Clinically relevant histopathological features and biomarkers in endometrial cancer

Czech version

Authors: B. Sehnal ¹; J. Drozenová ²; L. Vaněk ¹; M. O. Ndukwe ³; M. J. Halaška ¹; M. Hruda ¹; L. Rob ¹; R. Matěj ^2,4
Authors‘ workplace: Gynekologicko-porodnická klinika 3. LF UK a FNKV, Praha ¹; Ústav patologie, 3. LF UK a FNKV, Praha ²; Porodnická a gynekologická klinika LF UK a FN Hradec Králové ³; Ústav patologie a molekulární medicíny, 3. LF UK a FTN, Praha ⁴
Published in: Ceska Gynekol 2026; 91(2): 131-141
Category:
doi: https://doi.org/10.48095/cccg2026131

Overview

Objective: To provide an overview of the most important histopathological characteristics and biomarkers of endometrial carcinoma that have clinical relevance for prognosis, prediction of treatment response, and decision-making regarding adjuvant therapy. Methods and results: Endometrial carcinoma represents the most common malignancy of the female reproductive tract in developed countries. Disease prognosis is determined not only by the anatomical extent, but also by a number of non-anatomical factors. The histological tumour type, presence of lymphovascular space invasion, and specific patterns of myometrial invasion (such as the MELF pattern) play major roles. Current molecular classification divides endometrial carcinomas into four groups (POLEmut, MMRd, NSMP, and TP53mut), which differ in prognosis as well as in therapeutic response. Additional clinically applicable biomarkers include oestrogen and progesterone receptors, L1CAM, HER2, CA125, and HE4. Emerging research focuses on novel biomarkers such as TROP2, circulating tumour DNA (ctDNA), circular RNA (circRNA), tumour -⁠ -infiltrating lymphocytes (TILs), and folate receptor alpha (FRa). These markers enable more precise risk stratification and identification of patients suitable for targeted therapies. Integration of multiple biomarkers with clinicopathological parameters further enhances the accuracy of risk assessment and prediction of treatment response. Conclusion: Incorporating histopathological features and biomarkers into routine clinical practice allows for a more accurate estimation of prognosis and a more rational selection of adjuvant therapy. An increasing number of non-anatomical biomarkers are becoming an integral part of the decision-making algorithm in endometrial carcinoma management.

Keywords:

Prognosis – histopathology – biomarkers – targeted therapy – Endometrial carcinoma – molecular classification

Sources

1. Sung H, Ferlay J, Siegel RL 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 (3): 209–249. doi: 10.3322/caac.21660.

2. Bray F, Laversanne M, Sung H et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2024; 74 (3): 229–263. doi: 10.3322/caac.21834.

3. Svod.cz. Český národní webový portál epidemiologie nádorů. Systém pro vizualizaci onkologických dat. Institut biostatistiky a analýz Lékařské a Přírodovědecké fakulty Masarykovy univerzity (IBA MU). 2026 [online]. Dostupné z: http: //www.svod.cz.

4. Concin N, Matias-Guiu X, Vergote I et al. ESGO/ESTRO/ESP guidelines for the management of patients with endometrial carcinoma. Radiother Oncol 2021; 154 : 327–353. doi: 10.1016/j.radonc.2020.11.018.

5. Concin N, Matias-Guiu X, Cibula D et al. ESGO--ESTRO-ESP guidelines for the management of patients with endometrial carcinoma: update 2025. Lancet Oncol 2025; 26 (8): e423–e435. doi: 10.1016/S1470-2045 (25) 00167-6.

6. Berek JS, Matias-Guiu X, Creutzberg C et al. FIGO staging of endometrial cancer: 2023. Int J Gynaecol Obstet 2023; 162 (2): 383–394. doi: 10.1002/ijgo.14923.

7. Hruda M, Sehnal B, Halaška MJ et al. Nový staging karcinomu endometria –⁠ FIGO 2023. Ceska Gynekol 2024; 89 (2): 120–127. doi: 10.48095/cccg2024120.

8. Włodarczyk K, Kuryło W, Pawłowska-Łachut A et al. circRNAs in endometrial cancer –⁠ a promising biomarker: state of the art. Int J Mol Sci 2024; 25 (12): 6387. doi: 10.3390/ijms25126387.

9. Bokhman JV. Two pathogenetic types of endometrial carcinoma. Gynecol Oncol 1983; 15 (1): 10–17. doi: 10.1016/0090-8258 (83) 90111-7.

10. How JA, Jazaeri AA, Westin SN et al. Translating biological insights into improved management of endometrial cancer. Nat Rev Clin Oncol 2024; 21 (11): 781–800. doi: 10.1038/s41 571-024-00934-7.

11. Makker V, MacKay H, Ray-Coquard I et al. Endometrial cancer. Nat Rev Dis Primer 2021; 7 (1): 88. doi: 10.1038/s41572-021-00324-8.

12. Ørtoft G, Lausten-Thomsen L, Høgdall C et al. Lymph-vascular space invasion (LVSI) as a strong and independent predictor for non-locoregional recurrences in endometrial cancer: a Danish Gynecological Cancer Group Study. J Gynecol Oncol 2019; 30 (5): e84. doi: 10.3802/jgo.2019.30.e84.

13. Tortorella L, Restaino S, Zannoni GF et al. Substantial lymph-vascular space invasion (LVSI) as predictor of distant relapse and poor prognosis in low-risk early-stage endometrial cancer. J Gynecol Oncol 2021; 32 (2): e11. doi: 10.3802/jgo.2021.32.e11.

14. Sehnal B, Hruda M, Matej R et al. New FIGO 2023 staging system of endometrial cancer: an updated review on a current hot topic. Geburtshilfe Frauenheilkd 2025; 85 (4): 405–416. doi: 10.1055/a-2494-8395.

15. Dagher C, Bjerre Trent P, Alwaqfi R et al. Oncologic outcomes based on lymphovascular space invasion in node-negative FIGO 2009 stage I endometrioid endometrial adenocarcinoma: a multicenter retrospective cohort study. Int J Gynecol Cancer 2024; 34 (10): 1485–1492. doi: 10.1136/ijgc-2024-005746.

16. Peters EE, León-Castillo A, Smit VT et al. Defining substantial lymphovascular space invasion in endometrial cancer. Int J Gynecol Pathol 2022; 41 (3): 220–226. doi: 10.1097/PGP.000000 0000000806.

17. Espinosa I, Serrat N, Zannoni GF et al. Endometrioid endometrial carcinomas with microcystic, elongated, and fragmented (MELF) type of myoinvasion: role of immunohistochemistry in the detection of occult lymph node metastases and their clinical significance. Hum Pathol 2017; 70 : 6–13. doi: 10.1016/ j.humpath.2017.05.026.

18. van den Heerik AS, Aiyer KT, Stelloo E et al. Microcystic elongated and fragmented (MELF) pattern of invasion: molecular features and prognostic significance in the PORTEC-1 and -2 trials. Gynecol Oncol 2022; 166 (3): 530–537. doi: 10.1016/j.ygyno.2022.06.027.

19. Jia P, Zhang Y. Molecular classification and adjuvant treatment in endometrioid endometrial cancer with microcystic elongated and fragmented (MELF) invasion pattern. BMC Womens Health 2024; 24 (1): 607. doi: 10.1186/s129 05-024-03449-6.

20. Okcu O, Askan G, Sen B et al. Prognositc significance of Microcystic Elongated and Fragmanted (MELF) myometrial invasion pattern: a retrospective study. Medeni Med J 2022; 37 (3): 212–219. doi: 10.4274/MMJ.galenos.2022.40336.

21. Presl J, Vaněček T, Michal M et al. Molekulární klasifikace endometriálních karcinomů převedená do praxe. Ceska Gynekol 2021; 86 (4): 258–262. doi: 10.48095/cccg2021258.

22. Dundr P, Cibula D, Doležel M et al. Molekulární testování u karcinomu endometria –⁠ společné doporučení ČOS, onkogynekologické sekce ČGPS, SROBF a SČP ČLS JEP. Ceska Gynekol 2021; 86 (4): 264–272. doi: 10.48095/cccg2021264.

23. León-Castillo A, de Boer SM, Powell ME et al. Molecular classification of the PORTEC-3 trial for high-risk endometrial cancer: impact on prognosis and benefit from adjuvant therapy. J Clin Oncol 2020; 38 (29): 3388–3397. doi: 10.1200/JCO.20.00549.

24. Michalová K, Presl J, Straková-Peteříková A et al. Výhody sekvenování nové generace (NGS) v molekulární klasifikaci endometriálních karcinomů –⁠ naše zkušenosti s 270 případy. Ceska Gynekol 2024; 89 (5): 349–359. doi: 10.48095/cccg2024349.

25. Ballová Z, Gašparová P, Sitáš M et al. Pohľad na klasifikáciu a manažment endometriálneho karcinómu v kontexte molekulárnych subtypov. Ceska Gynekol 2024; 89 (2): 128–132. doi: 10.48095/cccg2024128.

26. Coll-de la Rubia E, Martinez-Garcia E, Dittmar G et al. Prognostic biomarkers in endometrial cancer: a systematic review and meta-analysis. J Clin Med 2020; 9 (6): 1900. doi: 10.3390/jcm9061900.

27. Vrede SW, Van Weelden WJ, Bulten J et al. Hormonal biomarkers remain prognostically relevant within the molecular subgroups in endometrial cancer. Gynecol Oncol 2024; 192 : 15–23. doi: 10.1016/j.ygyno.2024.10.028.

28. Przewoźny S, Rogaliński J, de Mezer M et al. Estrogen Receptor (ER) and Progesterone Receptor (PgR) expression in endometrial cancer –⁠ an immunohistochemical assessment. Diagnostics (Basel) 2024; 14 (3): 322. doi: 10.3390/diagnostics14030322.

29. Jamieson A, Huvila J, Chiu D et al. Grade and estrogen receptor expression identify a subset of no specific molecular profile endometrial carcinomas at a very low risk of disease-specific death. Mod Pathol 2023; 36 (4): 100085. doi: 10.1016/j.modpat.2022.100085.

30. Vermij L, Jobsen JJ, León-Castillo A et al. Prognostic refinement of NSMP high-risk endometrial cancers using oestrogen receptor immunohistochemistry. Br J Cancer 2023; 128 (7): 1360–1368. doi: 10.1038/s41416-023-02141-0.

31. Giannini A, D’Oria O, Corrado G et al. The role of L1CAM as predictor of poor prognosis in stage I endometrial cancer: a systematic review and meta-analysis. Arch Gynecol Obstet 2024; 309 (3): 789–799. doi: 10.1007/s00404-023-07149-8.

32. Guo M, Gong H, Nie D, et al. High L1CAM expression predicts poor prognosis of patients with endometrial cancer: a systematic review and meta-analysis. Medicine (Baltimore) 2021; 100 (13): e25330. doi: 10.1097/MD.0000000000025330.

33. Zeimet AG, Reimer D, Huszar M et al. L1CAM in early-stage type I endometrial cancer: results of a large multicenter evaluation. J Natl Cancer Inst 2013; 105 (15): 1142–1150. doi: 10.1093/jnci/djt144.

34. Abada E, Kim S, Jang H et al. Human epidermal growth factor receptor-2 (HER2) expression in FIGO3 high-grade endometrial endometrioid carcinoma: clinicopathologic characteristics and future directions. Gynecol Oncol 2024; 185 : 25–32. doi: 10.1016/j.ygyno.2024.01.048.

35. Shawn LyBarger K, Miller HA, Frieboes HB. CA125 as a predictor of endometrial cancer lymphovascular space invasion and lymph node metastasis for risk stratification in the preoperative setting. Sci Rep 2022; 12 (1): 19783. doi: 10.1038/s41598-022-22026-1.

36. Yu Z, Sun Y, Guo C. Evaluating pretreatment serum CA-125 levels as prognostic biomarkers in endometrial cancer: a comprehensive meta-analysis. Front Oncol 2024; 14 : 1442814. doi: 10.3389/fonc.2024.1442814.

37. Presl J, Novotny Z, Topolcan O et al. CA125 and HE4 levels in a Czech female population diagnosed with endometrial cancer in preoperative management. Anticancer Res 2014; 34 (1): 327–331.

38. Jiang T, Huang L, Zhang S. Preoperative serum CA125: a useful marker for surgical management of endometrial cancer. BMC Cancer 2015; 15 : 396. doi: 10.1186/s12885-015-1260-7.

39. Li J, Wang X, Qu W et al. Comparison of serum human epididymis protein 4 and CA125 on endometrial cancer detection: a meta-analysis. Clin Chim Acta Int J Clin Chem 2019; 488 : 215–220. doi: 10.1016/j.cca.2018.11.011.

40. Brennan DJ, Hackethal A, Metcalf AM et al. Serum HE4 as a prognostic marker in endometrial cancer –⁠ a population based study. Gynecol Oncol 2014; 132 (1): 159–165. doi: 10.1016/j.ygyno.2013.10.036.

41. Wang Y, Han C, Teng F et al. Predictive value of serum HE4 and CA125 concentrations for lymphatic metastasis of endometrial cancer. Int J Gynaecol Obstet 2017; 136 (1): 58–63. doi: 10.1002/ijgo.12010.

42. Ørbo A, Arnes M, Lyså LM et al. HE4 is a novel tissue marker for therapy response and progestin resistance in medium -⁠ and low-risk endometrial hyperplasia. Br J Cancer 2016; 115 (6): 725–730. doi: 10.1038/bjc.2016.247.

43. Barr CE, Sergeant JC, Agnew HJ et al. Serum HE4 predicts progestin treatment response in endometrial cancer and atypical hyperplasia: a prognostic study. BJOG 2023; 130 (8): 941–948. doi: 10.1111/1471-0528.17417.

44. Liu X, Li J, Deng J et al. Targeting Trop2 in solid tumors: a look into structures and novel epitopes. Front Immunol 2023; 14 : 1332489. doi: 10.3389/fimmu.2023.1332489.

45. Moufarrij S, Dopeso H, Brown DN et al. TROP2 expression and therapeutic targeting in uterine carcinosarcoma. Gynecol Oncol 2025; 197 : 129–138. doi: 10.1016/j.ygyno.2025.04.590.

46. Wen Y, Ouyang D, Zou Q et al. A literature review of the promising future of TROP2: a potential drug therapy target. Ann Transl Med 2022; 10 (24): 1403. doi: 10.21037/atm-22-5976.

47. Bellone S, McNamara B, Mutlu L et al. Monitoring treatment response, early recurrence, and survival in uterine serous carcinoma and carcinosarcoma patients using personalized circulating tumor DNA biomarkers. Int J Mol Sci 2023; 24 (10): 8873. doi: 10.3390/ijms24108873.

48. Moss EL, Gorsia DN, Collins A et al. Utility of circulating tumor DNA for detection and monitoring of endometrial cancer recurrence and progression. Cancers (Basel) 2020; 12 (8): 2231. doi: 10.3390/cancers12082231.

49. Liu Y, Lu XN, Guo HM et al. Development and validation of a circulating tumor DNA-based optimization-prediction model for short-term postoperative recurrence of endometrial cancer. World J Clin Cases 2024; 12 (18): 3385–3394. doi: 10.12998/wjcc.v12.i18.3385.

50. Pereira E, Camacho-Vanegas O, Anand S et al. Personalized circulating tumor DNA biomarkers dynamically predict rreatment response and survival in gynecologic cancers. PLoS One 2015; 10 (12): e0145754. doi: 10.1371/journal.pone.0145754.

51. Takenaka K, Olzomer EM, Hoehn KL et al. Investigation of circular RNA transcriptome in obesity-related endometrial cancer. Gene 2023; 855 : 147125. doi: 10.1016/j.gene.2022.147125.

52. Ye F, Tang QL, Ma F et al. Analysis of the circular RNA transcriptome in the grade 3 endometrial cancer. Cancer Manag Res 2019; 11 : 6215–6227. doi: 10.2147/CMAR.S197343.

53. Guo F, Dong Y, Tan Q et al. Tissue infiltrating immune cells as prognostic biomarkers in endometrial cancer: a meta-analysis. Dis Markers 2020; 2020 : 1805764. doi: 10.1155/2020/1805764.

54. Hattori S, Yoshikawa N, Liu W et al. Understanding the impact of spatial immunophenotypes on the survival of endometrial cancer patients through the ProMisE classification. Cancer Immunol Immunother 2025; 74 (2): 70. doi: 10.1007/s00262-024-03919-8.

55. Eskander RN, Sill MW, Beffa L et al. Pembrolizumab plus chemotherapy in advanced or recurrent endometrial cancer: overall survival and exploratory analyses of the NRG GY018 phase 3 randomized trial. Nat Med 2025; 31 (5): 1539–1546. doi: 10.1038/s41591-025-03566-1.

56. Matoba Y, Devins KM, Milane L et al. High--grade endometrial cancer: molecular subtypes, current challenges, and treatment options. Reprod Sci 2024; 31 (9): 2541–2559. doi: 10.1007/s43032-024-01.

57. Matulonis UA, Lorusso D, Oaknin A et al. Efficacy and safety of mirvetuximab soravtansine in patients with platinum-resistant ovarian cancer with high folate receptor alpha expression: results from the SORAYA study. J Clin Oncol 2023; 41 (13): 2436–2445. doi: 10.1200/JCO.22.01900.

58. Soberanis Pina P, Lheureux S. Novel molecular targets in endometrial cancer: mechanisms and perspectives for therapy. Biologics 2024; 18 : 79–93. doi: 10.2147/BTT.S369783.

59. Bretová P, Ndukwe MI, Laco J et al. Preoperative risk stratification in endometrial cancer using ESGO/ESTRO/ESP 2021 guidelines: accuracy with and without molecular classification. BMC Cancer 2025; 25 (1): 1302. doi: 10.1186/s12885-025-14741-5.

60. Soslow RA, Tornos C, Park KJ et al. Endometrial carcinoma diagnosis: use of FIGO grading and genomic subcategories in clinical practice: recommendations of the International Society of Gynecological Pathologists. Int J Gynecol Pathol 2019; 38 (Suppl 1): S64–S74. doi: 10.1097/PGP.0000000000000518.

61. Klat J, Mladenka A, Dvorackova J et al. L1CAM as a negative prognostic factor in endometrioid endometrial adenocarcinoma FIGO stage IA–IB. Anticancer Res 2019; 39 (1): 421–424. doi: 10.21873/anticanres.13128.

62. Qi X, Zhu L, Zhang B. Clinicopathologic association and prognostic impact of microcystic, elongated and fragmented pattern invasion, combined with tumor budding in endometrioid endometrial cancer. J Obstet Gynaecol Res 2022; 48 (9): 2431–2441. doi: 10.1111/jog. 15335.

63. Weinberger V, Bednarikova M, Hausnerova J et al. A novel approach to preoperative risk stratification in endometrial cancer: the added value of immunohistochemical markers. Front Oncol 2019; 9 : 265. doi: 10.3389/fonc.2019. 00265.

64. Reijnen C, Gogou E, Visser NC et al. Preoperative risk stratification in endometrial cancer (ENDORISK) by a Bayesian network model: a development and validation study. PLoS Med 2020; 17 (5): e1003111. doi: 10.1371/journal.pmed.1003111.

65. Kuhn E, Gambini D, Runza L et al. Unsolved issues in the integrated histo-molecular classification of endometrial carcinoma and therapeutic implications. Cancers (Basel) 2024; 16 (13): 2458. doi: 10.3390/cancers16132458.