Skip to main content

Advertisement

SpringerLink
Log in

Molecular expression characteristics confirm the malignancy concealed by morphological alterations in endometrial cancer after fertility-preserving treatment

  • Gynecologic Oncology
  • Published:
Archives of Gynecology and Obstetrics Aims and scope Submit manuscript

Abstract

Purpose

Fertility-preserving treatment (FPT) has been widely used for young patients with early stage endometrial cancer (EC). However, the literature on the effectiveness and safety of FPT remains controversial. The aim of this study was to investigate malignant transformation in EC after FPT by immunohistochemistry (IHC).

Methods

A retrospective analysis of pre- and post-treatment biopsy specimens from 24 patients with grade 1 endometrioid adenocarcinoma (EAC) or complex atypical hyperplasia (CAH) was performed. The expression levels of ARID1A, PTEN, and β-catenin were assessed by IHC.

Results

The protein expression levels of ARID1A, PTEN, and β-catenin were not significantly different between pre- and post-treatment specimens. However, there was a significant difference between pre-treatment and normal specimens as well as between post-treatment and normal specimens. The protein expression of β-catenin was significantly increased in patients with progression compared with those without progression after FPT.

Conclusion

The morphologic normalization of patients with EC after FPT may not be accompanied by the absence of tumor malignancy, and β-catenin may serve as a biomarker for the response to FPT. These results may contribute to a better understanding of the malignant transformation of EC after FPT and the optimization of treatment strategies for young patients with birth plans.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Siegel RL, Miller KD, Jemal A (2017) Cancer statistics. CA Cancer J Clin 67(1):7–30

    Article  PubMed  Google Scholar 

  2. Gallup DG, Stock RJ (1984) Adenocarcinoma of the endometrium in women 40 years of age or younger. Obstet Gynecol 64(3):417–420

    CAS  PubMed  Google Scholar 

  3. Kurman RJ, Kaminski PF, Norris HJ (1985) The behavior of endometrial hyperplasia A long-term study of “untreated” hyperplasia in 170 patients. Cancer 56(2):403–412

    Article  CAS  PubMed  Google Scholar 

  4. Montz FJ, Bristow RE, Bovicelli A, Tomacruz R, Kurman RJ (2002) Intrauterine progesterone treatment of early endometrial cancer. Am J Obstet Gynecol 186(4):651–657

    Article  CAS  PubMed  Google Scholar 

  5. Gotlieb WH, Beiner ME, Shalmon B, Korach Y, Segal Y, Zmira N, Koupolovic J, Ben-Baruch G (2003) Outcome of fertility-sparing treatment with progestins in young patients with endometrial cancer. Obstet Gynecol 102(4):718–725

    CAS  PubMed  Google Scholar 

  6. Jobo T, Imai M, Kawaguchi M, Kenmochi M, Kuramoto H (2000) Successful conservative treatment of endometrial carcinoma permitting subsequent pregnancy: report of two cases. Eur J Gynaecol Oncol 21(2):119–122

    CAS  PubMed  Google Scholar 

  7. Kaku T, Yoshikawa H, Tsuda H, Sakamoto A, Fukunaga M, Kuwabara Y, Hataeg M, Kodama S, Kuzuya K, Sato S, Nishimura T, Hiura M, Nakano H, Iwasaka T, Miyazaki K, Kamura T (2001) Conservative therapy for adenocarcinoma and atypical endometrial hyperplasia of the endometrium in young women: central pathologic review and treatment outcome. Cancer Lett 167(1):39–48

    Article  CAS  PubMed  Google Scholar 

  8. Koh WJ, Abu-Rustum NR, Bean S, Bradley K, Campos SM, Cho KR, Chon HS, Chu C, Cohn D, Crispens MA, Damast S, Dorigo O, Eifel PJ, Fisher CM, Frederick P, Gaffney DK, George S, Han E, Higgins S, Huh WK, Lurain JR, Mariani A, Mutch D, Nagel C, Nekhlyudov L, Fader AN, Remmenga SW, Reynolds RK, Tillmanns T, Ueda S, Wyse E, Yashar CM, McMillian NR, Scavone JL (2018) Uterine neoplasms, version 1.2018, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 16(2):170–199

    Article  PubMed  Google Scholar 

  9. Rodolakis A, Biliatis I, Morice P, Reed N, Mangler M, Kesic V, Denschlag D (2015) European Society of Gynecological Oncology Task Force for fertility preservation. Int J Gynecol Cancer 25(7):1258–1265

    Article  PubMed  Google Scholar 

  10. Baek JS, Lee WH, Kang WD, Kim SM (2016) Fertility-preserving treatment in complex atypical hyperplasia and early endometrial cancer in young women with oral progestin: is it effective? Obstet Gynecol Sci 59(1):24–31

    Article  PubMed  PubMed Central  Google Scholar 

  11. Carneiro MM, Lamaita RM, Ferreira MC, Silva-Filho AL (2016) Fertility-preservation in endometrial cancer: is it safe? Review of the literature. JBRA Assist Reprod 20(4):232–239

    Article  PubMed  PubMed Central  Google Scholar 

  12. Gallos ID, Yap J, Rajkhowa M, Luesley DM, Coomarasamy A, Gupta JK (2012) 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 207(4):261–266

    Article  Google Scholar 

  13. Sanderson PA, Critchley HO, Williams AR, Arends MJ, Saunders PT (2017) New concepts for an old problem: the diagnosis of endometrial hyperplasia. Hum Reprod Update 23(2):232–254

    PubMed  Google Scholar 

  14. Murali R, Soslow RA, Weigelt B (2014) Classification of endometrial carcinoma: more than two types. Lancet Oncol 15(7):e268–e278

    Article  PubMed  Google Scholar 

  15. DeSouza LV, Grigull J, Ghanny S, Dube V, Romaschin AD, Colgan TJ, Siu KW (2007) Endometrial carcinoma biomarker discovery and verification using differentially tagged clinical samples with multidimensional liquid chromatography and tandem mass spectrometry. Mol Cell Proteomics 6(7):1170–1182

    Article  CAS  PubMed  Google Scholar 

  16. Baak JP, Van Diermen B, Steinbakk A, Janssen E, Skaland I, Mutter GL, Fiane B, Lovslett K (2005) Lack of PTEN expression in endometrial intraepithelial neoplasia is correlated with cancer progression. Hum Pathol 36(5):555–561

    Article  CAS  PubMed  Google Scholar 

  17. Djordjevic B, Hennessy BT, Li J, Barkoh BA, Luthra R, Mills GB, Broaddus RR (2012) Clinical assessment of PTEN loss in endometrial carcinoma: immunohistochemistry outperforms gene sequencing. Mod Pathol 25(5):699–708

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Werner HM, Berg A, Wik E, Birkeland E, Krakstad C, Kusonmano K, Petersen K, Kalland KH, Oyan AM, Akslen LA, Trovik J, Salvesen HB (2013) ARID1A loss is prevalent in endometrial hyperplasia with atypia and low-grade endometrioid carcinomas. Mod Pathol 26(3):428–434

    Article  CAS  PubMed  Google Scholar 

  19. Mao TL, Ardighieri L, Ayhan A, Kuo KT, Wu CH, Wang TL, Shih I (2013) Loss of ARID1A expression correlates with stages of tumor progression in uterine endometrioid carcinoma. Am J Surg Pathol 37(9):1342–1348

    Article  PubMed  PubMed Central  Google Scholar 

  20. Aberle H, Butz S, Stappert J, Weissig H, Kemler R, Hoschuetzky H (1994) Assembly of the cadherin-catenin complex in vitro with recombinant proteins. J Cell Sci 107(Pt 12):3655–3663

    CAS  PubMed  Google Scholar 

  21. Scholten AN, Creutzberg CL, van den Broek LJ, Noordijk EM, Smit VT (2003) Nuclear β-catenin is a molecular feature of type I endometrial carcinoma. J Pathol 201(3):460–465

    Article  CAS  PubMed  Google Scholar 

  22. Saegusa M, Hashimura M, Yoshida T, Okayasu I (2001) β-Catenin mutations and aberrant nuclear expression during endometrial tumorigenesis. Br J Cancer 84(2):209–217

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Ayhan A, Mao TL, Suryo RY, Zeppernick F, Ogawa H, Wu RC, Wang TL, Shih I (2015) Increased proliferation in atypical hyperplasia/endometrioid intraepithelial neoplasia of the endometrium with concurrent inactivation of ARID1A and PTEN tumour suppressors. J Pathol Clin Res 1(3):186–193

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Pallares J, Bussaglia E, Martinez-Guitarte JL, Dolcet X, Llobet D, Rue M, Sanchez-Verde L, Palacios J, Prat J, Matias-Guiu X (2005) Immunohistochemical analysis of PTEN in endometrial carcinoma: a tissue microarray study with a comparison of four commercial antibodies in correlation with molecular abnormalities. Mod Pathol 18(5):719–727

    Article  CAS  PubMed  Google Scholar 

  25. Fleming GF, Filiaci VL, Marzullo B, Zaino RJ, Davidson SA, Pearl M, Makker V, Burke JN, Zweizig SL, Van Le L, Hanjani P, Downey G, Walker JL, Reyes HD, Leslie KK (2014) Temsirolimus with or without megestrol acetate and tamoxifen for endometrial cancer: a gynecologic oncology group study. Gynecol Oncol 132(3):585–592

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Visser N, Reijnen C, Massuger L, Nagtegaal ID, Bulten J, Pijnenborg J (2017) Accuracy of endometrial sampling in endometrial carcinoma: a systematic review and meta-analysis. Obstet Gynecol 130(4):803–813

    Article  PubMed  Google Scholar 

  27. Yang S, Thiel KW, Leslie KK (2011) Progesterone: the ultimate endometrial tumor suppressor. Trends Endocrinol Metab 22(4):145–152

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Smuc T, Rizner TL (2009) Aberrant pre-receptor regulation of estrogen and progesterone action in endometrial cancer. Mol Cell Endocrinol 301(1–2):74–82

    Article  CAS  PubMed  Google Scholar 

  29. Xu Y, Tong J, Ai Z, Wang J, Teng Y (2012) Epidermal growth factor receptor signaling pathway involved in progestin-resistance of human endometrial carcinoma: in a mouse model. J Obstet Gynaecol Res 38(12):1358–1366

    Article  CAS  PubMed  Google Scholar 

  30. Simpson AN, Feigenberg T, Clarke BA, Gien LT, Ismiil N, Laframboise S, Massey C, Ferguson SE (2014) Fertility sparing treatment of complex atypical hyperplasia and low grade endometrial cancer using oral progestin. Gynecol Oncol 133(2):229–233

    Article  CAS  PubMed  Google Scholar 

  31. Ramirez PT, Frumovitz M, Bodurka DC, Sun CC, Levenback C (2004) Hormonal therapy for the management of grade 1 endometrial adenocarcinoma: a literature review. Gynecol Oncol 95(1):133–138

    Article  CAS  PubMed  Google Scholar 

  32. Reyes HD, Carlson MJ, Devor EJ, Zhang Y, Thiel KW, Samuelson MI, McDonald M, Yang S, Stephan JM, Savage EC, Dai D, Goodheart MJ, Leslie KK (2016) Downregulation of FOXO1 mRNA levels predicts treatment failure in patients with endometrial pathology conservatively managed with progestin-containing intrauterine devices. Gynecol Oncol 140(1):152–160

    Article  CAS  PubMed  Google Scholar 

  33. van Gent MD, Nicolae-Cristea AR, de Kroon CD, Osse EM, Kagie MJ, Trimbos JB, Hazelbag HM, Smit VT, Bosse T (2016) Exploring morphologic and molecular aspects of endometrial cancer under progesterone treatment in the context of fertility preservation. Int J Gynecol Cancer 26(3):483–490

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank all the clinical researchers and patients for contributing to this study.

Funding

This study was supported by a grant from the Sichuan Youth Foundation of Science of Technology (Grant number: 2015JQ0026).

Author information

Authors and Affiliations

  1. Department of Gynecology and Obstetrics, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China

    Ting Wen Yi Hu, E. Yang, Dan Nie & Zheng Yu Li

  2. Key Laboratory of Obstetrics and Gynecologic and Pediatric Diseases and Birth Defects of the Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China

    Ting Wen Yi Hu & Zheng Yu Li

  3. Department of Pathology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China

    Lei Li

Authors
  1. Ting Wen Yi Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lei Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. E. Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dan Nie
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zheng Yu Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

ZyL: Hypothesis and project development; TwyH: Data collection, specimen collection, data analysis, and manuscript drafting; LL: Data analysis; EY: Data collection and specimen collection; DN: IHC and RT-PCR.

Corresponding author

Correspondence to Zheng Yu Li.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This study was approved by the Institutional Ethics Committee of West China Second University Hospital. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

As this was a retrospective study, formal consent was not required. However, informed consent was obtained from each patient for specimen collection.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hu, T.W.Y., Li, L., Yang, E. et al. Molecular expression characteristics confirm the malignancy concealed by morphological alterations in endometrial cancer after fertility-preserving treatment. Arch Gynecol Obstet 299, 1673–1682 (2019). https://doi.org/10.1007/s00404-019-05145-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00404-019-05145-5

Keywords

Search

Navigation