Endometrial Cancer: Risk Factors and Management
Risk Factors
The primary risk factors for endometrial cancer are obesity, unopposed estrogen exposure, and Lynch syndrome, with obesity increasing risk 3-4 fold and Lynch syndrome conferring up to 60% lifetime risk. 1
Modifiable Risk Factors
- Obesity (BMI >30) increases endometrial cancer risk 3-4 fold through chronic hyperestrogenism 1
- Unopposed estrogen therapy without progesterone creates prolonged endometrial stimulation 1, 2
- Tamoxifen therapy acts as an estrogen agonist on the endometrium 1, 2
- Nulliparity and anovulation result in chronic unopposed estrogen exposure 1, 2
- Polycystic ovary syndrome causes chronic anovulation and hyperestrogenism 1, 2
Non-Modifiable Risk Factors
- Age >50 years with median diagnosis at 63 years 1
- Early menarche and late menopause extend lifetime estrogen exposure 2
- Hypertension and diabetes mellitus are associated with metabolic syndrome 1, 2
Genetic Risk Factors
Universal tumor testing for mismatch repair (MMR) deficiency is recommended for all endometrial cancers to identify Lynch syndrome. 1
- Lynch syndrome accounts for ~5% of endometrial cancers with 40-60% lifetime risk 1, 3
- MLH1, MSH2, MSH6, PMS2, and EPCAM mutations cause Lynch syndrome 1
- MLH1 loss should be evaluated for promoter methylation to distinguish sporadic from germline mutations 1
- Genetic counseling and testing is mandatory for all MMR abnormalities except sporadic MLH1 methylation 1
Protective Factors
- Combined oral contraceptives significantly reduce endometrial cancer risk in premenopausal and perimenopausal women 1
Diagnosis and Workup
Postmenopausal bleeding is the presenting symptom in 90% of endometrial cancer cases and mandates immediate evaluation with endometrial sampling. 1
Initial Diagnostic Approach
- Endometrial biopsy (Pipelle or Vabra) has 97-99% sensitivity for detecting endometrial carcinoma 1
- Transvaginal ultrasound with endometrial thickness ≤3mm has 98% sensitivity but only 35% specificity 1
- Dilatation and curettage (D&C) with or without hysteroscopy provides definitive tissue diagnosis 1
- Hysteroscopy with biopsy should be the final diagnostic step if initial sampling is inadequate 1
Staging Workup
- Pelvic MRI is essential to assess myometrial invasion depth and cervical involvement 1
- Gynecologic oncologist involvement is recommended for primary management of all endometrial cancer patients 1
Prognostic Factors
Risk stratification depends on stage, grade, depth of myometrial invasion, lymphovascular space invasion (LVSI), and histologic subtype. 1
High-Risk Features for Recurrence
- Grade 3 endometrioid histology regardless of myometrial invasion 1
- Deep myometrial invasion (≥50%) increases recurrence risk 1
- Lymphovascular space invasion (LVSI) when unequivocally positive 1
- Non-endometrioid histologies (serous, clear cell, carcinosarcoma) have aggressive behavior 1
- Positive lymph nodes significantly worsen prognosis 1
- Lower uterine segment involvement increases risk 1
- Older age at diagnosis correlates with worse outcomes 1
Surgical Management
Total hysterectomy with bilateral salpingo-oophorectomy is the mainstay of treatment for endometrial cancer. 1, 2
Surgical Approach
- Minimally invasive surgery (laparoscopic/robotic) is recommended for low- and intermediate-risk disease and can be considered for high-risk disease 1
- Vaginal hysterectomy with BSO is an option for medically unfit patients who cannot tolerate laparoscopy 1
Lymphadenectomy Recommendations
For low-risk disease (Grade 1-2, <50% myometrial invasion): Lymphadenectomy can be considered for staging, with sentinel lymph node dissection (SLND) as an option 1
For high-risk disease (Grade 3 or ≥50% myometrial invasion or non-endometrioid histology): Systematic pelvic and para-aortic lymphadenectomy up to the renal veins is recommended to guide staging and adjuvant therapy 1
For Stage III-IV disease: Comprehensive lymphadenectomy is recommended as part of staging 1
Adjuvant Treatment
Low-Risk Disease (Stage I, Grade 1-2, <50% myometrial invasion, LVSI negative)
- No adjuvant treatment or observation alone is appropriate 1
Intermediate-Risk Disease (Stage I, Grade 1-2, ≥50% myometrial invasion, LVSI negative)
- Vaginal brachytherapy is the preferred adjuvant treatment 1
- No adjuvant treatment is an option, especially for patients <60 years old 1
- If Grade 3 or LVSI unequivocally positive: Consider adjuvant chemotherapy (combined and/or sequential) 1
High-Risk Disease (Stage I, Grade 3, ≥50% myometrial invasion)
With surgical nodal staging, node negative:
- Vaginal brachytherapy for Grade 1-2, LVSI negative 1
- Limited field external beam radiation therapy (EBRT) for Grade 3 or LVSI unequivocally positive 1
Without surgical nodal staging:
- Adjuvant EBRT is recommended 1
- Adjuvant chemotherapy (combined and/or sequential) can be considered, with greater evidence supporting combined chemotherapy plus EBRT 1
Non-Endometrioid Histologies (Serous, Clear Cell, Carcinosarcoma, Undifferentiated)
- Carcinosarcoma and undifferentiated tumors: Adjuvant chemotherapy is recommended 1
- Stage IIIC2 disease: Chemotherapy plus extended field EBRT should be considered 1
Management of Advanced/Recurrent Disease
For recurrent endometrial cancer, MSI-H or dMMR testing should be performed if not previously done. 1
Systemic Therapy Options
- Pembrolizumab is indicated for MSI-H or dMMR tumors that have progressed following prior cytotoxic chemotherapy 1
- Bevacizumab may be considered for patients who have progressed on prior cytotoxic chemotherapy 1
- Hormonal therapy (progestins) may be used for lower-grade endometrioid histologies only (not for Grade 3 endometrioid, serous, clear cell, or carcinosarcoma), preferably in patients with small tumor volume or indolent growth 1
Fertility-Sparing Management
Fertility-sparing treatment with progestins is a non-standard option reserved only for highly selected patients with atypical hyperplasia/EIN or Grade 1 endometrioid endometrial cancer. 1, 4
Eligibility Criteria for Fertility Preservation
Patients must meet ALL of the following criteria 1, 4:
- Referral to specialized centers is mandatory
- D&C with or without hysteroscopy to confirm diagnosis
- Confirmation by specialist gynaecopathologist of atypical hyperplasia/EIN or Grade 1 endometrioid cancer
- Pelvic MRI to exclude myometrial invasion and adnexal involvement
- Full informed consent that this is non-standard treatment
- Willingness to accept close follow-up with endometrial sampling every 3-6 months
Treatment Regimens
- Medroxyprogesterone acetate (MPA) or megestrol acetate (MA) are recommended 1, 4
- Progestin-loaded IUD is also an option 1, 4
- Complete response occurs in ~50% of patients with progestin therapy 4
- Recurrence rates remain high at 35% even after initial response 4
Post-Treatment Management
- Hysterectomy and bilateral salpingo-oophorectomy is recommended after completion of childbearing 1, 4
Lynch Syndrome Screening and Prevention
All women with newly diagnosed endometrial cancer should undergo universal tumor screening for Lynch syndrome using immunohistochemistry for MMR proteins. 1
Screening Protocol for Lynch Syndrome Carriers
- Annual endometrial biopsy starting at age 35 or 5-10 years before earliest family diagnosis 1, 4
- Annual gynecological examination and transvaginal ultrasound 4
- Annual colonoscopy for colorectal cancer screening 1
Prevention Strategies
- Prophylactic hysterectomy and bilateral salpingo-oophorectomy should be discussed after childbearing is complete or at age 40-45 1, 4, 3
- Oral contraceptives may reduce risk but data specific to Lynch syndrome are limited 3
Critical Caveats
- Negative Pap smear does NOT rule out endometrial cancer - it is inefficient for endometrial cancer detection 5
- Occult endometrial cancer may be present in Lynch syndrome patients undergoing prophylactic hysterectomy; consider preoperative endometrial biopsy 6
- Albumin-bound paclitaxel is NOT a substitute for paclitaxel if skin test is positive 1
- Progestin therapy is contraindicated in women with history of breast cancer, stroke, MI, PE, DVT, or active smoking 4
- Hormonal therapy should NOT be used for Grade 3 endometrioid, serous, clear cell, or carcinosarcoma histologies 1