Epidemiology
Endometrial cancer is more common in industrialised, developed Western societies where it is the most common gynaecological cancer. The incidence of endometrial cancer rose by 43% between 1993 and 2009, which is believed to be linked to the increasing rates of obesity. Approximately 75% of women diagnosed with endometrial cancer are post-menopausal with the incidence rising steeply over the age of 50, with the median age at presentation being 61 years. However, approximately 20–5% of women are premenopausal at diagnosis, with up to 5% of them below the age of 40.
Aetiology
At least three quarters of endometrial cancers are endometrioid endometrial adenocarcinomas. Atypical endometrial hyperplasia is a precursor lesion for endometrioid- type tumours and is frequently seen in the uterine specimens removed as a treatment for endometrial cancer. The underpinning link between the risk factors for atypical hyperplasia and endometrioid endometrial cancer (EEC) is the effect of unopposed oestrogen on the endometrium.
Endometrial hyperplasia
• Precursor lesion for endometrioid-type tumours.
• The risk of malignant progression is the highest for atypical hyperplasia (8–28% from 4 to 19 years after diagnosis).
• The long-term risk of malignant progression from hyperplasia without atypia is low (only 3%).
Although cigarette smoking is associated with a lower risk of developing EEC, smoking concurrently with exogenous oestrogen use multiplies the risk of developing endometrial cancer.
Risk factors for EEC
• Obesity
• Prolonged anovulation
• Early menarche
• Late menopause
• Use of unopposed oestrogen replacement therapy
• Polycystic ovarian syndrome
• Nulliparity
• Infertility
• Diabetes
• Hypertension
• Tamoxifen use
• Oestrogen-secreting granulosa cell tumour of ovary
• Genetic predisposition, e.g. Lynch syndrome (see Genetic Associations)
The risk factors for non-endometrioid cancers are less well established. Although these tumours frequently arise in non-obese, multiparous women, recent epidemiological evidence suggests that the risk factors for both endometrioid and non-EECs may overlap.
Genetic Associations
Lynch Syndrome
Lynch syndrome (previously known as hereditary nonpolyposis colorectal cancer syndrome) is caused by germline mutations in mismatch repair (MMR) genes (MSH2, MLH1, MSH6, and PMS2). The germline mutation is passed on via autosomal dominant inheritance. Lynch syndrome is associated with an increased risk of early onset of endometrial and colorectal cancers. The lifetime risk of developing endometrial cancer with Lynch syndrome is 40–60%, compared to 3% in the general population.