Association of PTEN and ARID1A Expression in Patients with Atypical Endometrial Hyperplasia and Concurrent Endometrioid Carcinoma: A Retrospective Cohort Study
DOI:
https://doi.org/10.31584/psumj.2025275748Keywords:
ARID1A, atypical endometrial hyperplasia, endometrioid carcinoma, immunohistochemistry, PTENAbstract
Objective: Some endometrial biopsies from patients with atypical hyperplasia/endometrial intraepithelial neoplasia (AH/EIN) show concurrent endometrioid carcinoma (EC). Hysterectomy is the standard treatment for AH/EIN; however, hormonal therapy is also acceptable for women who wish to preserve fertility. Few studies have simultaneously evaluated the expressions of PTEN and ARID1A in endometrial biopsies to predict concurrent EC. This study aim evaluated whether the loss of PTEN and ARID1A expressions in endometrial biopsies indicate the presence of concurrent EC.
Material and Methods: Endometrial biopsies from 46 patients with AH/EIN who underwent hysterectomy within 3 months between 2011 and 2021 were reviewed. Loss of or intact PTEN and ARID1A expressions was evaluated using immunohistochemistry. The presence or absence of EC in the hysterectomy specimen indicated the presence or absence of concurrent EC. Logistic regression analysis was used to determine associations.
Results: Concurrent EC was found in 32.6% (15/46) of the patients. Loss of PTEN and ARID1A was observed in 54.3% and 8.7% of the endometrial biopsies, respectively. Endometrial biopsies with loss of PTEN expression had an insignificantly higher prevalence of concurrent EC than those with intact PTEN expression (44% versus [vs.] 19%, p-value=0.107). Loss and intact ARID1A expressions showed no difference in the prevalence of concurrent EC (25% vs. 33.3%, p-value=1). Multivariate analysis showed loss of PTEN tended to be associated with concurrent EC (odd ratio [OR]=2.38, 95% CI 0.52–10.96), while loss of ARIDA showed no evidence of association (OR=0.92, 95% CI=0.07–12.97).
Conclusion: One-third of the endometrial biopsies with AH/EIN have concurrent EC. The loss of PTEN expression in AH/EIN may indicate the presence of concurrent cancer. However, further studies with larger sample sizes are needed to confirm the results.
References
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021;71:209-49. doi: 10.3322/caac.21660.
Lortet-Tieulent J, Ferlay J, Bray F, Jemal A. International Patterns and Trends in Endometrial Cancer Incidence, 19782013. J Natl Cancer Inst 2018;110:354-61. doi: 10.1093/jnci/djx214.
Sorosky JI. Endometrial Cancer. Obstet Gynecol 2012;120(2 Part 1):383-97. doi: 10.1097/AOG.0b013e3182605bf1.
Trimble CL, Method M, Leitao M, Lu K, Loffe O, Hampton M, et al. Management of endometrial precancers. Obstet Gynecol 2012;120:1160-75. doi: 10.1097/aog.0b013e31826bb121.
Ordi J, Bergeron C, Hardisson D, McCluggage WG, Hollema H, Felix A, et al. Reproducibility of current classifications of endometrial endometrioid glandular proliferations: further evidence supporting a simplified classification. Histopathology 2014;64:284-92. doi: 10.1111/his.12249.
Sakna NA, Elgendi M, Salama MH, Zeinhom A, Labib S, Nabhan AF. Diagnostic accuracy of endometrial sampling tests for detecting endometrial cancer: a systematic review and meta-analysis. BMJ Open 2023;13:e072124. doi: 10.1136/bmjopen-2023-072124.
Trimble CL, Kauderer J, Zaino R, Silverberg S, Lim PC, Burke JJ, et al. Concurrent endometrial carcinoma in women with a biopsy diagnosis of atypical endometrial hyperplasia: a Gynecologic Oncology Group study. Cancer 2006;106:812-9. doi: 10.1002/cncr.21650.
Rakha E, Wong SC, Soomro I, Chaudry Z, Sharma A, Deen S, et al. Clinical outcome of atypical endometrial hyperplasia diagnosed on an endometrial biopsy: institutional experience and review of literature. Am J Surg Pathol 2012;36:1683-90. doi: 10.1097/PAS.0b013e31825dd4ff.
Wang Y, Yu M, Yang JX, Cao DY, Zhang Y, Zhou HM, et al. Genomic comparison of endometrioid endometrial carcinoma and its precancerous lesions in Chinese patients by high-depth next generation sequencing. Front Oncol 2019;9. doi: 10.3389/fonc.2019.00123.
Li L, Yue P, Song Q, Yen TT, Asaka S, Wang TL, et al. Genome-wide mutation analysis in precancerous lesions of endometrial carcinoma. J Pathol 2021;253:119-28. doi: 10.1002/path.5566.
Chalhoub N, Baker SJ. PTEN and the PI3-kinase pathway in cancer. Annu Rev Pathol 2009;4:127-50. doi: 10.1146/annurev.pathol.4.110807.092311.
Toumpeki C, Liberis A, Tsirkas I, Tsirka T, Kalagasidou S, Inagamova L, et al. The role of ARID1A in endometrial cancer and the molecular pathways associated with pathogenesis and cancer progression. In Vivo 2019;33:659-67. doi: 10.21873/invivo.11524.
Zhang HM, Fan TT, Li W, Li XX. Expressions and significances of TTF-1 and PTEN in early endometrial cancer. Eur Rev Med Pharmacol Sci 2017;21(3 Suppl):20-6.
Mao TL, Ardighieri L, Ayhan A, Kuo KT, Wu CH, Wang TL, et al. Loss of ARID1A expression correlates with stages of tumor progression in uterine endometrioid carcinoma. Am J Surg Pathol 2013;37:1342-8. doi: 10.1097/PAS.0b013e3182889dc3.
Ayhan A, Mao TL, Suryo Rahmanto Y, Zeppernick F, Ogawa H, Wu RC, et al. Increased proliferation in atypical hyperplasia/ endometrioid intraepithelial neoplasia of the endometrium with concurrent inactivation of ARID1A and PTEN tumour suppressors. J Pathol Clin Res 2015;1:186-93. doi: 10.1002/cjp2.22.
Yen TT, Miyamoto T, Asaka S, Chui MH, Wang Y, Lin SF, et al. Loss of ARID1A expression in endometrial samplings is associated with the risk of endometrial carcinoma. Gynecol Oncol 2018;150:426-31. doi: 10.1016/j.ygyno.2018.06.025.
Pavlakis K, Messini I, Vrekoussis T, Panoskaltsis T, Chrissanthakis D, Yiannou P, et al. PTEN-loss and nuclear atypia of EIN in endometrial biopsies can predict the existence of a concurrent endometrial carcinoma. Gynecol Oncol 2010;119:516-9. doi: 10.1016/j.ygyno.2010.08.023.
Robbe EJM, van Kuijk SMJ, de Boed EM, Smits LJM, van der Wurff AAM, Kruitwagen RFPM, et al. Predicting the coexistence of an endometrial adenocarcinoma in the presence of atypical complex hyperplasia: immunohistochemical analysis of endometrial samples. Int J Gynecol Cancer 2012;22:1264-72. doi: 10.1097/IGC.0b013e31826302a3.
Vierkoetter K, Wong J, Ahn HJ, Shimizu D, Kagami L, Terada K. Using gene expression in patients with endometrial intraepithelial neoplasia to assess the risk of cancer. Gynecol Oncol Rep 2018;24:24-6. doi: 10.1016/j.gore.2018.02.006.
Raffone A, Travaglino A, Saccone G, Cieri M, Mascolo M, Mollo A, et al. Diagnostic and prognostic value of ARID1A in endometrial hyperplasia: a novel marker of occult cancer. APMIS 2019;127:597-606. doi: 10.1111/apm.12977.
Raffone A, Travaglino A, Saccone G, Viggiani M, Giampaolino P, Insabato L, et al. PTEN expression in endometrial hyperplasia and risk of cancer: a systematic review and meta-analysis. Arch Gynecol Obstet 2019;299:1511-24. doi: 10.1007/s00404019-05123-x.
Emons G, Beckmann MW, Schmidt D, Mallmann P. New WHO classification of endometrial hyperplasias. Geburtshilfe Frauenheilkd 2015;75:135-6. doi: 10.1055/s-0034-1396256.
World Health Organization. Female Genital Tumours [homepage on the Internet] Geneva; WHO: 2020 [cited 2023 Mar 11] Available from: https://publications.iarc.fr/Book-And-ReportSeries/Who-Classification-Of-Tumours/Female-GenitalTumours-2020
Gbelcová H, Bakeš P, Priščáková P, Šišovský V, Hojsíková I, Straka L, et al. PTEN Sequence analysis in endometrial hyperplasia and endometrial carcinoma in slovak women. Anal Cell Pathol (Amst) 2015;2015:746856. doi: 10.1155/2015/746856.
Wang L, Piskorz A, Bosse T, Jimenez-Linan M, Rous B, Gilks CB, et al. Immunohistochemistry and next-generation sequencing are complementary tests in identifying PTEN abnormality in endometrial carcinoma biopsies. Int J Gynecol Pathol 2022;41:12-9. doi: 10.1097/PGP.0000000000000763.
Aguilar M, Chen H, Rivera-Colon G, Niu H, Carrick K, Gwin K, et al. Reliable identification of endometrial precancers through combined Pax2, β-Catenin, and Pten Immunohistochemistry. Am J Surg Pathol 2022;46:404-14. doi: 10.1097/PAS.0000000000001810.
Berg A, Hoivik EA, Mjøs S, Holst F, Werner HMJ, Tangen IL, et al. Molecular profiling of endometrial carcinoma precursor, primary and metastatic lesions suggests different targets for treatment in obese compared to non-obese patients. Oncotarget 2015;6:1327-39. doi: 10.18632/oncotarget.2675.
Takeda T, Banno K, Okawa R, Yanokura M, Iijima M, IrieKunitomi H, et al. ARID1A gene mutation in ovarian and endometrial cancers (Review). Oncol Rep 2016;35:607-13. doi: 10.3892/or.2015.4421.
Wiegand KC, Shah SP, Al-Agha OM, Zhao Y, Tse K, Zeng T, et al. ARID1A mutations in endometriosis-associated ovarian carcinomas. N Engl J Med 2010;363:1532-43. doi: 10.1056/NEJMoa1008433.
Guan B, Mao TL, Panuganti PK, Kuhn E, Kurman RJ, Maeda D, et al. Mutation and loss of expression of ARID1A in uterine low-grade endometrioid carcinoma. Am J Surg Pathol 2011;35:625-32. doi: 10.1097/PAS.0b013e318212782a.
D’Angelo E, Espinosa I, Cipriani V, Szafranska J, Barbareschi M, Prat J. Atypical endometrial hyperplasia, low-grade: “Much ADO about nothing.” Am J Surg Pathol 2021;45:988-96. doi: 10.1097/PAS.0000000000001705.
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