Endometrial Carcinoma

Pathogenesis - Two Types

• Estrogen-dependent, arises from a background of endometrial hyperplasia
• Occurs in younger, perimenopausal women with unopposed estrogen exposure (endogenous or exogenous)
• Usually well-differentiated (endometrioid histology), favorable prognosis
• Early molecular changes: inactivation of DNA mismatch repair genes and the PTEN gene

• Estrogen-independent, arises against a background of endometrial atrophy, not hyperplasia
• Occurs in older, postmenopausal, often thin women; disproportionately affects African American and Asian women
• Poorly differentiated (serous, clear cell histology), worse prognosis
• Early molecular event: TP53 mutation, often present even in the precursor lesion (serous endometrial intraepithelial carcinoma)
• Serous and clear cell carcinomas make up less than 10% of cases but cause more than half of all endometrial cancer deaths

Risk Factors

• Nulliparity (2-3x risk)
• Anovulatory cycles / infertility / irregular menses
• Late menopause (after 52, 2.4x risk vs. before 49)
• Obesity (1.5x overweight, >2.5x obese - from peripheral aromatization of androstenedione to estrone)
• Unopposed exogenous estrogen therapy (4-8x risk, increases with dose and duration)
• Diabetes, hypertension, PCOS, tamoxifen use, Lynch syndrome/HNPCC

Clinical Presentation

• Postmenopausal bleeding is the cardinal symptom - though only about 10% of women with postmenopausal bleeding actually have endometrial cancer (endometrial atrophy 60-80%, estrogen therapy 15-25%, polyps 2-12%, hyperplasia 5-10% account for the rest).
• Premenopausal women may have menometrorrhagia, oligomenorrhea, or bleeding persisting past the usual age of menopause.
• Physical exam is often unremarkable early; look for peripheral lymphadenopathy, adnexal masses, parametrial induration, or cul-de-sac nodularity in advanced disease.

Diagnosis

• Office endometrial aspiration biopsy is the first-line diagnostic step (90-98% diagnostic accuracy vs. D&C/hysterectomy).
• Transvaginal ultrasound and hysteroscopy are useful adjuncts, especially if biopsy is inconclusive or polyps are suspected.
• Preoperative workup: history/physical, chest X-ray (to exclude pulmonary metastases), CBC, EKG. CT or MRI can help assess myometrial invasion and guide extent of surgery, particularly in type II disease.

Pathologic Types

• Endometrioid adenocarcinoma (most common)
• Mucinous carcinoma
• Serous carcinoma
• Clear cell carcinoma
• Squamous carcinoma

Staging (FIGO, surgical)

• Combined former stages IA/IB into a single Stage I
• Eliminated old Stage IIA - only cervical stromal invasion now defines Stage II
• Removed positive peritoneal cytology as an upstaging criterion (though washings are still recommended and retain prognostic value)
• Split Stage IIIC into IIIC1 (positive pelvic nodes) and IIIC2 (positive para-aortic nodes)
• Recognized parametrial involvement as Stage IIIB

Prognostic Factors

Treatment

• Surgery (hysterectomy, BSO, staging) is primary treatment for most patients.
• Adjuvant radiotherapy (vaginal vault brachytherapy, external pelvic radiation, or extended-field/whole-abdomen radiation depending on risk factors) reduces local/vaginal recurrence and improves disease-free survival in selected higher-risk patients.
• Chemotherapy is used for advanced-stage, high-grade, or recurrent disease.
• Hormonal therapy (progestins) has a role in low-grade, hormone-receptor-positive disease and in fertility-sparing management of early (Stage IA) endometrioid cancer in young women who wish to preserve fertility.
• Recurrent disease: isolated vaginal recurrences can be salvaged with radiotherapy in up to 80% of previously unirradiated patients.

Recent Evidence Worth Noting

• Fertility-sparing treatment for atypical hyperplasia and early endometrial cancer (progestins, levonorgestrel IUD, +/- metformin) - Cochrane systematic review, 2025 (PMID: 40626388), and a related meta-analysis specific to Stage IA cancer (PMID: 39032722, 2024). These support fertility preservation as a reasonable option in carefully selected young patients with well-differentiated, superficial disease, but with recurrence risk that needs counseling.
• First-line treatment for advanced/recurrent disease has shifted meaningfully with immunotherapy (e.g., pembrolizumab combinations) - systematic review, 2025 (PMID: 39557140). This reflects a significant update from older chemotherapy-only paradigms, particularly relevant for mismatch-repair-deficient (dMMR) tumors.