Endometrial Cancer

Endometrial cancer arises from the endometrial glandular epithelium. It is the commonest gynaecological malignancy in high-income settings.

Two broad patterns exist. Type 1 (endometrioid histology, the commoner pattern) is characteristically oestrogen-driven and arises in the context of endometrial hyperplasia. It generally carries a more favourable prognosis because it typically presents at an earlier stage.

Type 2 (serous and clear cell histology) occurs independent of oestrogen excess and arises from atrophic endometrium. It carries a less favourable prognosis because of more aggressive tumour biology.

Postmenopausal bleeding is the classic, near-universal presenting symptom. It drives earlier-stage diagnosis than in several other gynaecological malignancies, so prompt, thorough evaluation of this symptom is critical.

Pathophysiology and risk factors

• Type 1 endometrial cancer is the culmination of the oestrogen-driven hyperplasia-carcinoma sequence. Sustained, unopposed oestrogen exposure drives progressive glandular proliferation through simple and, atypical hyperplasia before malignant transformation. This explains the risk factors shared with other causes of unopposed oestrogen exposure.
• Obesity is a particularly significant risk factor. Peripheral adipose tissue aromatisation is an ongoing source of oestrogen, and the dominant remaining source in postmenopausal women.
• Other risk factors for type 1 disease: unopposed oestrogen therapy, tamoxifen use, polycystic ovary syndrome and associated chronic anovulation, nulliparity, early menarche, late menopause and type 2 diabetes.
• Lynch syndrome (hereditary non-polyposis colorectal cancer syndrome) substantially elevates lifetime endometrial cancer risk, in addition to the more classically recognised colorectal cancer risk. Consider genetic counselling in appropriately selected women, particularly those presenting at a younger age or with a relevant family history.
• Type 2 endometrial cancer arises independent of the oestrogen-driven hyperplasia pathway. It typically occurs in older, often thinner postmenopausal women, from atrophic rather than hyperplastic endometrium.
• It has a distinct molecular pathogenesis and more aggressive behaviour, including a greater propensity for deep myometrial invasion and extrauterine spread even at smaller tumour size than type 1 disease.
• Combined hormonal contraception is associated with a protective reduction in endometrial cancer risk, reflecting the progestogen component's counterbalancing effect against unopposed oestrogen. Include this in risk counselling.

• Postmenopausal bleeding is the classic, near-universal presenting symptom, occurring in the substantial majority of affected women. It generally allows diagnosis at an earlier, more favourable stage than several other gynaecological malignancies (including ovarian cancer), which more typically present with vague, non-specific or advanced-stage symptoms.
• In premenopausal women, endometrial cancer may present with abnormal uterine bleeding, including intermenstrual bleeding or a significant change in menstrual pattern. This is particularly relevant with chronic anovulation and its associated risk factors, but is much less common than postmenopausal bleeding because the malignancy predominates in postmenopausal women.
• Abnormal vaginal discharge, sometimes blood-stained or watery, may occasionally be an alternative or additional presenting feature. In more advanced disease, pelvic pain or a palpable pelvic mass may occur.
• Any postmenopausal woman with vaginal bleeding needs prompt, thorough evaluation directed at excluding this diagnosis. Early diagnosis is relevant to the generally favourable prognosis achievable at an early stage.

• Transvaginal ultrasound assessing endometrial thickness is a valuable initial investigation for postmenopausal bleeding.
• A thin endometrium (generally below an established threshold according to local protocol) gives substantial, though not absolute, reassurance against significant endometrial pathology. A thickened endometrium warrants direct histological evaluation.
• Endometrial biopsy provides the definitive histological diagnosis. It is the essential investigation for any woman with postmenopausal bleeding and a thickened endometrium, or with any other clinical concern warranting histology despite a reassuring endometrial thickness.
• Obtain the biopsy by outpatient pipelle sampling. Use hysteroscopic-directed biopsy where outpatient sampling is inadequate or not tolerated, or where a focal abnormality is suspected.
• After histological confirmation, full staging is an essential part of preoperative evaluation. Magnetic resonance imaging of the pelvis assesses local tumour extent, including the depth of myometrial invasion, which is relevant to prognosis and surgical planning.
• For higher-grade or higher-risk histology, add computed tomography of the chest and abdomen to assess for distant metastatic spread.
• Genetic counselling and testing for Lynch syndrome is increasingly recommended as a routine part of evaluation for every woman with endometrial cancer. Use tumour-based mismatch repair protein immunohistochemistry or microsatellite instability testing, with abnormal results prompting germline genetic testing.
• The result matters for the individual's own future cancer risk (including colorectal cancer) and for family cascade testing and risk-reduction counselling.

• Standard primary treatment for the great majority of confirmed cases is total hysterectomy with bilateral salpingo-oophorectomy, together with full surgical staging.
• Staging includes pelvic lymph node assessment and, where indicated by tumour grade and other risk factors, para-aortic lymph node assessment. Many contemporary centres increasingly use sentinel lymph node biopsy.
• Use a minimally invasive (laparoscopic or robotic-assisted) approach where feasible. Oncological outcome is equivalent to open surgery, with reduced perioperative morbidity.
• Adjuvant treatment is selected by risk stratification incorporating tumour grade, histological subtype, stage and depth of myometrial invasion. Options are radiotherapy (vaginal brachytherapy for lower-risk disease, external beam pelvic radiotherapy for higher-risk disease) and, for higher-risk or higher-stage disease, chemotherapy.
• Molecular classification, using the molecular subgroups identified by contemporary tumour profiling, is increasingly incorporated into risk stratification and treatment planning alongside these traditional clinicopathological factors.
• Fertility-sparing management is an option for carefully selected young women who strongly desire fertility preservation and have early-stage, low-grade, endometrioid disease confined to the endometrium without myometrial invasion. It comprises high-dose progestogen therapy with close, structured surveillance rather than immediate hysterectomy.
• Provide specialist counselling on the specific risks of this conservative approach compared with standard definitive surgery.
• Advanced or recurrent disease is managed with systemic chemotherapy and, increasingly, targeted and immunotherapy approaches for patients selected by tumour molecular characteristics. Hormonal therapy (progestogens) suits selected patients with hormone receptor-positive, lower-grade recurrent disease.
• The treatment goal in advanced disease is disease control and quality of life, with integrated palliative care involvement where relevant.
• Counsel on modifiable risk factors, particularly weight management, which is relevant to both primary disease risk and general health in survivors. Provide structured, long-term follow-up surveillance and psychosocial support.
• This common gynaecological malignancy has a generally favourable prognosis when identified at an early stage.