Endometrial Cancer

Symptoms

• Abnormal Uterine Bleeding (AUB)
• Postmenopausal Bleeding (any bleeding after menopause)
• Premenopausal AUB (heavy, prolonged, or intermenstrual bleeding)
• Abnormal, non-bloody vaginal discharge (watery or purulent)
• Pelvic pain or pressure
• Dyspareunia (pain during intercourse)
• A palpable pelvic mass
• Unintentional weight loss
• Bowel or bladder symptoms (e.g., change in habits, tenesmus) in advanced disease
• Abdominal distension (ascites) in advanced disease
• Symptoms of distant metastases (e.g., cough, bone pain) in advanced disease

Causes & Risk Factors

• Hormonal Imbalance: Prolonged exposure of the endometrium to estrogen without the counteracting effects of progesterone, which can lead to endometrial proliferation and cancer, primarily for Type I endometrial cancer.
• Genetic Mutations: Acquired (somatic) mutations in genes such as PTEN, PIK3CA, KRAS, CTNNB1 (Type I) and TP53, PPP2R1A (Type II).
• Inherited (germline) mutations: Most notably in DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, PMS2) causing Lynch syndrome, which accounts for 2-5% of all endometrial cancers.
• Molecular Classification: Current understanding categorizes endometrial cancers into four prognostic groups based on molecular features: POLE ultramutated (excellent prognosis), Microsatellite instability-high (MSI-H, intermediate prognosis), Copy-number low / Microsatellite stable (MSS, intermediate prognosis), and Copy-number high / Serous-like (poor prognosis). This classification helps refine risk and guide treatment.
• Unopposed Estrogen Exposure (e.g., use of estrogen-only hormone replacement therapy)
• Obesity (peripheral conversion of androgens to estrone in adipose tissue)
• Nulliparity (no history of childbirth)
• Early Menarche (first menstruation at a young age)
• Late Menopause (longer lifetime exposure to endogenous estrogen)
• Polycystic Ovary Syndrome (PCOS) (chronic anovulation leading to unopposed estrogen)
• Tamoxifen Use (has a weak estrogenic effect on the endometrium)
• Age (risk increases with age, most cases diagnosed in postmenopausal women)
• Diabetes Mellitus (associated with hyperinsulinemia and obesity)
• Hereditary Syndromes (e.g., Lynch syndrome, Cowden syndrome)
• High-fat diet (possible risk factor)
• Physical inactivity (possible risk factor)
• Hypertension (possible risk factor)
• Race (Black women have a higher incidence of aggressive subtypes and higher mortality)
• History of pelvic radiation

Diagnosis

• History and Physical Examination: Detailed menstrual, obstetric, and medication history, assessment of risk factors, family history of cancer, general physical exam, abdominal exam, and pelvic exam.
• Transvaginal Ultrasound (TVUS): Initial imaging to measure endometrial thickness (ET). In postmenopausal women, an ET of ≤4 mm has a high negative predictive value for endometrial cancer. Further investigation is needed for ET >4 mm or persistent bleeding.
• Endometrial Sampling: Required for definitive diagnosis. This includes office endometrial biopsy (e.g., Pipelle) as a first-line procedure, or hysteroscopy with dilatation and curettage (D&C) if the biopsy is non-diagnostic or clinical suspicion remains high.
• Laboratory Tests: CA-125 (may be elevated in advanced disease, used to monitor treatment response, not for screening or diagnosis), Complete Blood Count (CBC) to check for anemia.
• Staging Workup (after diagnosis): Imaging such as Chest X-ray, CT of the chest/abdomen/pelvis, or PET/CT to assess for metastatic disease in high-risk cancers. Definitive staging is surgical, based on the FIGO 2023 staging system.

Treatment Options

• Surgical Treatment: The primary treatment involves total hysterectomy (removal of the uterus and cervix) and bilateral salpingo-oophorectomy (removal of fallopian tubes and ovaries). Minimally invasive approaches (laparoscopy or robotic-assisted laparoscopy) are preferred when possible. Surgical staging includes peritoneal washings and lymph node assessment, with sentinel lymph node (SLN) biopsy being the preferred method for uterine-confined disease.
• Adjuvant Treatment (Post-Surgical): Based on surgical stage, tumor grade, and other factors. This may include radiation therapy (vaginal brachytherapy for vaginal cuff recurrence risk or external beam radiation therapy for higher-risk features) or chemotherapy (typically platinum-based regimens like carboplatin and paclitaxel for advanced or high-risk disease). Hormone therapy (progestins or aromatase inhibitors) may be used for low-grade, hormone receptor-positive tumors.
• Treatment for Advanced or Recurrent Disease: May involve a combination of surgery, radiation, chemotherapy, hormone therapy, targeted therapy, and immunotherapy. Immunotherapy with immune checkpoint inhibitors (e.g., pembrolizumab, dostarlimab) is effective for tumors that are mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H). Targeted therapy, such as lenvatinib in combination with pembrolizumab, is an option for advanced endometrial cancer that is not MSI-H or dMMR.
• Fertility-Sparing Treatment: For highly selected premenopausal patients with a strong desire for fertility and early-stage, low-grade endometrioid adenocarcinoma confined to the endometrium. Treatment involves high-dose oral progestin therapy or a levonorgestrel-releasing IUD, with close surveillance through endometrial biopsies every 3-6 months. Hysterectomy is recommended after childbearing is complete.

Frequently Asked Questions