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Endometrial hyperplasia and progression to cancer: which classification system stratifies the risk better? A systematic review and meta-analysis

Archives of Gynecology and Obstetrics volume 299, pages 1233–1242 (2019)Cite this article

Abstract

Purpose

Benign and precancerous endometrial hyperplasias (EH) are differentiated thorough two possible histomorphologic classifications: WHO (adopting the subjective evaluation of cytologic atypia) and EIN (adopting several histomorphologic parameters, evaluable subjectively, or objectively with a computerized analysis calculating a prognostic score, the D score). ACOG recommends the use of EIN system although no distinction was made between objective assessment (not widely available), and subjective assessment (more applicable in the common practice). Moreover, it is still unclear if subjective EIN system is actually preferable to WHO classification. We aimed to assess the reliability of WHO system, D score and subjective EIN system in stratifying the risk of progression to cancer in EH.

Methods

MEDLINE, EMBASE, Web of Sciences, Scopus, ClinicalTrial.gov, OVID, Cochrane Library and Google Scholar were searched for relevant articles from the inception to August 2018. All studies assessing the rates of progression of EH to cancer were included.

Results

Twelve cohort studies and one case–control study, assessing 3629 EH, were included. Relative risk (RR) for cancer progression was calculated with 95% confidence interval (CI), and results were compared using Chi-square test (significant p value < 0.05). WHO system showed a RR of 8.74 (95% CI 6.66–11.47). Objective D score showed a RR of 29.22 (95% CI 13.24–64.51), significantly higher than WHO (p = 0.005). Subjective EIN system showed a RR of 19.37 (95% CI 5.86–64.01), intermediate between WHO and D score, without significant differences (p = 0.20 and p = 0.57, respectively).

Conclusion

Objective EIN criteria with D score are significantly more reliable than WHO criteria in stratifying the risk of progression of EH to cancer. Subjective EIN criteria did not show significant superiority over WHO instead. Further studies are necessary to determine if subjective EIN system should replace WHO system in the routine diagnosis of EH.

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References

  1. Kurman R, Carcangiu M, Herrington C, Young R (2014) World Health Organisation classification of tumors of female reproductive organs, 4th edn. International Agency for Research on Cancer (IARC) Press, Lyon France

    Google Scholar 

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

    PubMed  Google Scholar 

  3. Mutter GL (2000) Endometrial intraepithelial neoplasia (EIN): will it bring order to chaos? The Endometrial Collaborative Group. Gynecol Oncol 76(3):287–290

    Article  CAS  PubMed  Google Scholar 

  4. Management of Endometrial Hyperplasia Green-top Guideline No. 67 RCOG/BSGE Joint Guideline|February 2016

  5. Chandra V, Kim JJ, Benbrook DM, Dwivedi A, Rai R (2016) Therapeutic options for management of endometrial hyperplasia. J Gynecol Oncol 27(1):e8

    Article  PubMed  Google Scholar 

  6. Baak JP, Mutter GL (2005) EIN and WHO94. J Clin Pathol 58(1):1–6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Endometrial Intraepithelial Neoplasia, ACOG/SGO, Committee Opinion, Number 631, May 2015

  8. Usubutun A, Mutter GL, Saglam A et al (2012) Reproducibility of endometrial intraepithelial neoplasia diagnosis is good, but influenced by the diagnostic style of pathologists. Mod Pathol 25(6):877–884

    Article  PubMed  Google Scholar 

  9. Baak JP, Mutter GL, Robboy S et al (2005) The molecular genetics and morphometry-based endometrial intraepithelial neoplasia classification system predicts disease progression in endometrial hyperplasia more accurately than the 1994 World Health Organization classification system. Cancer 103(11):2304–2312

    Article  CAS  PubMed  Google Scholar 

  10. Baak JP, Ørbo A, van Diest PJ et al (2001) Prospective multicenter evaluation of the morphometric D-score for prediction of the outcome of endometrial hyperplasias. Am J Surg Pathol 25(7):930–935

    Article  CAS  PubMed  Google Scholar 

  11. Orbo A, Baak JP, Kleivan I et al (2000) Computerised morphometrical analysis in endometrial hyperplasia for the prediction of cancer development. A long-term retrospective study from northern Norway. J Clin Pathol 53(9):697–703

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Lacey JV Jr, Mutter GL, Nucci MR et al (2008) Risk of subsequent endometrial carcinoma associated with endometrial intraepithelial neoplasia classification of endometrial biopsies. Cancer 113(8):2073–2081

    Article  PubMed  Google Scholar 

  13. Salman MC, Usubutun A, Boynukalin K, Yuce K (2010) Comparison of WHO and endometrial intraepithelial neoplasia classifications in predicting the presence of coexistent malignancy in endometrial hyperplasia. J Gynecol Oncol 21(2):97–101

    Article  PubMed  PubMed Central  Google Scholar 

  14. Ordi J, Bergeron C, Hardisson D et al (2014) Reproducibility of current classifications of endometrial endometrioid glandular proliferations: further evidence supporting a simplified classification. Histopathology 64(2):284–292

    Article  PubMed  Google Scholar 

  15. Moher D, Shamseer L, Clarke M et al (2015) Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev 4:1

    Article  PubMed  PubMed Central  Google Scholar 

  16. Whiting PF, Rutjes AW, Westwood ME et al (2011) QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies. Ann Intern Med 155(8):529–536

    Article  PubMed  Google Scholar 

  17. 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):403–442

    Article  CAS  PubMed  Google Scholar 

  18. Baak JP, Nauta JJ, Wisse-Brekelmans EC, Bezemer PD (1988) Architectural and nuclear morphometrical features together are more important prognosticators in endometrial hyperplasias than nuclear morphometrical features alone. J Pathol 154(4):335–341

    Article  CAS  PubMed  Google Scholar 

  19. Baak JP, Wisse-Brekelmans EC, Fleege JC, van der Putten HW, Bezemer PD (1992) Assessment of the risk on endometrial cancer in hyperplasia, by means of morphological and morphometrical features. Pathol Res Pract 188(7):856–859

    Article  CAS  PubMed  Google Scholar 

  20. Ho SP, Tan KT, Pang MW, Ho TH (1997) Endometrial hyperplasia and the risk of endometrial carcinoma. Singapore Med J 38(1):11–15

    CAS  PubMed  Google Scholar 

  21. Horn LC, Schnurrbusch U, Bilek K, Hentschel B, Einenkel J (2004) Risk of progression in complex and atypical endometrial hyperplasia: clinicopathologic analysis in cases with and without progestogen treatment. Int J Gynecol Cancer 14(2):348–353

    Article  PubMed  Google Scholar 

  22. Baak JP, Van Diermen B, Steinbakk A et al (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 

  23. Hecht JL, Ince TA, Baak JP, Baker HE, Ogden MW, Mutter GL (2005) Prediction of endometrial carcinoma by subjective endometrial intraepithelial neoplasia diagnosis. Mod Pathol 18(3):324–330

    Article  PubMed  PubMed Central  Google Scholar 

  24. Reed SD, Newton KM, Garcia RL et al (2010) Complex hyperplasia with and without atypia: clinical outcomes and implications of progestin therapy. Obstet Gynecol 116:365–373

    Article  PubMed  PubMed Central  Google Scholar 

  25. Steinbakk A, Gudlaugsson E, Aasprong OG et al (2011) Molecular biomarkers in endometrial hyperplasias predict cancer progression. Am J Obstet Gynecol 204(4):357.e1–357.e12

    Article  Google Scholar 

  26. Ferenczy A, Gelfand MM, Tzipris F (1983) The cytodynamics of endometrial hyperplasia and carcinoma. A review. Ann Pathol 3(3):189–201

    CAS  PubMed  Google Scholar 

  27. Travaglino A, Raffone A, Saccone G et al (2018) Loss of Bcl-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 97(12):1415–1426

    Article  CAS  PubMed  Google Scholar 

  28. Raffone A, Travaglino A, Saccone G et al (2018) PAX2 in endometrial carcinogenesis and in differential diagnosis of endometrial hyperplasia. A systematic review and meta-analysis of diagnostic accuracy. Acta Obstet Gynecol Scand. https://doi.org/10.1111/aogs.13512 [Epub ahead of print]

    Article  PubMed  Google Scholar 

  29. Raffone A, Travaglino A, Saccone G et al (2018) Loss of PTEN expression as diagnostic marker of endometrial precancer: a systematic review and meta-analysis. Acta Obstet Gynecol Scand. https://doi.org/10.1111/aogs.13513 [Epub ahead of print]

    Article  PubMed  Google Scholar 

  30. Yang YF, Liao YY, Peng NF, Li LQ, Xie SR, Wang RB (2012) Prediction of coexistent carcinomas risks by subjective EIN diagnosis and comparison with WHO classification in endometrial hyperplasias. Pathol Res Pract 208(12):708–712

    Article  PubMed  Google Scholar 

  31. Travaglino A, Raffone A, Saccone G et al (2018) Endometrial hyperplasia and risk of coexistent cancer: WHO vs EIN criteria. Histopathology. https://doi.org/10.1111/his.13776 [Epub ahead of print]

    Article  Google Scholar 

  32. Lacey JV Jr, Sherman ME, Rush BB et al (2010) Absolute risk of endometrial carcinoma during 20-year follow-up among women with endometrial hyperplasia. J Clin Oncol 28(5):788–792

    Article  PubMed  PubMed Central  Google Scholar 

  33. Gallos ID, Shehmar M, Thangaratinam S, Papapostolou TK, Coomarasamy A, Gupta JK (2010) Oral progestogens vs levonorgestrel-releasing intrauterine system for endometrial hyperplasia: a systematic review and metaanalysis. Am J Obstet Gynecol 203(6):547.e1–547.e10

    Article  CAS  Google Scholar 

  34. Giampaolino P, Di Spiezio Sardo A, Mollo A et al (2018) 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. https://doi.org/10.1016/j.jmig.2018.07.001 [Epub ahead of print]

  35. Travaglino A, Raffone A, Saccone G et al (2018) 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 231:104–110

    Article  CAS  PubMed  Google Scholar 

  36. Raffone A, Travaglino A, Saccone A et al (2019) Management of women with atypical polypoid adenomyoma of the uterus: a quantitative systematic review. Acta Obstet Gynecol Scand. https://doi.org/10.1111/aogs.13553 [Epub ahead of print]

    Article  PubMed  Google Scholar 

  37. Orbo A, Nilsen MN, Arnes MS, Pettersen I, Larsen K (2003) Loss of expression of MLH1, MSH2, MSH6, and PTEN related to endometrial cancer in 68 patients with endometrial hyperplasia. Int J Gynecol Pathol 22(2):141–148

    Article  CAS  PubMed  Google Scholar 

  38. Orbo A, Kaino T, Arnes M, Kopp M, Eklo K (2004) Genetic derangements in the tumor suppressor gene PTEN in endometrial precancers as prognostic markers for cancer development: a population-based study from northern Norway with long-term follow-up. Gynecol Oncol 95(1):82–88

    Article  CAS  PubMed  Google Scholar 

  39. Lacey JV Jr, Mutter GL, Ronnett BM et al (2008) PTEN expression in endometrial biopsies as a marker of progression to endometrial carcinoma. Cancer Res 68(14):6014–6020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Lacey JV Jr, Ioffe OB, Ronnett BM et al (2008) Endometrial carcinoma risk among women diagnosed with endometrial hyperplasia: the 34-year experience in a large health plan. Br J Cancer 98(1):45–53

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Obstetrics and Gynecology Unit, Department of Neuroscience, Reproductive Sciences and Dentistry, School of Medicine, University of Naples Federico II, Naples, Italy

    Antonio Raffone, Gabriele Saccone, Antonio Mollo, Giuseppe De Placido & Fulvio Zullo

  2. Anatomic Pathology Unit, Department of Advanced Biomedical Sciences, School of Medicine, University of Naples Federico II, Via Sergio Pansini, 5, Naples, 80131, Italy

    Antonio Travaglino & Luigi Insabato

Authors
  1. Antonio Raffone
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  2. Antonio Travaglino
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  3. Gabriele Saccone
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  4. Luigi Insabato
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  5. Antonio Mollo
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  6. Giuseppe De Placido
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  7. Fulvio Zullo
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Contributions

AR, AT: protocol/project development, data collection, data analysis, and manuscript writing/editing. GS: data analysis and manuscript writing/editing. AM: protocol/project development and study supervision. LI: manuscript writing/editing and study supervision. FZ: protocol/project development, manuscript writing/editing and study supervision. GDP: protocol/project development and study supervision.

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Correspondence to Antonio Travaglino.

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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 299, 1233–1242 (2019). https://doi.org/10.1007/s00404-019-05103-1

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  • DOI: https://doi.org/10.1007/s00404-019-05103-1

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