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Cited by 323Endometrial and Cervical Cancer TreatmentsCervical Cancer and HPV ResearchGynecological conditions and treatments

New concepts for an old problem: the diagnosis of endometrial hyperplasia

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Sanderson, Peter A., Critchley, Hilary O.D., Williams, Alistair R.W., Arends, Mark J., Saunders, Philippa T.K.·2016·Human Reproduction Update
DOI 10.1093/humupd/dmw042PMC PMC5850217
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Abstract

BACKGROUND: 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. OBJECTIVE AND RATIONALE: 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. SEARCH METHODS: 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'. OUTCOMES: 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. WIDER IMPLICATIONS: 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.

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  • Established risk factors for endometrial cancer include obesity and premalignant lesions associated with endometrial hyperplasia, with oestrogen exposure considered a key driver of both endometrial hyperplasia and Type I endometrial cancer, which make up 75% of endometrial cancer cases.

    “Established risk factors for development of EC include obesity and the presence of premalignant lesions associated with endometrial hyperplasia [75,76], with oestrogen exposure considered a key driver of both endometrial hyperplasia and Type I EC that make up 75% of EC cases [76].”

    From Endometrial Intracrinology: Oestrogens, Androgens and Endometrial Disorders (2018) · cites this paper as [76]

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Authors
Sanderson, P. A., Critchley, H. O. D., Williams, A. R. W., Arends, M. J., & Saunders, P. T. K.
Affiliations
  • Centre for Inflammation Research (GB)
  • MRC Centre for Reproductive Health (GB)
  • Edinburgh Royal Infirmary (GB)
  • Western General Hospital (GB)
Corresponding author
Saunders, Philippa T.K.
ORCID
Venue
Human Reproduction Update
Publisher
Oxford University Press (OUP)
Published
2016-12-04
Volume
23
Issue
2
Pages
232-254
ISSN
  • 1355-4786 (ISSN-L)
  • 1460-2369
DOI
10.1093/humupd/dmw042
PMC
PMC5850217
OpenAlex
W2560061424
Cited by
323
References
3
Citations by year
2026: 13 · 2025: 23 · 2024: 39 · 2023: 33 · 2022: 60 · 2021: 50 · 2020: 46 · 2019: 31 · 2018: 20 · 2017: 6
FWCI
3.34
Type
journal article
Language
en
Open access
Locations
  • Human Reproduction Update (publishedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
Funders
MRC Programme (G1100356/1)
Topics
  • Health Sciences › Medicine › Obstetrics and Gynecology › Endometrial and Cervical Cancer Treatments
  • Health Sciences › Medicine › Epidemiology › Cervical Cancer and HPV Research
  • Health Sciences › Medicine › Obstetrics and Gynecology › Gynecological conditions and treatments
Keywords
endometrial hyperplasia, endometrial intraepithelial neoplasia, atypical hyperplasia, complex atypical hyperplasia, endometrioid endometrial cancer, malignant progression, immunohistochemical markers, genome analysis, histological classification, risk stratification, obesity, endometrial cancer incidence, precancerous lesions, diagnostic reproducibility
MeSH terms
Endometrial Hyperplasia, Endometrium, Female, Humans, Precancerous Conditions, Risk, Reproducibility of Results, Biomarkers, Endometrial Neoplasms, Disease Progression

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