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.

/pdf/new-concepts-for-an-old-problem-the-diagnosis-of-endometrial-1ry8rb5eor.pdf

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

Adenocarcinoma of the endometrium (also known as endometrial cancer, or more broadly as uterine cancer or carcinoma of the uterine corpus) is the most common malignancy of the female genital tract in the United States. It is estimated that 65,950 new uterine cancer cases will have occurred in 2022, with 12,550 deaths resulting from the disease. Endometrial carcinoma includes pure endometrioid cancer and carcinomas with high-risk endometrial histology (including uterine serous carcinoma, clear cell carcinoma, carcinosarcoma [also known as malignant mixed Müllerian tumor], and undifferentiated/dedifferentiated carcinoma). Stromal or mesenchymal sarcomas are uncommon subtypes accounting for approximately 3% of all uterine cancers. This selection from the NCCN Guidelines for Uterine Neoplasms focuses on the diagnosis, staging, and management of pure endometrioid carcinoma. The complete version of the NCCN Guidelines for Uterine Neoplasms is available online at NCCN.org.

/pdf/uterine-neoplasms-version-1-2023-nccn-clinical-practice-1ibqe40t.pdf

Uterine Neoplasms, Version 1.2023, NCCN Clinical Practice Guidelines in Oncology.

Over the past century, the world has seen unprecedented declines in mortality rates, leading to an accelerated increase in the world population. This century will realise falling fertility rates alongside ageing populations. The 20th century was the century of population growth; the 21st century will be remembered as the century of ageing. Increase in life expectancy is one of the highest achievements of humankind; however, ageing and age-related disease is a mounting challenge for individuals, families, and for social, economic, and healthcare systems. Since healthy life expectancy has lagged behind the increase in life expectancy, the rise in morbidity will increase the burden on healthcare systems. Implementation of preventive health strategies to decrease, delay or prevent frailty, lung, breast and colon cancer, cardiovascular disease, metabolic syndrome, osteoporosis and osteopaenia, may increase health expectancy, and permit women to age gracefully and maintain independent living, without disability, for as long as possible.

/pdf/the-clinical-consequences-of-an-ageing-world-and-preventive-221aoin5s0.pdf

The clinical consequences of an ageing world and preventive strategies.

Endometrial hyperplasia (EH) comprises a spectrum of changes in the endometrium ranging from a slightly disordered pattern that exaggerates the alterations seen in the late proliferative phase of the menstrual cycle to irregular, hyperchromatic lesions that are similar to endometrioid adenocarcinoma. Generally, EH is caused by continuous exposure of estrogen unopposed by progesterone, polycystic ovary syndrome, tamoxifen, or hormone replacement therapy. Since it can progress, or often occur coincidentally with endometrial carcinoma, EH is of clinical importance, and the reversion of hyperplasia to normal endometrium represents the key conservative treatment for prevention of the development of adenocarcinoma. Presently, cyclic progestin or hysterectomy constitutes the major treatment option for EH without or with atypia, respectively. However, clinical trials of hormonal therapies and definitive standard treatments remain to be established for the management of EH. Moreover, therapeutic options for EH patients who wish to preserve fertility are challenging and require nonsurgical management. Therefore, future studies should focus on evaluation of new treatment strategies and novel compounds that could simultaneously target pathways involved in the pathogenesis of estradiol-induced EH. Novel therapeutic agents precisely targeting the inhibition of estrogen receptor, growth factor receptors, and signal transduction pathways are likely to constitute an optimal approach for treatment of EH.

/pdf/therapeutic-options-for-management-of-endometrial-1cori44y0i.pdf

Therapeutic options for management of endometrial hyperplasia

Endometrioid endometrial carcinoma, the most common form of endometrial cancer, usually develops out of a typical sequence of endometrial hyperplasias. The underlying cause of these hyperplasias is a relative predominance of estrogen combined with insufficient progesterone levels. Typical causes include corpus luteum insufficiency/anovulatory cycles (premenopause), polycystic ovary syndrome and obesity with metabolic syndrome (aromatase conversion of ovarian androgens in adipose tissue), inappropriate hormone therapy post menopause (insufficient dosage of gestagens) or an estrogen or androgen-producing tumor 1.

Even in patients with Lynch syndrome (formerly known as HNPCC), tumorigenesis of hereditary endometrioid carcinoma usually follows the usual progression with development of the respective hyperplasias 1.

Up to now, the correct clinical evaluation of endometrial hyperplasias was made more difficult by the different classification systems still in use: in Germany hyperplasias are sometimes still differentiated according to the classification “glandular-cystic hyperplasia” and “adenomatous hyperplasia grade I to III”. In 1994, the WHO classified endometrial hyperplasias into 4 categories:


simple hyperplasia without atypia,


complex hyperplasia without atypia,


simple atypical hyperplasia,


complex atypical hyperplasia 1, 2.



While categories 1, 2 and 4 were generally accepted, pathologists continued to debate the existence of group 3-type hyperplasias. Hyperplasias without atypia (categories 1 and 2) are considered benign pathologies which will regress with conservative treatment (oral gestagens, gestagen IUD, elimination of the cause of anovulation/corpus luteum insufficiency) 1. A large percentage (up to 60 %) 3 of atypical endometrial hyperplasias (categories 3 and 4) are found to be coexistent with invasive endometrial carcinoma or develop into invasive endometrial carcinoma within the space of just a few years 1, 2, 4. Hysterectomy (total hysterectomy, not supracervical hysterectomy!) is therefore the treatment of choice for atypical endometrial hyperplasia 4 or – in selected patients, i.e. younger patients wanting to have children – high-dose gestagen therapy with appropriate close histological monitoring 1, 4.

The WHO classification of 1994 and even more so the parallel use of the older classification system led to confusion among clinicians. The consequence of this was inadequate diagnosis, with hysterectomies performed for hyperplasias without atypia or gestagens administered in HRT dosages for atypical hyperplasia. Pathologists also experienced difficulties with categorization. This was made even more difficult by the development and parallel use of a further classification system: benign hyperplasia and endometrial intraepithelial neoplasia (EIN) 2.

In its latest classification 5 published in 2014, the WHO has clarified the matter: it now only differentiates between 2 categories of endometrial hyperplasia:


hyperplasia without atypia


atypical hyperplasia/endometrioid intraepithelial neoplasia (Table 1).



Table 1 New WHO classification of endometrial hyperplasias 5.





This reduction to 2 categories was not only due to the need to do away with the confusing multitude of terms currently in use. Rather, it reflects a new understanding of molecular genetic changes.

Hyperplasias without atypia exhibit no relevant genetic changes. They are benign changes and will regress again after the endocrine milieu (physiological gestagen levels) has normalized. In a few cases (1–3 %), progression to invasive disease may occur if the endocrine disorder (long-term estrogen dominance or relative or absolute gestagen deficiency) persists over the long term.

Atypical endometrial hyperplasias exhibit many of the mutations typical for invasive endometrioid endometrial cancer 7. In up to 60 % of cases, patients have coexisting invasive cancer or are at extremely high risk of developing invasive cancer (Table 1).

The implications for treatment are obvious: hyperplasias without atypia should generally be treated conservatively (normalization of the cycle through weight loss, metformin; oral contraceptives; cyclical gestagens; gestagen IUD). Preventive hysterectomy should only be considered in exceptional cases (e.g., extreme obesity without any prospect of weight loss) 1, 4. The surgery should be done as a total hysterectomy, i.e., it must include removal of the cervix 4.

Treatment of atypical hyperplasia/endometrioid intraepithelial neoplasia should generally consist of total (not supracervical) hysterectomy 1, 4. Conservative treatment with high-dose gestagens and close histological monitoring should only be considered in exceptional cases (when the patient wants to have children, satisfactory compliance) 1, 4, 6.

/pdf/new-who-classification-of-endometrial-hyperplasias-4nocujjmq1.pdf

New WHO Classification of Endometrial Hyperplasias

https://www.sgo.org/wp-content/uploads/2012/09/Management-of-Endometrial-Precancers-Nov-2012.pdf

Management of Endometrial Precancers

Women's Health Care Teams and the Future of Obstetrics and Gynecology.

Trending the association of pregnancy-associated severe sepsis and maternal death: a population study.

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Management of Endometrial Precancers

Women's Health Care Teams and the Future of Obstetrics and Gynecology.

Trending the association of pregnancy-associated severe sepsis and maternal death: a population study.