Uterine cancer (endometrial cancer)

Histological types and molecular classification

Risk factors

• Obesity: most important and prevalent risk factor - adipose tissue is a major source of estrogen production by aromatization of adrenal androgens (androstenedione → estrone); risk multiplied by 3 to 6 in obese women (BMI > 30) compared with normal-weight women ; chronic hyperestrogenism without progestin opposition stimulates endometrial proliferation and favors progression to atypical hyperplasia and then cancer; risk is proportional to BMI - women with BMI > 40 have a 10 to 15-fold higher risk
• Late menopause and early menarche: total estrogen exposure prolonged over the reproductive lifespan - each additional year of menstrual cycles moderately increases the cumulative risk; menopause after age 55: risk increased by 1.5 to 2 times.
• Nulliparity: pregnancy and breastfeeding expose the endometrium to high levels of progesterone (protective effect) - each full-term pregnancy reduces the risk by 30-40 %; nulliparous women have a risk 2 to 3 times higher than multiparous women
• Estrogen-only hormone replacement therapy (HRT) without progestin: estrogen-only HRT in women with an intact uterus multiplies the risk of endometrial cancer by 2 to 10, depending on dose and duration - the associated progestin neutralizes this effect; combined estrogen-progestin HRT is considered to be neutral or even slightly protective for the endometrium, if properly managed.
• Tamoxifen: selective estrogen receptor modulator (SERM) used as adjuvant treatment for breast cancer - breast estrogen antagonist effect but partial agonist effect on the endometrium; risk of endometrial cancer multiplied by 2 to 3 after 5 years of treatment; annual gynecological monitoring with pelvic ultrasound recommended for women taking tamoxifen
• Polycystic ovary syndrome (PCOS): chronic anovulation with continuous estrogen hyperstimulation and relative progestin insufficiency - 3 to 4 times greater risk of endometrial cancer, particularly in obese women with PCOS
• Type 2 diabetes and metabolic syndrome: 2 to 3 times greater risk - hyperinsulinemia and insulin resistance stimulate endometrial proliferation via IGF-1; independent risk factor for obesity in multivariate studies
• Lynch syndrome (HNPCC): mutations in MMR genes (MLH1, MSH2, MSH6, PMS2) - cumulative endometrial cancer risk of 40-60 % (higher than colorectal cancer risk in women with MSH6 or PMS2 mutation); genetic screening and annual gynecological surveillance recommended in Lynch women; prophylactic hysterectomy discussed after completion of maternity plans
• Protective factors: combined oral contraception (risk reduction of 50 % after 5 years of use - lasting effect 10-15 years after cessation), smoking (anti-estrogenic effect - not a reason to smoke), regular physical activity (reduction in insulin resistance and visceral adiposity), multiparity, breastfeeding.

Symptoms

• Post-menopausal vaginal bleeding (cardinal symptom): any vaginal bleeding occurring in a post-menopausal woman (at least 12 months after the last menstrual period) should be considered endometrial cancer until proven otherwise - even if the bleeding is minimal, punctual or in the form of pinkish or brownish discharge; this symptom is present in 90 % of endometrial cancers and is the earliest and most reliable warning signal for this cancer; in post-menopausal women, only 10 to 15 % of post-menopausal vaginal bleeding is due to cancer (benign causes - endometrial atrophy, polyps, endometritis - being more frequent) - but all should be investigated
• Atypical metrorrhagia or menorrhagia in premenopausal women: inter-menstrual bleeding, abnormally heavy or prolonged periods, or bleeding after intercourse in women over 40 - indication for endometrial biopsy; endometrial cancer is rare before age 40, but its incidence increases in young, obese women with PCOS
• Leucorrhoea or abnormal vaginal discharge: purulent, serous or bloody discharge with no obvious infectious cause - may precede bleeding in early forms or accompany advanced forms (tumour necrosis).
• Chronic pelvic pain: late onset, associated with local or lymph node extension - pelvic heaviness, bladder compression (pollakiuria, urgency) or rectal compression (tenesmus, constipation).
• Haematometry or pyometra: accumulation of blood or pus in the uterine cavity due to cervical tumour obstruction - may be revealed by acute pelvic pain or a palpable pelvic mass; diagnosis by ultrasound.
• Symptoms of advanced forms: weight loss, asthenia, anorexia; edema of lower limbs (lymphatic or pelvic venous compression); leg pain due to ureteral compression or deep vein thrombosis; urinary or rectal symptoms due to invasion of adjacent organs.

Diagnosis

• Transvaginal pelvic ultrasound: first examination in case of postmenopausal bleeding - measures endometrial thickness; thickness < 4 mm in postmenopausal women without HRT = very low risk of cancer (< 1 %) - may avoid biopsy if clinical picture is reassuring; thickness ≥ 4 mm or heterogeneous endometrium = endometrial biopsy mandatory; also assesses adnexa, myometrium and parameters for local extension work-up
• Ambulatory endometrial biopsy (Pipelle de Cornier): reference diagnostic examination for endometrial cancer - sampling by aspiration of the uterine cavity in consultation without general anaesthesia; sensitivity of 90-99 % for endometrial cancer if adequate sampling; results in 7 to 14 days; insufficient sampling in 5-10 % of cases (cervical stenosis, atrophic uterine cavity) requiring diagnostic hysteroscopy under anaesthesia.
• Diagnostic hysteroscopy with directed biopsies: direct exploration of the uterine cavity using a camera introduced through the cervix - direct visualization of endometrial lesions and directed biopsies on suspicious areas; gold standard if Pipelle is insufficient or results are discordant; also detects endometrial polyps, submucosal fibroids and focal hyperplasia.
• pelvic MRI with gadolinium injection: reference local staging examination - evaluates myometrial invasion (depth of invasion - stage IA vs IB), cervical invasion (stage II), extension to parameters and adjacent organs (stage III), pelvic and para-aortic lymph node invasion; essential before any surgical decision to plan the extent of resection and lymph node exploration
• Thoraco-abdomino-pelvic CT: assessment of distant extension (pulmonary and hepatic metastases, para-aortic and mediastinal lymph nodes, peritoneal carcinosis); complements pelvic MRI in the preoperative assessment of advanced or high-risk histological stages.
• FDG PET-CT: optional - useful for serous carcinomas and high-risk forms to detect distant metastases and recurrences; not systematic for low-risk stage I carcinomas.
• Biological work-up and tumour markers: CA-125 (elevated in 20-40 % endometrial cancers, especially types II and advanced stages - useful for post-therapy follow-up if initially elevated); HE4 (human epididymal protein 4 - more sensitive than CA-125 for the endometrium according to certain studies); CBC, liver work-up, pre-operative renal function.

FIGO staging (2023)

Treatment

• Surgery (reference treatment for operable stages I-III): total extra-fascial hysterectomy + bilateral salpingo-oophorectomy (adnexectomy) by robot-assisted laparoscopy or laparotomy; sentinel lymph node (sentinel lymph node technique with isotopic or fluorescent dye and tracer - indocyanine green ICG) for intermediate- and high-risk stages I, to replace or complement systematic pelvic lymph node curage; pelvic ± para-aortic lymph node dissection for stages II and III or high-risk stage I (serous carcinoma, clear-cell carcinoma, carcinosarcoma); peritoneal cytology performed at the start of the operation
• Adjuvant radiotherapy: vaginal brachytherapy (CVI): post-hysterectomy irradiation of the vaginal fundus to reduce the risk of vaginal recurrence in stages IB grade 3 and II - low toxicity, performed on an outpatient basis (3 to 5 sessions); external pelvic radiotherapy (EBRT): for stages III with pelvic lymph node involvement; combination radiochemotherapy (carboplatin/paclitaxel + EBRT) for stages IIIC and IVA according to protocols (PORTEC-3 trial)
• Adjuvant chemotherapy (type II and stage III-IV carcinomas): carboplatin + paclitaxel (6 cycles) - reference regimen for serous, clear cell, carcinosarcoma and advanced stage carcinomas; GOG 209 trial confirming superiority of carboplatin/paclitaxel vs cisplatin/doxorubicin/paclitaxel for safety with equal efficacy
• Immunotherapy and targeted therapies (advanced stages and recurrence) : pembrolizumab (anti-PD1) + lenvatinib (anti-VEGFR) - combination approved for advanced MSS endometrial cancer after chemotherapy failure (KEYNOTE-775 trial - improved overall survival) ; dostarlimab (anti-PD1) for MSI-H/dMMR tumors - 42 % response rate (GARNET trial); pembrolizumab monotherapy for MSI-H tumors; mTOR inhibitors (everolimus, ridaforolimus) for tumors with PI3K/mTOR pathway mutations.
• Conservative treatment of atypical hyperplasia and stages IA grade 1 in women wishing to become pregnant: levonorgestrel intrauterine device (LNG - Mirena IUD) or high-dose oral megestrol acetate - complete response rate of 70-80 % in 6 months; hysteroscopic monitoring and biopsy every 3 months during treatment; management in an expert center; pregnancy possible after complete regression; hysterectomy recommended after completion of the maternity plan.
• Palliative hormone therapy (ER/PR+ tumours): high-dose megestrol acetate or medroxyprogesterone acetate for well-differentiated hormone-receptor-positive grades 1-2 metastatic endometrioid carcinomas - response rate 15-30 %; well tolerated; used as an option for frail patients unable to receive chemotherapy

Consult at Clinique Omicron

Clinique Omicron physicians assess any post-menopausal vaginal bleeding or gynecological abnormalities suggestive of endometrial pathology, prescribe transvaginal pelvic ultrasound and appropriate workup, and refer to partner gynecologists and gynecologic oncologists based on results. Consultations are available in our Quebec branches, as well as via telemedicine for the entire province. To book an appointment, visit cliniqueomicron.ca.

The content of this page is provided for information purposes only and does not replace the advice of a qualified healthcare professional. The diagnosis and management of uterine cancer require specialized gynecological evaluation and a multidisciplinary decision.