What is endometrial cancer and how is it diagnosed and treated?

Endometrial Cancer: Comprehensive Overview

Epidemiology and Incidence

Endometrial cancer is the most common gynecologic malignancy in the United States and the fourth most common cancer in women overall, with a crude incidence of 16 cases per 100,000 women per year in the European Union. 1, 2

• The lifetime risk of developing endometrial cancer is 1.7–2%, with mortality rates of 4–5 per 100,000 women per year 1
• Age-standardized incidence rates have been rising in most developed countries, with a 132% increase over the last 30 years 3
• More than 90% of cases occur in women older than 50 years 4
• Approximately 75% of patients present with stage I disease confined to the uterus 4

Risk Factors

The primary risk factors relate to excessive unopposed estrogen exposure to the endometrium. 2

Hormonal Risk Factors:

• Unopposed estrogen therapy 2
• Early menarche and late menopause 2
• Tamoxifen therapy 5, 2
• Nulliparity and infertility 5, 2
• Polycystic ovary syndrome (PCOS) 5, 2
• Chronic anovulation 5

Metabolic Risk Factors:

• Obesity (major modifiable risk factor) 2
• Diabetes mellitus 5, 2
• Hypertension 5, 2

Genetic Risk Factors:

• Lynch syndrome (hereditary nonpolyposis colorectal cancer) confers a 30–60% lifetime risk of endometrial cancer 6, 5, 2

Clinical Presentation

Abnormal uterine bleeding is present in 90% of endometrial cancer cases, particularly postmenopausal bleeding. 5, 4

• Postmenopausal bleeding is the hallmark presentation and mandates evaluation 5
• Premenopausal women may present with irregular, heavy, or intermenstrual bleeding 5
• Approximately 10% of patients may be asymptomatic 4

Diagnostic Approach

Initial Evaluation Algorithm:

Step 1: Transvaginal Ultrasound (TVUS)

TVUS measuring endometrial thickness is the first-line diagnostic test for suspected endometrial cancer. 6, 4

• An endometrial thickness ≤3–4 mm in postmenopausal women has a negative predictive value for endometrial cancer of nearly 100% 6, 4
• Endometrial thickness ≥5 mm in postmenopausal women requires endometrial tissue sampling 6, 4
• TVUS should be combined with transabdominal ultrasound whenever possible for complete pelvic assessment 4

Step 2: Endometrial Sampling

Office-based endometrial sampling using Pipelle or Vabra devices is the preferred method, with sensitivities of 99.6% and 97.1% respectively for detecting endometrial carcinoma. 6, 5

• These devices are less invasive, can be performed without anesthesia, and provide adequate tissue in most cases 6
• Office endometrial biopsies have a false-negative rate of approximately 10% 5, 4

Step 3: Hysteroscopy with Directed Biopsy

When initial sampling is negative, non-diagnostic, or inadequate in a symptomatic patient, hysteroscopy with directed biopsy must be performed. 5

• Hysteroscopy allows direct visualization and targeted biopsy of focal lesions such as polyps 5
• This is particularly important for focal endometrial abnormalities that may be missed by blind sampling 4

Special Diagnostic Considerations:

Saline Infusion Sonohysterography (SIS):

• Should be considered when focal lesions are suspected on initial TVUS 6, 4
• Has high sensitivity (96–100%) and negative predictive value (94–100%) for assessing uterine pathology 5

MRI with Contrast:

• Contrast-enhanced dynamic MRI is the best way to assess uterine and locoregional pelvic extension of disease 1
• Reserved for cases where ultrasound is inconclusive or further characterization is needed 4

Specific Clinical Scenarios:

Postmenopausal Women:

• All postmenopausal bleeding with endometrial thickness ≥3–4 mm warrants endometrial biopsy 5
• Persistent or recurrent bleeding despite negative initial biopsy requires hysteroscopy 5

Premenopausal Women:

• Women with risk factors (unopposed estrogen, PCOS, tamoxifen, obesity, nulliparity) should undergo endometrial sampling despite age 6
• Women ≥35 years with atypical glandular cells on cervical cytology require endometrial biopsy 5

Lynch Syndrome Patients:

• Annual endometrial biopsy starting at age 30–35 years is required due to 30–60% lifetime risk 6, 5

Critical Pitfalls to Avoid:

• Never accept an inadequate or negative endometrial biopsy as reassuring in a symptomatic postmenopausal woman—persistent bleeding mandates further evaluation 5
• Fractional D&C has largely been replaced by office-based sampling and hysteroscopy, though it may still be needed when office biopsy fails 6, 5
• D&C has a 30% risk of missing concurrent cancer in patients with complex atypical hyperplasia 6

Histopathological Classification

Diagnosis requires histopathological confirmation according to WHO classification. 1

Histological Subtypes:

• Endometrioid carcinoma: 80% of cases 1
• Serous carcinoma: 5–10% (poor prognosis) 1
• Clear cell carcinoma: 1–5% (poor prognosis) 1
• Mucinous, mixed, squamous cell, transitional cell, and undifferentiated carcinomas 1
• Endometrial carcinosarcoma: special poor-prognosis subtype 1

Note: Serous and clear cell carcinomas account for almost half of all relapses despite their lower incidence. 7

Histological Grading:

Cases must be graded according to degree of differentiation: 1

• G1: Non-squamous, non-morular solid growth pattern ≤5% of tumor 1
• G2: Non-squamous, non-morular solid growth pattern 5–50% of tumor 1
• G3: Non-squamous, non-morular solid growth pattern >50% of tumor 1

Notable nuclear atypia inappropriate for architectural grade raises the grade by one level. 1

Staging and Risk Assessment

Endometrial carcinoma is a surgically staged disease using the FIGO staging system. 1

FIGO Staging System:

Stage I: Confined to the uterine corpus 1

• Ia: Tumor limited to the endometrium 1
• Ib: Invasion to less than one-half of the myometrium 1
• Ic: Invasion to more than one-half of the myometrium 1

Stage II: Extension to the uterine cervix 1

• IIa: Endocervical glandular involvement only 1
• IIb: Cervical stromal invasion 1

Stage III: Extension beyond the uterus 1

• IIIa: Tumor invades serosa and/or adnexa, and/or positive peritoneal cytology 1
• IIIb: Vaginal involvement 1
• IIIc: Metastasis to pelvic or para-aortic lymph nodes 1

Stage IV: Invasion in neighboring organs or distant metastases 1

• IVa: Tumor invasion of bladder and/or bowel mucosa 1
• IVb: Distant metastases including intra-abdominal or inguinal lymph nodes 1

Preoperative Workup:

Before surgery, patients should have: 1

• Chest X-ray 1
• Clinical and gynecological examination including transvaginal ultrasound 1
• Blood counts, liver and renal function profiles 1
• CT scan of abdomen and retroperitoneal nodes may be helpful for extra-uterine spread 1
• Contrast-enhanced dynamic MRI is the best method to assess uterine and locoregional pelvic extension 1

Surgical Staging Procedure:

The minimal surgical procedure should include: 1

• Acquisition of peritoneal fluid or washings 1
• Thorough exploration of abdominal cavity and pelvic and para-aortic nodal areas 1
• Total hysterectomy with bilateral salpingo-oophorectomy 1
• In high-risk cases: retroperitoneal lymph node dissection and omentectomy (for serous carcinomas), though survival benefit is debated 1

Prognostic Factors:

Established independent prognostic factors include: 1

• FIGO surgical stage 1
• Histological grade 1
• Depth of myometrial invasion 1
• Histological type 1
• Age 1
• Lymph-vascular space invasion 1
• Endocervical involvement 1
• Tumor diameter 1

Risk Stratification for Stage I Disease:

Approximately 75% of patients present with stage I disease and can be subdivided into three risk categories: 1

Low Risk:

• Stage Ia/Ib, grade 1 or 2, endometrioid histology 1

Intermediate Risk:

• Stage Ic, grade 1 or 2, endometrioid histology 1
• Stage Ia/Ib, grade 3, endometrioid histology 1

High Risk:

• Stage Ic, grade 3, endometrioid histology 1
• Any stage with serous or clear cell histology 1

Important caveat: Preoperative histological diagnosis based on endometrial sampling is changed at final histological evaluation in up to 25% of cases. 1

Molecular Classification

Four endometrial cancer molecular classes have been identified by The Cancer Genome Atlas (TCGA) project, with stronger prognostic impact than histopathological characteristics: 8

1. POLE ultra-mutated (best prognosis) 8
2. Microsatellite instable hypermutated 8
3. Copy-number-low 8
4. Copy-number-high (worst prognosis) 8

All four molecular subtypes are found across all stages, histological types, and grades, introducing a new era of molecular classification-based diagnostics and treatment. 8

Treatment

Stage I Disease:

Low-Risk Disease:

• No adjuvant therapy required—surgery alone is adequate 1, 8

High-Intermediate Risk Disease:

• Adjuvant vaginal brachytherapy is recommended to maximize local control 8
• Has only mild side effects without impact on quality of life 8

High-Risk Disease:

• Pelvic radiotherapy is supported for stage I-II endometrial cancer with risk factors 8

Advanced Stage Disease:

Stage III Disease and Serous Cancers:

• Chemoradiation increased both recurrence-free and overall survival 1, 8
• Combined chemotherapy and radiotherapy provides better pelvic and para-aortic nodal control compared to chemotherapy alone 8

Stage III and IV Optimally Debulked Disease:

• Cisplatin and doxorubicin combination chemotherapy significantly improves progression-free survival (PFS) and overall survival (OS) compared to whole abdominal radiation therapy 1
• Alternative option: carboplatin and paclitaxel combination due to lower toxicity 1
• Dosages and number of courses follow recommendations for advanced-stage ovarian cancer 1

Hormonal Therapy:

Progestational agents (e.g., medroxyprogesterone acetate 200 mg daily) are active in steroid-receptor positive tumors, mostly G1 and G2 lesions. 1

Targeted and Immunotherapy:

Molecular classification is increasingly used to guide adjuvant treatment decisions and targeted therapies, particularly immunotherapy for microsatellite instable tumors. 8, 3

Recurrent Disease:

Treatment requires an individualized approach including: 7

• Surgery (for isolated recurrences) 7
• Radiation therapy 7
• Hormonal therapy 7
• Cytotoxic chemotherapy 7
• Biological agents 7

Prognosis

Survival is defined by stage and histology: 2

• Most patients with stage I and II disease have favorable prognosis 2
• Early diagnosis is associated with improved survival, with excellent survival rates when diagnosed at early stages 4
• Serous and clear cell carcinomas have poor prognosis and account for almost half of all relapses despite lower incidence 7

Prevention Strategies

Controlling modifiable risk factors could play a role in prevention: 2

• Weight management to address obesity 2
• Control of diabetes mellitus 2
• Management of hypertension 2

There is no evidence to support endometrial cancer screening in asymptomatic women, but the American Cancer Society recommends that all women older than 65 years be informed of risks and symptoms. 2