Uterine Cancer

Endometrial carcinoma subtypes, Lynch syndrome screening, staging, and evolving immunotherapy-based treatment strategies

Key Points

• Uterine cancer is the most common gynecologic malignancy in the US; ~67,880 new cases and ~13,250 deaths were projected in 2024.
• Two main types: Type I (endometrioid, estrogen-driven, low-grade, better prognosis) and Type II (serous, clear cell, carcinosarcoma — aggressive, p53-mutated, poor prognosis).
• Lynch syndrome (MMR deficiency) accounts for ~3–5% of endometrial cancers; women with Lynch syndrome have a 40–60% lifetime risk of endometrial cancer.
• Universal MMR/MSI testing of all endometrial cancers is now recommended for Lynch syndrome screening and treatment stratification.
• Surgical staging (total hysterectomy + bilateral salpingo-oophorectomy ± lymph node assessment) is the cornerstone of treatment.
• Pembrolizumab + lenvatinib is a standard second-line therapy for advanced/recurrent non-MSI-H endometrial cancer after chemotherapy.
• dMMR/MSI-H endometrial cancer responds remarkably to immune checkpoint inhibition — pembrolizumab monotherapy achieves durable responses.

Epidemiology & Incidence

Uterine cancer (predominantly endometrial carcinoma, arising from the uterine lining) is the most common gynecologic malignancy and the fourth most common cancer in American women. In 2024, approximately 67,880 new cases and 13,250 deaths were projected in the US — mortality has been rising, particularly among Black women who have ~2× the mortality rate of White women despite similar or lower incidence, reflecting disparities in access, comorbidities, and tumor biology. Incidence has increased over recent decades, largely attributed to the obesity epidemic (adipose tissue is a source of…

Genetic Predispositions & Risk Factors

Risk factors for Type I (endometrioid) endometrial cancer are predominantly estrogen-related: • Obesity: The strongest modifiable risk factor; BMI >40 confers ~6× increased risk. Peripheral aromatization of androgens to estrogen in adipose tissue drives unopposed estrogenic stimulation. • Unopposed estrogen therapy: Exogenous estrogen without progestogen markedly increases risk (4–8×); addition of progestogen eliminates excess risk. • Tamoxifen: Selective estrogen receptor modulator acting as a partial agonist in the uterus; ~2× increased risk with long-term use for breast cancer. •…

Clinical Presentation

Unlike most cancers, uterine cancer typically presents early due to the highly symptomatic nature of the primary symptom: • Abnormal uterine bleeding (AUB): The cardinal symptom; present in ~90% of cases. In postmenopausal women, ANY vaginal bleeding warrants endometrial evaluation — postmenopausal bleeding is endometrial cancer until proven otherwise (cancer found in ~10% of cases). In premenopausal women, presentation is often irregular or heavy menstrual bleeding, intermenstrual bleeding, or unexpected bleeding. • Pelvic pain or pressure: Suggests larger tumors or extrauterine extension.…

Staging & Treatment

Uterine cancer is staged surgically (FIGO 2023): Stage I: Confined to uterine corpus • IA: ≤50% myometrial invasion (or polyp/no invasion) • IB: >50% myometrial invasion • IC: Serous, clear cell, undifferentiated, or carcinosarcoma — any myometrial invasion Stage II: Cervical stromal invasion Stage III: Regional spread (adnexa, vagina, parametria, pelvic/para-aortic nodes) Stage IV: Bladder/bowel mucosa (IVA) or distant metastases (IVB) Surgical treatment: Total hysterectomy + bilateral salpingo-oophorectomy (TH/BSO) is the cornerstone; can be performed minimally invasively…