Mismatch repair status in endometrial cancer: detection with immunohistochemical markers and its relationship with clinical outcome

Background: Over the past decade, molecular classification in endometrial cancer has provided valuable insights into its pathogenesis, prognosis, and implications for adjuvant therapy. However, the prognostic impact of mismatch repair deficiency in endometrioid endometrial cancer (EEC) remains uncertain. The goal of this study is to determine the clinicopathological significance of mismatch repair (MMR) protein defects in EEC. Methods: A total of 100 patients diagnosed with EEC between 2002 and 2017 were retrospectively reviewed. Immunohistochemical analysis was performed to assess the expression of MMR proteins, including MutL Homolog 1 (MLH1), MutS Homolog 2 (MSH-2), MutS Homolog 6 (MSH-6), and PostMeiotic Segregation increased 2 (PMS-2). Associations between MMR status, clinicopathologic features, and survival outcomes were analyzed. Results: Twenty-nine samples (29%) had at least one loss of MMR protein expression which was categorized as MMR-deficient. There was a significant relation of lymphovascular space invasion (LVSI) in MMR-deficient (MMRd) group compared to MMR-proficient group (MMRp) (55.2% vs. 28.2%, p = 0.020). However, MMRd tumors were not associated with recurrence, lymph node involvement, administration of adjuvant therapy, overall and progression-free survival. Conclusions: MMR-deficient tumors were more frequently associated with lymphovascular space invasion. The marked association suggests a potentially more aggressive clinical phenotype, despite the absence of significant differences in survival outcomes in this cohort. Further prospective, multi-institutional studies are warranted to clarify the prognostic and therapeutic implications of MMR status in EEC.

Endometrioid cancer; Mismatch repair; Immunohistochemistry; Survival; Prognostic factors

[1] Huang Z, Li X, Li L. Early recurrence after surgery in FIGO 2023 stage I–III endometrial cancer: characteristics and risk factors. Frontiers in Oncology. 2025; 14: 1500658.
[2] Crosbie EJ, Kitson SJ, McAlpine JN, Mukhopadhyay A, Powell ME, Singh N. Endometrial cancer. The Lancet. 2022; 399: 1412–1428.
[3] Jia P, Zhang Y. Molecular classification and adjuvant treatment in endometrioid endometrial cancer with microcystic elongated and fragmented (MELF) invasion pattern. BMC Women’s Health. 2024; 24: 607.
[4] Altın D, Akıncı T, Taşkın S, Ortaç F. Predictors of recurrence and survival in lymphovascular space invasion negative early-stage endometrioid endometrial cancer patients. Journal of the Turkish-German Gynecological Association. 2023; 24: 261–270.
[5] Dou Y, Song K, Fu Y, Shen Y, Zhang C, Yao S, et al.; Chinese Endometrial Carcinoma Consortium (CECC). Risk factors and prognosis of early recurrence in stage I–II endometrial cancer: a large-scale, multi-center, and retrospective study. Frontiers in Medicine. 2022; 9: 808037.
[6] Chen JR, Chang TC, Fu HC, Lau HY, Chen IH, Ke YM, et al. Outcomes of patients with surgically and pathologically staged IIIA–IVB pure endometrioid-type endometrial cancer: a Taiwanese Gynecology Oncology Group (TGOG-2005) retrospective cohort study (a STROBE-compliant article). Medicine. 2016; 95: e3330.
[7] Mitric C, Bernardini MQ. Endometrial cancer: transitioning from histology to genomics. Current Oncology. 2022; 29: 741–757.
[8] de Biase D, Maloberti T, Corradini AG, Rosini F, Grillini M, Ruscelli M, et al. Integrated clinicopathologic and molecular analysis of endometrial carcinoma: prognostic impact of the new ESGO-ESTRO-ESP endometrial cancer risk classification and proposal of histopathologic algorithm for its implementation in clinical practice. Frontiers in Medicine. 2023; 10: 1146499.
[9] Keverline KJ, Hill B, Hom-Tedla M, Jacobs M, Eskander RN. Impact of mismatch repair (MMR) status on recurrence in high intermediate risk endometrial cancer. Gynecologic Oncology. 2025; 197: 116–120.
[10] Salvesen HB, Haldorsen I, Trovic J. Markers for individualised therapy in endometrial carcinoma. The Lancet Oncology. 2012; 13: e353–e361.
[11] Liu J, Zheng Y, Liu J. Fertility preservation and assisted reproductive strategies in endometrial cancer patients with lynch syndrome. Frontiers in Oncology. 2025; 15: 1630301.
[12] Yamaguchi M, Akabane S, Niitsu H, Nakahara H, Toshida A, Mochizuki T, et al. The usefulness of comprehensive genome profiling test in screening of Lynch syndrome independent of the conventional clinical screening or microsatellite instability tests. Journal of Human Genetics. 2025; 70: 385–393.
[13] National Comprehensive Cancer Network® (NCCN®). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Version 3.2025. 2025. Available at: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1473 (Accessed: 04 October 2025).
[14] Riedinger CJ, Esnakula A, Haight PJ, Suarez AA, Chen W, Gillespie J, et al. Characterization of mismatch-repair/microsatellite instability-discordant endometrial cancer. Cancer. 2024; 130: 385–399.
[15] Chaowiwatkun K, Trongwongsa T, Rodpenpear N, Nutthachote P. Comparison of tissue mismatch repair protein deficiency between early- and advanced-stage endometrial cancer. Asian Pacific Journal of Cancer Prevention. 2023; 24: 345–351.
[16] Concin N, Matias-Guiu X, Cibula D, Colombo N, Creutzberg CL, Ledermann J, et al. ESGO-ESTRO-ESP guidelines for the management of patients with endometrial carcinoma: update 2025. The Lancet Oncology. 2025; 26: e423–e435.
[17] Kim M, So KA, Chun Y, Kim YH, Lim KT, Lee KH, et al. Clinicopathologic significance of mismatch repair protein expression in endometrioid endometrial cancer. Taiwanese Journal of Obstetrics and Gynecology. 2023; 62: 724–728.
[18] Angelina YA, Tjokroprawiro BA, Sandhika W. Mismatch repair protein deficiency does not affect disease free survival in type I endometrial carcinoma. Asian Pacific Journal of Cancer Prevention. 2023; 24: 3229–3234.
[19] Diaz-Padilla I, Romero N, Amir E, Matias-Guiu X, Vilar E, Muggia F, et al. Mismatch repair status and clinical outcomes in endometrial cancer: a systematic review and meta-analysis. Critical Reviews in Oncology/Hematology. 2013; 88: 154–167.
[20] McMeekin DS, Tritchler DL, Cohn DE, Mutch DG, Lankes HA, Geller MA, et al. Clinicopathologic significance of mismatch repair defects in endometrial cancer: an NRG Oncology/Gynecologic Oncology group study. Journal of Clinical Oncology. 2016; 34: 3062–3068.
[21] Zighelboim I, Goodfellow PJ, Gao F, Gibb RK, Powell MA, Rader JS, et al. Microsatellite instability and epigenetic inactivation of MLH1 and outcomes of patients with endometrial carcinomas of the endometrioid type. Journal of Clinical Oncology. 2007; 25: 2042–2048.
[22] Creasman W. Revised FIGO staging for carcinoma of the endometrium. International Journal of Gynecology and Obstetrics. 2009; 105: 109.
[23] Aytekin O, Cesur N, Gözel S, Karslı SE, Tokalıoğlu AA, Kılıç F, et al. Mismatch repair protein deficiency and its relationship with clinicopathological factors in endometrial cancer: a retrospective study. Journal of Cancer. 2025; 16: 2778–2786.
[24] Terada KY, Black M, Terada LH, Davis J, Shimizu DM. Survival of endometrial cancer patients with lymphatic invasion and deficient mismatch repair expression. Gynecologic Oncology. 2013; 129: 188–192.
[25] Dagher C, Trent PB, Alwaqfi R, Davidson B, Ellenson L, Zhou QC, et al. Oncologic outcomes based on lymphovascular space invasion in node-negative FIGO 2009 stage I endometrioid endometrial adenocarcinoma: a multicenter retrospective cohort study. International Journal of Gynecological Cancer. 2024; 34: 1485–1492.
[26] Shiozawa T, Konishi I. Early endometrial carcinoma: clinicopathology, hormonal aspects, molecular genetics, diagnosis, and treatment. International Journal of Clinical Oncology. 2006; 11: 13–21.
[27] Sowter P, Gallon R, Hayes C, Phelps R, Borthwick G, Prior S, et al. Detection of mismatch repair deficiency in endometrial cancer: assessment of IHC, fragment length analysis, and amplicon sequencing based MSI testing. Cancers. 2024; 16: 3970.
[28] Cosgrove CM, Tritchler DL, Cohn DE, Mutch DG, Rush CM, Lankes HA, et al. An NRG Oncology/GOG study of molecular classification for risk prediction in endometrioid endometrial cancer. Gynecologic Oncology. 2018; 148: 174–180.
[29] Raffone A, Travaglino A, Mascolo M, Carotenuto C, Guida M, Mollo A, et al. Histopathological characterization of ProMisE molecular groups of endometrial cancer. Gynecologic Oncology. 2020; 157: 252–259.
[30] Pina A, Wolber R, McAlpine JN, Gilks B, Kwon JS. Endometrial cancer presentation and outcomes based on mismatch repair protein expression from a population-based study. International Journal of Gynecological Cancer. 2018; 28: 1624–1630.
[31] Kim J, Kong JK, Yang W, Cho H, Chay DB, Lee BH, et al. DNA mismatch repair protein immunohistochemistry and MLH1 promotor methylation testing for practical molecular classification and the prediction of prognosis in endometrial cancer. Cancers. 2018; 10: 279.
[32] Li JY, Park HS, Huang GS, Young MR, Ratner E, Santin A, et al. Prognostic impact of mismatch repair deficiency in high- and low-intermediate-risk, early-stage endometrial cancer following vaginal brachytherapy. Gynecologic Oncology. 2021; 163: 557–562.
[33] Cosgrove CM, Cohn DE, Hampel H, Frankel WL, Jones D, McElroy JP, et al. Epigenetic silencing of MLH1 in endometrial cancers is associated with larger tumor volume, increased rate of lymph node positivity and reduced recurrence-free survival. Gynecologic Oncology. 2017; 146: 588–595.
[34] Kim J, Kwon B, Kim H, Suh DH, Kim K, Kim YB, et al. Clinicopathologic significance of DNA mismatch repair protein status in endometrial cancer. Taiwanese Journal of Obstetrics and Gynecology. 2022; 61: 415–421.
[35] Lee JHS, Li JJX, Chow C, Chan RCK, Kwan JSH, Lau TS, et al. Long-term survival and clinicopathological implications of DNA mismatch repair status in endometrioid endometrial cancers in Hong Kong Chinese women. Biomedicines. 2021; 9: 1385.
[36] Ruiz I, Martin-Arutti M, Lopez-Lopez E, Garcia-Orad A. Lack of association between deficient mismatch repair expression and outcome in endometrial carcinomas of the endometrioid type. Gynecologic Oncology. 2014; 134: 20–23.
[37] Black D, Soslow RA, Levine DA, Tornos C, Chen SC, Hummer AJ, et al. Clinicopathologic significance of defective DNA mismatch repair in endometrial carcinoma. Journal of Clinical Oncology. 2006; 24: 1745–1753.
[38] Arabi H, Guan H, Kumar S, Cote M, Bandyopadhyay S, Bryant C, et al. Impact of microsatellite instability (MSI) on survival in high grade endometrial carcinoma. Gynecologic Oncology. 2009; 113: 153–158.
[39] Kanopienė D, Smailytė G, Vidugirienė J, Bacher J. Impact of microsatellite instability on survival of endometrial cancer patients. Medicina. 2014; 50: 216–221.
[40] Kato M, Takano M, Miyamoto M, Sasaki N, Goto T, Tsuda H, et al. DNA mismatch repair-related protein loss as a prognostic factor in endometrial cancers. Journal of Gynecologic Oncology. 2015; 26: 40–45.