Clinical Predictive Factors of Response to Treatment in Patients Undergoing Conservative Management of Atypical Endometrial Hyperplasia and Early Endometrial Cancer
Publication: Journal of Adolescent and Young Adult Oncology
Volume 10, Issue Number 2
Abstract
Purpose: Predictive markers of response to conservative treatment of atypical endometrial hyperplasia (AEH) or early endometrial cancer (EEC) are still lacking. We aimed to assess clinical predictive factors of response to conservative treatment of AEH and EEC.
Methods: All patients with AEH or EEC conservatively treated from January 2007 to June 2018 were retrospectively assessed. The associations between 23 clinical factors and outcomes of response to treatment were assessed with standard univariate analyses and multivariate logistic regression (significant p-value <0.05).
The primary outcome was the association of each clinical factor with treatment failure (i.e., no regression or relapse of the disease). Secondary outcomes were the associations of each clinical factor with: (1) no regression, (2) relapse, or (3) pregnancy after treatment.
Results: Forty-three women, 37 (86%) with AEH and 6 (14%) with EEC were included. At univariate analyses, treatment failure was associated with longer menstrual cycle (p = 0.002), infrequent menstrual bleeding (p = 0.04), and a diagnosis of EEC instead of AEH (p = 0.008). Among the secondary outcomes, no regression was associated with infrequent menstrual bleeding (p = 0.04), and a diagnosis of EEC instead of AEH (p < 0.001), while relapse was associated with longer menstrual cycles (p = 0.007). At multivariate analyses, odds ratio for treatment failure was 4.54 (95% confidence interval [CI], 0.24–84.4) for a diagnosis of EEC instead of AEH (p = 0.3), and 2.10 (95% CI, 1.03–4.29) for longer menstrual cycles (p = 0.042), while infrequent menstrual bleeding perfectly predicted treatment failure.
Conclusions: Longer menstrual cycles and infrequent menstrual bleeding appear as independent predictive factors for conservative treatment failure in AEH and EEC. Further and larger studies are necessary to confirm these findings.
Get full access to this article
View all available purchase options and get full access to this article.
References
1. Kurman RJ, Carcangiu ML, Herrington CS, Young RH (Eds). WHO classification of tumours of female reproductive organs. 4th ed. Lyon, France: IARC; 2014.
2. Lacey JV, 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):788–92.
3. Gallos ID, Alazzam M, Clark TJ, et al. Management of endometrial hyperplasia green-top guideline no. 67 RCOG/BSGE joint guideline (February 2016). Accessed August 08, 2020 from https://www.rcog.org.uk/globalassets/documents/guidelines/green-top-guidelines/gtg_67_endometrial_hyperplasia.pdf
4. Travaglino A, Raffone A, Saccone G, et al. Loss of B-cell lymphoma 2 immunohistochemical expression in endometrial hyperplasia: a specific marker of precancer and novel indication for treatment: a systematic review and meta-analysis. Acta Obstet Gynecol Scand. 2018;97(12):1415–26.
5. Travaglino A, Raffone A, Saccone G, et al. Endometrial hyperplasia and risk of coexistent cancer: WHO vs EIN criteria. Histopathology. 2019;74(5):676–87.
6. Travaglino A, Raffone A, Saccone G, et al. Congruence between 1994 WHO classification of endometrial hyperplasia and endometrial intraepithelial neoplasia system. Am J Clin Pathol. 2019; [Epub ahead of print];.
7. Raffone A, Travaglino A, Saccone G, et al. PAX2 in endometrial carcinogenesis and in differential diagnosis of endometrial hyperplasia. A systematic review and meta-analysis of diagnostic accuracy. Acta Obstet Gynecol Scand. 2019;98(3):287–99.
8. Raffone A, Travaglino A, Saccone G, et al. Loss of PTEN expression as diagnostic marker of endometrial precancer: a systematic review and meta-analysis. Acta Obstet Gynecol Scand. 2019;98(3):275–86.
9. Travaglino A, Raffone A, Saccone G, et al. Complexity of glandular architecture should be reconsidered in the classification and management of endometrial hyperplasia. APMIS. 2019;127(6):427–34.
10. Travaglino A, Raffone A, Saccone G, et al. PTEN immunohistochemistry in endometrial hyperplasia: which are the optimal criteria for the diagnosis of precancer? APMIS. 2019;127(4):161–69.
11. Raffone A, Travaglino A, Saccone G, et al. Endometrial hyperplasia and progression to cancer: which classification system stratifies the risk better? A systematic review and meta-analysis. Arch Gynecol Obstet. 2019;299(5):1233–42.
12. Raffone A, Travaglino A, Saccone G, et al. PTEN expression in endometrial hyperplasia and risk of cancer: a systematic review and meta-analysis. Arch Gynecol Obstet. 2019;299(6):1511–24.
13. Sherman ME. Theories of endometrial carcinogenesis: a multidisciplinary approach. Mod Pathol. 2000;13(3):295–308.
14. Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136(5):E359–86.
15. Reed SD, Newton KM, Clinton WL, et al. Incidence of endometrial hyperplasia. Am J Obstet Gynecol. 2009;200(6):678.e1–6.
16. Raffone A, Travaglino A, Saccone G, et al. Management of women with atypical polypoid adenomyoma of the uterus: a quantitative systematic review. Acta Obstet Gynecol Scand. 2019; [Epub ahead of print];.
17. Chandra V, Kim JJ, Benbrook DM, et al. Therapeutic options for management of endometrial hyperplasia. J Gynecol Oncol. 2016;27(1):e8.
18. Giampaolino P, Di Spiezio Sardo A, Mollo A, et al. Hysteroscopic endometrial focal resection followed by levonorgestrel intrauterine device insertion as a fertility-sparing treatment of atypical endometrial hyperplasia and early endometrial cancer: a retrospective study. J Minim Invasive Gynecol. 2019;26(4):648–56.
19. Colombo N, Creutzberg C, Amant F, et al. ESMO-ESGO-ESTRO consensus conference on endometrial cancer: diagnosis, treatment and follow-up. Ann Oncol. 2016;27(1):16–41.
20. Yuk JS, Song JY, Lee JH, et al. Levonorgestrel-releasing intrauterine systems versus oral cyclic medroxyprogesterone acetate in endometrial hyperplasia therapy: a meta-analysis. Ann Surg Oncol. 2017;24(5):1322–9.
21. Gallos ID, Yap J, Rajkhowa M, et al. Regression, relapse, and live birth rates with fertility-sparing therapy for endometrial cancer and atypical complex endometrial hyperplasia: a systematic review and metaanalysis. Am J Obstet Gynecol. 2012;207(4):266.e1–12.
22. Raffone A, Travaglino A, Saccone G, et al. Diabetes mellitus and responsiveness of endometrial hyperplasia and early endometrial cancer to conservative treatment. Gynecol Endocrinol. 2019; [Epub ahead of print];.
23. Koskas M, Uzan J, Luton D, et al. Prognostic factors of oncologic and reproductive outcomes in fertility-sparing management of endometrial atypical hyperplasia and adenocarcinoma: systematic review and meta-analysis. Fertil Steril. 2014;101(3):785–94.
24. Travaglino A, Raffone A, Saccone G, et al. PTEN as a predictive marker of response to conservative treatment in endometrial hyperplasia and early endometrial cancer. A systematic review and meta-analysis. Eur J Obstet Gynecol Reprod Biol. 2018;231:104–10.
25. Sato M, Arimoto T, Kawana K, et al. Measurement of endometrial thickness by transvaginal ultrasonography to predict pathological response to medroxyprogesterone acetate in patients with grade 1 endometrioid adenocarcinoma. Mol Clin Oncol. 2016;4(4):492–6.
26. Travaglino A, Raffone A, Saccone G, et al. Immunohistochemical nuclear expression of β-catenin as a surrogate of CTNNB1 exon 3 mutation in endometrial cancer. Am J Clin Pathol. 2019;151(5):529–38.
27. Penner KR, Dorigo O, Aoyama C. et al. Predictors of resolution of complex atypical hyperplasia or grade 1 endometrial adenocarcinoma in premenopausal women treated with progestin therapy. Gynecol Oncol. 2012;124(3):542–8.
28. Travaglino A, Raffone A, Saccone G, et al. Nuclear expression of β-catenin in endometrial hyperplasia as marker of premalignancy. APMIS. 2019; [Epub ahead of print];.
29. Raffone A, Travaglino A, Saccone G, et al. Should progesterone and estrogens 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):976–87.
30. Travaglino A, Raffone A, Saccone G, et al. Immunohistochemical predictive markers of response to conservative treatment of endometrial hyperplasia and early endometrial cancer: a systematic review. Acta Obstet Gynecol Scand. 2019;98(9):1086–99.
31. Raffone A, Travaglino A, Saccone G, et al. Diagnostic and prognostic value of ARID1A in endometrial hyperplasia: a novel marker of occult cancer. APMIS. 2019;127(9):597–606.
32. Raffone A, Travaglino A, Saccone G, et al. Diabetes mellitus is associated with occult cancer in endometrial hyperplasia. Pathol Oncol Res. 2019; [Epub ahead of print];.
33. Zhou R, Yang Y, Lu Q, et al. Prognostic factors of oncological and reproductive outcomes in fertility-sparing treatment of complex atypical hyperplasia and low-grade endometrial cancer using oral progestin in Chinese patients. Gynecol Oncol. 2015;139(3):424–8.
34. Fukui Y, Taguchi A, Adachi K, et al. Polycystic ovarian morphology may be a positive prognostic factor in patients with endometrial cancer who achieved complete remission after fertility-sparing therapy with progestin. Asian Pac J Cancer Prev. 2017;18(11):3111–6.
35. Burleigh A, Talhouk A, Gilks CB, McAlpine JN. Clinical and pathological characterization of endometrial cancer in young women: identification of a cohort without classical risk factors. Gynecol Oncol. 2015;138(1):141–6.
36. Yang YF, Liao YY, Liu XL, et al. Prognostic factors of regression and relapse of complex atypical hyperplasia and well-differentiated endometrioid carcinoma with conservative treatment. Gynecol Oncol. 2015;139(3):419–23.
37. Yang B, Xie L, Zhang H, et al. Insulin resistance and overweight prolonged fertility-sparing treatment duration in endometrial atypical hyperplasia patients. J Gynecol Oncol. 2018;29(3):e35.
38. Von Elm E, Altman DG, Egger M, et al. The strengthening the reporting of observational studies in epidemiology (STROBE) statement: guidelines for reporting observational studies. Int J Surg. 2014;12(12):1495–9.
39. Kalogera E, Dowdy SC, Bakkum-Gamez JN. Preserving fertility in young patients with endometrial cancer: current perspectives. Int J Womens Health. 2014;6:691–701.
40. Sanderson PA, Critchley HOD, Williams ARW, et al. New concepts for an old problem: the diagnosis of endometrial hyperplasia. Hum Reprod Update. 2017;23(2):232–54.
41. Baak JP, Mutter GL. EIN and WHO94. J Clin Pathol. 2005;58(1):1–6.
42. Shan BE, Ren YL, Sun JM, et al. A prospective study of fertility-sparing treatment with megestrol acetate following hysteroscopic curettage for well-differentiated endometrioid carcinoma and atypical hyperplasia in young patients. Arch Gynecol Obstet. 2013;288(5):1115–23.
43. Haoula Z, Salman M, Atiomo W. Evaluating the association between endometrial cancer and polycystic ovary syndrome. Hum Reprod. 2012;27(5):1327.
44. Patel BG, Rudnicki M, Yu J, et al. Progesterone resistance in endometriosis: origins, consequences and interventions. Acta Obstet Gynecol Scand. 2017;96(6):623–32.
45. Li X, Feng Y, Lin JF, et al. Endometrial progesterone resistance and PCOS. J Biomed Sci. 2014;21(1):2.
46. Shen ZQ, Zhu HT, Lin JF. Reverse of progestin-resistant atypical endometrial hyperplasia by metformin and oral contraceptives. Obstet Gynecol. 2008;112(2 Pt 2):465–7.
47. Savaris RF, Groll JM, Young SL, et al. Progesterone resistance in PCOS endometrium: a microarray analysis in clomiphene citrate-treated and artificial menstrual cycles. J Clin Endocrinol Metab. 2011;96(6):1737–46.
48. Park JY, Kim DY, Kim JH, et al. Long-term oncologic outcomes after fertility-sparing management using oral progestin for young women with endometrial cancer (KGOG 2002). Eur J Cancer. 2013;49(4):868–74.
49. Chen M, Jin Y, Li Y, et al. Oncologic and reproductive outcomes after fertility-sparing management with oral progestin for women with complex endometrial hyperplasia and endometrial cancer. Int J Gynaecol Obstet. 2016;132(1):34–8.
50. Gunderson CC, Fader AN, Carson KA, Bristow RE. Oncologic and reproductive outcomes with progestin therapy in women with endometrial hyperplasia and grade 1 adenocarcinoma: a systematic review. Gynecol Oncol. 2012;125(2):477–82.
51. Sovino H, Sir-Petermann T, Devoto L. Clomiphene citrate and ovulation induction. Reprod Biomed Online. 2002;4(3):303.
52. Althuis MD, Moghissi KS, Westhoff CL, et al. Uterine cancer after use of clomiphene citrate to induce ovulation. Am J Epidemiol. 2005;161(7):607–15.
53. Silva Idos S, Wark PA, McCormack VA, et al. Ovulation-stimulation drugs and cancer risks: a longterm follow-up of a British cohort. Br J Cancer. 2009;100(11):1824–31.
54. Jensen A, Sharif H, Kjaer SK. Use of fertility drugs and risk of uterine cancer: results from a large Danish population-based cohort study. Am J Epidemiol. 2009;170(11):1408–14.
55. Dor J, Lerner-Geva L, Rabinovici J, et al. Cancer incidence in a cohort of infertile women who underwent in vitro fertilization. Fertil Steril. 2002;77(2):324.
56. Gilks CB, Oliva E, Soslow RA. Poor interobserver reproducibility in the diagnosis of high-grade endometrial carcinoma. Am J Surg Pathol. 2013;37(6):874–81.
57. Hoang LN, McConechy MK, Kobel M, et al. Histotype-genotype correlation in 36 high-grade endometrial carcinomas. Am J Surg Pathol. 2013;37(9):1421–32.
58. Guillon S, Popescu N, Phelippeau J, Koskas M. A systematic review and meta-analysis of prognostic factors for remission in fertility-sparing management of endometrial atypical hyperplasia and adenocarcinoma. Int J Gynaecol Obstet. 2019;146(3):277–88.
59. Guan H, Semaan A, Bandyopadhyay S, et al. Prognosis and reproducibility of new and existing binary grading systems for endometrial carcinoma compared to FIGO grading in hysterectomy specimens. Int J Gynecol Cancer. 2011;21(4):654–60.
60. Han G, Sidhu D, Duggan MA, et al. Reproducibility of histological cell type in high-grade endometrial carcinoma. Mod Pathol. 2013;26(12):1594–604.
61. McCluggage WG. My approach to the interpretation of endometrial biopsies and curettings. J Clin Pathol. 2006;59(8):801–12.
62. Soliman PT, Oh JC, Schmeler KM, et al. Risk factors for young premenopausal women with endometrial cancer. Obstet Gynecol. 2005;105(3):575–80.
Information & Authors
Information
Published In
Journal of Adolescent and Young Adult Oncology
Volume 10 • Issue Number 2 • April 2021
Pages: 193 - 201
PubMed: 32799597
Copyright
Copyright 2021, Mary Ann Liebert, Inc., publishers.
History
Published online: 15 April 2021
Published in print: April 2021
Published ahead of print: 14 August 2020
Topics
Authors
Author Contributions
A.R.: study conception, study design, study methods, data analysis, article preparation, methods supervision, whole study supervision; A.T.: study conception, study design, study methods, data analysis, article preparation, methods supervision; M.E.F.: study design, study methods, data analysis, article preparation; M.I: study design, study methods, data collection, article preparation; A.M.: study conception, data collection, data analysis, responsible surgeon; M.G.: study conception, data analysis, responsible surgeon, methods supervision; L.I.: study conception, data analysis, responsible pathologist, whole study supervision; A.D.S.: study conception, data analysis, responsible surgeon, article preparation, whole study supervision; J.C.: study design, data analysis, article preparation, methods supervision, whole study supervision; F.Z.: study conception, study design, data analysis, responsible surgeon, methods supervision, whole study supervision.
Author Disclosure Statement
No competing financial interests exist.
Funding Information
No funding was received for this article.
Metrics & Citations
Metrics
Citations
Export Citation
Export citation
Select the format you want to export the citations of this publication.
View Options
Access content
To read the fulltext, please use one of the options below to sign in or purchase access.⚠ Society Access
If you are a member of a society that has access to this content please log in via your society website and then return to this publication.