New concepts for an old problem: The diagnosis of Endometrial Hyperplasia

Peter Sanderson, Hilary Critchley, Alistair Williams, Mark Arends, Philippa Saunders

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Background: Endometrial hyperplasia (EH) is a uterine pathology representing a spectrum of morphological endometrial alterations. It is predominantly characterised by an increase in the endometrial gland-to-stroma ratio when compared to normal proliferative endometrium.
The clinical significance of EH lies in the associated risk of progression to endometrioid endometrial cancer and ‘atypical’ forms of EH are regarded as pre-malignant lesions. Traditional histopathological classification systems for EH exhibit wide and varying degrees of diagnostic reproducibility and as a consequence standardised patient management can be challenging.

Objective and rationale: Endometrial cancer (EC) is the most common gynaecological malignancy in developed countries. The incidence of EC is rising, with alarming increases described in the 40-44 year-old age group. This review appraises the current EH classification systems used to stratify women at risk of malignant progression to EC. In addition, we summarise the evidence base regarding the use of immunohistochemical biomarkers for EH and discuss an emerging role for genomic analysis.

Search methods: PubMed, Medline and the Cochrane Database were searched for original peer-reviewed primary and review articles, from January 2000 to January 2016. Thefollowing search terms were used: ‘Endometrial hyperplasia’, ‘Endometrial intraepithelial neoplasia’, ‘Atypical hyperplasia’, ‘Complex atypical hyperplasia’, ‘Biomarker’, ‘Immunohistochemistry’, ‘Progression’, ‘Genomic’, ‘Classification’ and ‘Stratification’.

Outcomes: Recent changes to EH classification reflects our current understanding of the genesis of endometrioid ECs. The concept of Endometrial Intraepithelial Neoplasia (EIN) as a mutationally activated, monoclonal pre-malignancy represents a fundamental shift from the previously held notion that unopposed oestrogenic stimulation causes ever-increasing hyperplastic proliferation, with accumulating cytological atypia that imperceptibly leads to the development of endometrioid EC. Our review highlights sev ral key biomarker candidates that have been described as both diagnostic tools for EH and markers of
progression to EC. We propose that moving forwards a ‘panel’ approach of combinations of the Human Reproduction Update the immunohistochemical biomarkers described in this review may be more informative since no single candidate can currently fill the entire role.

Wider Implications: EC has historically been considered a predominantly post-menopausal disease. Owing in part to the current unprecedented rates of obesity, we are starting to see signs of a shift towards a rising incidence of EC amongst pre and peri-menopausal woman. This creates unique challenges both diagnostically and therapeutically. Furthering our understanding of the pre-malignant stages of EC development will allow us to pursue earlier
diagnosis and facilitate appropriate stratification of women at risk of developing EC, permitting timely and appropriate therapeutic interventions.
Original languageEnglish
JournalHuman Reproduction Update
Early online date4 Dec 2016
Publication statusE-pub ahead of print - 4 Dec 2016


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