Endometrial Cancer: Causes, Symptoms, Diagnosis and Treatment — Overview, Diagnosis & Treatment Options | MyMedicPlus

Endometrial cancer (EC) is the most common gynecologic malignancy in developed countries and the 4th most common cancer in women, with approximately 66,000 new US cases and 13,000 deaths annually. The vast majority — approximately 80% — are endometrioid adenocarcinomas arising from the uterine lining, classified historically as type 1 (estrogen-driven, low-grade, favorable prognosis) or type 2 (estrogen-independent, high-grade serous or clear cell, aggressive). The contemporary TCGA/ProMisE molecular classification has superseded this two-type model, defining four prognostically distinct groups: POLE-ultramutated (best prognosis), MSI-H/MMR-deficient, copy number low, and copy number high/TP53-mutated. Most EC presents in postmenopausal women aged 60–70 years with early-stage disease due to the symptom of postmenopausal bleeding, which prompts timely evaluation and contributes to an overall 5-year survival of approximately 80%.

Type 1 endometrioid adenocarcinoma is driven by unopposed estrogen exposure, which stimulates endometrial proliferation without the opposing effect of progesterone. Major risk factors include obesity (adipose tissue converts androgens to estrogens, increasing risk 2–4-fold for each 5-unit BMI increase), polycystic ovary syndrome (chronic anovulation and unopposed estrogen), nulliparity, late menopause (after age 55), type 2 diabetes mellitus, tamoxifen use (increases risk approximately 2.5-fold after 5 years), and estrogen-only postmenopausal HRT. Lynch syndrome — caused by germline mutations in MMR genes (MLH1, MSH2, MSH6, PMS2) — accounts for 3–5% of EC with lifetime risk up to 40–60%. Type 2 tumors (serous, clear cell, carcinosarcoma) are estrogen-independent and associated with TP53 mutations, PTEN loss, and chromosomal instability.

Postmenopausal vaginal bleeding is the cardinal presenting symptom, occurring in approximately 90% of endometrial cancer cases and should always prompt urgent evaluation regardless of the quantity of bleeding — even a single episode of spotting warrants investigation. Premenopausal or perimenopausal women may present with heavy, prolonged, or irregular menstrual bleeding, or bleeding between periods (intermenstrual bleeding). Advanced disease causes pelvic pain or pressure, a sensation of pelvic fullness, cervical discharge (watery, mucopurulent, or bloody), dyspareunia, and bowel or bladder symptoms from local extension. Peritoneal carcinomatosis causes ascites and abdominal distension. Constitutional symptoms including weight loss, fatigue, and anorexia indicate systemic or advanced disease.

Transvaginal ultrasound (TVUS) is the initial investigation in postmenopausal bleeding: an endometrial thickness greater than 4 mm requires histological sampling. Endometrial biopsy via pipelle aspiration provides tissue diagnosis in the outpatient setting; hysteroscopy with targeted biopsy is used when office biopsy is non-diagnostic or the endometrial cavity is not accessible. MRI of the pelvis is the standard imaging modality to assess depth of myometrial invasion (superficial versus deep), cervical stromal involvement, and lymph node status — critical for surgical planning and risk stratification. CT or PET-CT evaluates nodal and distant metastases in high-grade or advanced disease. Comprehensive molecular profiling — POLE sequencing, MSI/MMR testing by IHC or PCR, and TP53 mutation analysis — is now standard and guides adjuvant therapy decisions per ESGO/ESTRO/ESP guidelines.

Primary treatment is total hysterectomy with bilateral salpingo-oophorectomy and comprehensive surgical staging, including pelvic and para-aortic lymphadenectomy or sentinel lymph node mapping (which has comparable accuracy with reduced morbidity). Minimally invasive approaches (laparoscopic or robotic) are preferred for most cases. Adjuvant therapy is determined by ESGO/ESTRO/ESP risk stratification incorporating stage, histological grade, LVSI, and molecular subtype. Low-risk disease: vaginal brachytherapy alone (for stage IB endometrioid, grade 1–2). Intermediate-risk: external beam pelvic radiation. High-intermediate to high-risk: carboplatin plus paclitaxel chemotherapy (4–6 cycles) with or without external beam RT. POLE-ultramutated: surgery alone (excellent prognosis). MSI-H advanced/recurrent EC: pembrolizumab; KEYNOTE-158 showed durable ORR of approximately 57%. Chemotherapy-refractory advanced disease: pembrolizumab plus lenvatinib (KEYNOTE-775, superior OS vs chemotherapy).

Five-year survival by FIGO stage: Stage I exceeds 85% (Stage IA low-grade: approximately 95%); Stage II approximately 75%; Stage III approximately 52%; Stage IV approximately 15–20%. Overall 5-year survival is approximately 80% due to predominantly early-stage presentation. POLE-ultramutated tumors carry greater than 95% survival. MSI-H advanced disease responds well to pembrolizumab-based therapy with durable responses. TP53-mutated serous-type EC has the worst prognosis (5-year survival Stage III–IV: approximately 20–30%). The prognosis for Endometrial Cancer: Causes, Symptoms, Diagnosis and Treatment varies depending on severity at diagnosis, the patient's overall health, and how promptly treatment is initiated. With early diagnosis and appropriate management, many patients achieve good outcomes and maintain quality of life. Regular follow-up with healthcare providers is essential to monitor progress, adjust treatment as needed, and detect any complications early. Adherence to prescribed treatments and lifestyle modifications significantly improves long-term prognosis.

No population-based screening for endometrial cancer is recommended for average-risk women, as postmenopausal bleeding prompts early detection in most cases. Women with Lynch syndrome should undergo annual endometrial biopsy starting at age 30–35 and consider risk-reducing hysterectomy after completing childbearing. Obesity management — through diet, exercise, and pharmacotherapy or bariatric surgery when indicated — substantially reduces EC risk. Oral contraceptive use reduces lifetime EC risk by 40–50% through progesterone-mediated endometrial shedding. Progestogen-containing IUDs similarly reduce risk. Tamoxifen therapy in breast cancer patients carries elevated EC risk and requires prompt evaluation of any abnormal uterine bleeding. Combined estrogen-progestogen HRT, rather than estrogen alone, eliminates the EC risk associated with HRT.

Any postmenopausal vaginal bleeding — regardless of how minimal — must be evaluated by a physician promptly, ideally within 2 weeks. This includes any spotting, discharge, or bleeding that occurs 12 or more months after the final menstrual period. Premenopausal women with heavy, irregular, or prolonged periods that are new for them, or intermenstrual bleeding persisting beyond one menstrual cycle, warrant investigation. Pelvic pain, feeling of fullness, or pressure in the lower abdomen in a postmenopausal woman requires assessment. Women with Lynch syndrome or on tamoxifen therapy should report any abnormal bleeding immediately to their gynecologist. Abnormal uterine bleeding in the context of obesity, diabetes, or polycystic ovary syndrome should not be attributed to these conditions without appropriate endometrial evaluation.