2022. Vol. 12. P. 311. doi: 10.3390/jpm12020311

[23] Ponomarenko IV, Verzilina IN, Sorokina IN, et al. Polymorphism rs222003 of GC gene as a predictor of endometrial hyperplasia. Gynecology, Obstetrics and Perinatology. 2019;18(6):28–33. (In Russ). doi: 10.20953/1726-1678-2019-6-28-33

[24] Пономаренко И.В., Верзилина И.Н., Сорокина И.Н., и др. Полиморфизм rs222003 гена GC как предиктор развития гиперплазии эндометрия // Вопросы гинекологии, акушерства и перинатологии. 2019. Vol. 18, N 6. P. 28–33. doi: 10.20953/1726-1678-2019-6-28-33

[25] Hutt S, Tailor A, Ellis P, et al. The role of biomarkers in endometrial cancer and hyperplasia: a literature review. Acta Oncol. 2019;58(3):342–352. doi: 10.1080/0284186X.2018.1540886

[26] Hutt S., Tailor A., Ellis P., et al. The role of biomarkers in endometrial cancer and hyperplasia: a literature review // Acta Oncol. 2019. Vol. 58, N 3. P. 342–352. doi: 10.1080/0284186X.2018.1540886

[27] Savelyeva GM, Breusenko VG, Kareva EN, et al. Investigation of the role of estrogen receptor and progesterone receptor gene expressions in the occurrence of endometrial proliferative processes to address the issue of management tactics for patients with these pathological changes in the endometrium. Russian Bulletin of Obstetrician-Gynecologist. 2018;18(6):1724. (In Russ). doi: 10.17116/rosakush20181806117

[28] Савельева Г.М., Бреусенко В.Г., Карева Е.Н., и др. Изучение роли экспрессии генов рецепторов эстрогенов и прогестерона в возникновении пролиферативных процессов в эндометрии для решения вопроса о тактике ведения больных с указанными патологическими изменениями эндометрия // Российский вестник акушера-гинеколога. 2018. Т. 18, № 6. С. 17–24. doi: 10.17116/rosakush20181806117

[29] Miкhaleva LM, Patsap OI, Bezuglova TV, et al. Novel clinical and morphological predictors of malignancy in patients with ovarian endometrioid cysts. Clinical and Experimental Morphology. 2021;10(1):21–32. (In Russ). doi: 10.31088/CEM2021.10.1.21-32

[30] Михалева Л.М., Пацап О.И., Безуглова Т.В., и др. Новые клинико-морфологические предикторы неопластической трансформации у пациенток с эндометриоидными кистами яичников // Клиническая и экспериментальная морфология. 2021. Т. 10, № 1. С. 21–32. doi: 10.31088/CEM2021.10.1.21-32

[31] Neal AS, Nunez M, Lai T, et al. Expression of stromal progesterone receptor and differential methylation patterns in the endometrium may correlate with response to progesterone therapy in endometrial complex atypical hyperplasia. Reprod Sci. 2020;27(9):1778–1790. doi: 10.1007/s43032-020-00175-w

[32] Neal A.S., Nunez M., Lai T., et al. Expression of stromal progesterone receptor and differential methylation patterns in the endometrium may correlate with response to progesterone therapy in endometrial complex atypical hyperplasia // Reprod Sci. 2020. Vol. 27, N 9. P. 1778–1790. doi: 10.1007/s43032-020-00175-w

[33] Mikhaleva LM, Solomatina AA, Kurtser MA, et al. Immunohistochemical phenotype of recurrent ovarian endometriomas. Clinical and Experimental Morphology. 2017;4(24):15–21. (In Russ).

[34] Михалева Л.М., Соломатина А.А., Курцер М.А., и др. Иммуногистохимический фенотип рецидивирующих эндометриоидных образований яичников // Клиническая и экспериментальная морфология. 2017. № 4. С. 15–21.

[35] Kreizman-Shefer H, Pricop J, Goldman S, et al. Distribution of estrogen and progesterone receptors isoforms in endometrial cancer. Diagn Pathol. 2014;9:77. doi: 10.1186/1746-1596-9-77

[36] Kreizman-Shefer H., Pricop J., Goldman S., et. al. Distribution of estrogen and progesterone receptors isoforms in endometrial cancer // Diagn Pathol. 2014. Vol. 9. P. 77. doi: 10.1186/1746-1596-9-77

[37] Raffone A, Travaglino A, Saccone G, et al. Should progesterone and estrogen receptors be assessed for predicting the response to conservative treatment of endometrial hyperplasia and cancer? A systematic review and meta-analysis. Acta Obstet Gynecol Scand. 2019;98(8):976–987. doi: 10.1111/aogs.13586

[38] Raffone A., Travaglino A., Saccone G., et al. Should progesterone and estrogen receptors be assessed for predicting the response to conservative treatment of endometrial hyperplasia and cancer? A systematic review and meta-analysis // Acta Obstet Gynecol Scand. 2019. Vol. 98, N 8. P. 976–987. doi: 10.1111/aogs.13586

[39] Unanjan AL, Sidorova IS, Kogan EA, Baburin DV. Clinico-pathogenetic features of hyperplastic endometrial processes in women of perimenopausal age. RMJ. Medical Review. 2018;1(I):67–71. (In Russ).

[40] Унанян А.Л., Сидорова И.С., Коган Е.А., Д.В. Бабурин. Клинико-патогенетические особенности гиперпластических процессов эндометрия у женщин перименопаузального возраста // РМЖ «Медицинское обозрение». 2018. № I. С. 67–71.

RIGHTS & PERMISSIONS

Mikhaleva L.M., Kappusheva L.M., Golukhov G.N., Shcherbatyuk K.V., Gutorova D.S., Ovchinnikova A.V., Baisova B.I., Breusenko V.G