Screening tests for endometrial cancer in the general population

Objectives This is a protocol for a Cochrane Review (diagnostic). The objectives are as follows: To assess the diagnostic accuracy of potential screening tests for the detection of atypical hyperplasia (pre-cancer) and endometrial cancer of all stages and grades in asymptomatic (healthy) women in the general population. Secondary objectives • To determine the optimal endometrial thickness cut-oD value using transvaginal ultrasound scan for the screening of asymptomatic women for endometrial cancer and atypical hyperplasia. • To investigate sources of heterogeneity in endometrial cancer screening studies, including: * characteristics of the studied population including age, menopausal status (preand postmenopausal), country of study and risk status (body mass index (BMI) categories, diabetes mellitus, polycystic ovary syndrome (PCOS)); * characteristics of index test such as cytological classification used and sampling device; * methodological quality (low risk of bias compared to high risk of bias); * disease factors (endometrioid versus non-endometrioid, low grade versus high grade). Screening tests for endometrial cancer in the general population (Protocol) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 1 Cochrane Library Trusted evidence. Informed decisions. Better health. Cochrane Database of Systematic Reviews B A C K G R O U N D Target condition being diagnosed Endometrial cancer, also known as uterine or womb cancer, is a type of cancer that originates in the inner lining of the womb (the endometrium) and is mostly a disease of postmenopausal women. Globally, there were an estimated 380,000 incident cases in 2018 and about 89,000 died from their disease, making endometrial cancer the sixth most common female cancer, and the 14th leading cause of death from cancer in women (Bray 2018; Lortet-Tieulent 2018). Its incidence is projected to rise in the coming years in parallel with the growing prevalence of obesity (Crosbie 2014). Declining rates of hysterectomy for benign womb conditions and an ageing population also contribute to the rising trends (Morice 2016; Temkin 2016). Approximately two-thirds of women with endometrial cancer reside in the developed world, especially in countries with a high human development index (Lortet-Tieulent 2018). Most endometrial cancers are sporadic, with only about 5% occurring in the context of an inherited predisposing condition, such as Lynch syndrome (Ryan 2019; Sundar 2017). Diabetes mellitus, hypertension, polycystic ovary syndrome, use of tamoxifen and oestrogen-only hormone replacement therapy are other important risk factors (Njoku 2019). There are various histological subtypes of endometrial cancer that diDer in incidence, clinical presentations, prognoses and associated risk factors. These include endometrioid endometrial cancer, serous endometrial cancer, clear cell endometrial cancer and uterine carcinosarcoma (Colombo 2016). Whilst the majority of the endometrioid cancers are low grade, and in general have a good prognosis, a significant minority are high grade (aggressive-looking and faster-growing) and are associated with poorer outcomes (Brinton 2013). The non-endometrioid cancers, on the other hand, are mostly high grade and are oKen diagnosed at an advanced stage (Brooks 2019; Suarez 2017). There is emerging evidence to suggest that the growing incidence of endometrial cancer in several Western countries is due to an upward trend in the diagnosis of the clinically aggressive, non-endometrioid endometrial cancers (Clarke 2019; Faber 2017; Urick 2019). Screening tests that are able to detect all endometrial cancers at an early stage, especially the non-endometrioid tumours, are likely to improve survival outcomes. The processes underlying endometrial cancer development are dependent on the histological subtype (Figure 1; Brinton 2013). Endometrioid tumours, for instance, result from the unopposed stimulation of the epithelial lining of the womb by the female sex hormone, oestrogen, which results in hyperplasia without atypia (i.e. individual cells still look relatively normal, although there is an overgrowth of cells), with the potential to evolve into atypical hyperplasia (where individual cells look more abnormal), an endometrial cancer precursor lesion, and ultimately endometrial cancer (Setiawan 2013). There is substantial histopathological overlap between severe atypical hyperplasia and low-grade endometrial cancer, making a diagnostic distinction between the two diDicult and unnecessary in the context of screening. A particular gene fault, phosphatase and tensin homologue (PTEN) mutation, is the most frequent genetic abnormality in endometrioid endometrial cancer and occurs early in its development (Figure 1; Cancer Genome Atlas Research Network 2013; Levine 1998. It may thus be a potential target for endometrial cancer screening, although studies have shown that it is insuDicient on its own to initiate tumour formation (Mutter 2000). Nonendometrioid endometrial cancers, on the other hand, are oestrogen-independent. Serous endometrial cancer, for instance, commonly develops on the surface of an endometrial polyp on a background of an atrophic endometrium (El-Sahwi 2012; Lax 2000). Although serous tumours are frequently diagnosed at an advanced stage, p53 gene faults have been suggested to occur early in serous tumour development (Figure 1). This raises the possibility that p53 gene faults may be targets for early detection of serous tumours (Sherman 1995). Uterine carcinosarcomas and clear cell endometrial cancers are other aggressive non-endometrioid types of endometrial cancer (Cherniack 2017; Le 2017). Whilst the underlying gene faults of carcinosarcoma closely resemble those of serous endometrial tumours, clear cell tumours share similar genetic abnormalities with endometrioid endometrial cancer (Cherniack 2017; Le 2017; Urick 2019). Recently, a classification by the Cancer Genome Atlas (TCGA) Research Network categorised endometrial cancer into four groups based on specific gene faults: polymerase epsilon (POLE) ultramutated, microsatellite instability (MSI) hypermutated, copy number low tumours and copy number high tumours (Cancer Genome Atlas Research Network 2013). This classification has been shown to predict outcomes for women with endometrial cancer (Stelloo 2015; Talhouk 2017).