Uterine Cancer

Uterine cancer is a malignancy arising from the body of the uterus. The great majority — around 90% — are endometrial carcinomas, arising from the glandular lining; the remainder are uterine sarcomas, arising from the myometrium or stroma, which behave far more aggressively and are managed differently.

Endometrial carcinoma divides into two types, and the distinction governs risk, presentation and prognosis.

Type I (endometrioid, ~80%) is estrogen-driven, and this is the central fact about the disease. Unopposed estrogen — estrogen acting on the endometrium without progesterone to oppose it — drives proliferation, which progresses through hyperplasia to atypical hyperplasia to carcinoma. It typically occurs in younger postmenopausal women, is usually low grade, presents early because it bleeds, and carries a good prognosis. Because the mechanism is understood, so are the risk factors: they are almost all routes to unopposed estrogen.

Type II (serous, clear cell, carcinosarcoma, ~20%) is not estrogen-driven. It arises in older women in an atrophic endometrium, is high grade, and carries a substantially worse prognosis. TP53 mutation is characteristic.

Most reflect prolonged unopposed estrogen exposure:

• Obesity — the dominant modifiable risk factor. Adipose tissue aromatizes androgens to estrogen, so postmenopausal women with a high BMI have continuous endometrial stimulation with no progesterone to oppose it. Risk rises steeply with BMI.
• Nulliparity, and early menarche or late menopause — more lifetime ovulatory cycles
• Polycystic ovary syndrome — chronic anovulation means chronically absent progesterone
• Estrogen-only hormone therapy in a woman with an intact uterus
• Tamoxifen — antiestrogenic in breast tissue but estrogenic in the endometrium
• Diabetes and hypertension, largely though not entirely through their association with obesity
• Lynch syndrome (hereditary non-polyposis colorectal cancer) — a lifetime endometrial cancer risk of 40–60%, often presenting before age 50, and frequently the first cancer in an affected woman. This is why testing matters: it identifies a family at risk of colorectal and ovarian cancer too.
• Age — the median at diagnosis is in the sixties

Protective: combined oral contraception, progesterone-containing hormone therapy, the levonorgestrel intrauterine system, multiparity, and physical activity.

Postmenopausal bleeding is the cardinal symptom and must always be investigated. Around 90% of endometrial cancers present with abnormal bleeding, which is why the disease is so often caught at an early, curable stage. The corollary matters as much: only about 10% of women with postmenopausal bleeding turn out to have cancer, so the great majority will be reassured — but only after assessment.

In premenopausal women the presentation is less obvious and more easily dismissed: heavy or prolonged periods, intermenstrual bleeding, or bleeding after intercourse. Any of these in a woman with obesity, PCOS or a family history warrants investigation rather than hormonal management alone.

Other features are watery, blood-stained or offensive vaginal discharge; pelvic pain or pressure, usually a later feature; and in advanced disease, weight loss, a palpable mass, urinary or bowel symptoms, and leg swelling from lymphatic or venous obstruction. Uterine sarcomas more often present with a rapidly enlarging uterus or pelvic mass than with bleeding, which is part of why they present later.

Assessment of postmenopausal bleeding is standardized and should be prompt.

Transvaginal ultrasound measures endometrial thickness. In a postmenopausal woman a thickness of 4 mm or less has a high negative predictive value and makes carcinoma very unlikely; above that threshold, tissue is required. The measurement is not reliable in premenopausal women, in whom thickness varies with the cycle, nor in women on tamoxifen, in whom the endometrium is often thickened without malignancy.

Endometrial sampling — an outpatient Pipelle biopsy — is the diagnostic test and is usually straightforward. Hysteroscopy with directed biopsy or curettage is used where sampling fails, is inadequate, or is normal despite persistent bleeding, since a focal lesion can be missed by a blind sample. Persistent bleeding after a negative biopsy always warrants hysteroscopy.

Staging is surgical, by total hysterectomy with bilateral salpingo-oophorectomy and assessment of lymph nodes; MRI assesses myometrial invasion and cervical involvement preoperatively, and CT looks for distant disease. Mismatch repair immunohistochemistry or microsatellite instability testing is now recommended on all endometrial cancers, both to identify Lynch syndrome and because it guides immunotherapy. Molecular classification into four groups — POLE-ultramutated, mismatch repair deficient, p53-abnormal and no specific molecular profile — increasingly determines adjuvant treatment.

Obesity, type 2 diabetes and hypertension cluster with endometrial cancer and frequently complicate surgery, anaesthesia and recovery; they also mean that many women with early-stage disease die of cardiovascular causes rather than of their cancer, which shapes long-term follow-up. Venous thromboembolism risk is raised by malignancy, obesity and pelvic surgery together. A diagnosis of Lynch syndrome has implications for the whole family and triggers colonoscopic surveillance. Treatment in younger women causes surgical menopause and loss of fertility, and fertility-sparing progestin treatment is only an option in carefully selected early, low-grade disease.