title: New concepts for an old problem: the diagnosis of endometrial hyperplasia.
abstract: Endometrial hyperplasia (EH) is a uterine pathology representing a spectrum of morphological endometrial alterations. It is predominantly characterized 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 (EC) and 'atypical' forms of EH are regarded as premalignant lesions. Traditional histopathological classification systems for EH exhibit wide and varying degrees of diagnostic reproducibility and, as a consequence, standardized patient management can be challenging.
  
  
  
  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 summarize the evidence base regarding the use of immunohistochemical biomarkers for EH and discuss an emerging role for genomic analysis.
  
  
  
  PubMed, Medline and the Cochrane Database were searched for original peer-reviewed primary and review articles, from January 2000 to January 2016. The following search terms were used: 'endometrial hyperplasia', 'endometrial intraepithelial neoplasia', 'atypical hyperplasia', 'complex atypical hyperplasia', 'biomarker', 'immunohistochemistry', 'progression', 'genomic', 'classification' and 'stratification'.
  
  
  
  Recent changes to EH classification reflect 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 several 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 immunohistochemical biomarkers described in this review may be more informative since no single candidate can currently fill the entire role.
  
  
  
  EC has historically been considered a predominantly postmenopausal 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 premalignant 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.
authors.affiliation: MRC Centre for Inflammation Research, The University of Edinburgh, The Queen's Medical Research Institute, 47 Little France Crescent, EdinburghEH16 4TJ, UK.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Sanderson
authors.affiliation: MRC Centre for Reproductive Health, The University of Edinburgh, The Queen's Medical Research Institute, 47 Little France Crescent, EdinburghEH16 4TJ, UK.
authors.forename: Hilary O D
authors.initials: HO
authors.lastname: Critchley
authors.affiliation: Division of Pathology, The Royal Infirmary of Edinburgh, 51 Little France Crescent, EdinburghEH16 4SA, UK.
authors.forename: Alistair R W
authors.initials: AR
authors.lastname: Williams
authors.affiliation: Division of Pathology, Edinburgh Cancer Research Centre, Western General Hospital, Crewe Road South, Edinburgh EH4 2XR, UK.|Centre for Comparative Pathology, The University of Edinburgh, Easter Bush, Midlothian EH25 9RG, UK.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Arends
authors.affiliation: MRC Centre for Inflammation Research, The University of Edinburgh, The Queen's Medical Research Institute, 47 Little France Crescent, EdinburghEH16 4TJ, UK.
authors.forename: Philippa T K
authors.initials: PT
authors.lastname: Saunders
mesh_terms: D015415:Biomarkers / Q000032:analysis; D018450:Disease Progression; D004714:Endometrial Hyperplasia / Q000175:diagnosis* / Q000473:pathology*; D016889:Endometrial Neoplasms / Q000473:pathology*; D004717:Endometrium / Q000473:pathology*; D005260:Female; D006801:Humans; D011230:Precancerous Conditions / Q000473:pathology*; D015203:Reproducibility of Results; D012306:Risk
chemical_list: D015415:Biomarkers
keywords: biomarkers; endometrial hyperplasia; endometrial intraepithelial neoplasia; endometrioid endometrial cancer; genomic classification; immunohistochemistry; patient stratification; personalized medicine; progression