Overview

Endometrial cancer originates in the endometrium, the inner lining of the uterus that thickens each month in preparation for potential pregnancy and sheds during menstruation. This cancer represents approximately 3.5% of all new cancer cases and is the fourth most common cancer among women in the United States. The disease primarily affects postmenopausal women, with the average age at diagnosis being 60 years, though it can occur in younger women, particularly those with genetic predispositions or hormonal imbalances.

There are two main types of endometrial cancer. Type I endometrial cancers, accounting for about 80% of cases, are typically estrogen-dependent, lower-grade tumors that develop from endometrial hyperplasia. These generally have a better prognosis. Type II endometrial cancers are estrogen-independent, higher-grade tumors that tend to be more aggressive and have a poorer prognosis. They include serous carcinoma, clear cell carcinoma, and carcinosarcoma. Understanding the type is crucial for determining appropriate treatment strategies.

The incidence of endometrial cancer has been rising, largely attributed to increasing obesity rates and longer life expectancy. However, the overall prognosis remains favorable when detected early, with five-year survival rates exceeding 95% for localized disease. The key to successful outcomes lies in recognizing symptoms early, as endometrial cancer typically presents with warning signs even in early stages. This characteristic distinguishes it from many other cancers that remain asymptomatic until advanced stages, making awareness of symptoms particularly important for women's health.

Symptoms

Endometrial cancer often presents with noticeable symptoms early in its development, which contributes to better outcomes compared to many other cancers. Recognition of these symptoms is crucial for prompt diagnosis and treatment.

Primary Symptoms

• Vaginal bleeding after menopause - The most common and important warning sign
• Intermenstrual bleeding - Bleeding between periods in premenopausal women
• Absence of menstruation - Irregular periods or changes in menstrual pattern
• Abnormal vaginal discharge - May be watery, pink, or blood-tinged
• Pelvic pain or pressure - Often occurs in more advanced stages

Associated Symptoms

• Vaginal itching - May accompany other vaginal symptoms
• Hot flashes - Can be related to hormonal changes
• Pain during intercourse (dyspareunia)
• Unintended weight loss - Typically in advanced stages
• Fatigue and weakness
• Difficulty or pain when urinating

Symptom Patterns by Menopausal Status

Postmenopausal women: Any vaginal bleeding after menopause is abnormal and requires immediate evaluation. This includes spotting, light bleeding, or heavier bleeding. Approximately 90% of women with endometrial cancer experience postmenopausal bleeding, though only 5-10% of women with such bleeding have cancer.

Premenopausal women: Changes in menstrual patterns are key indicators. This includes heavier periods than normal, prolonged bleeding (lasting more than 7 days), bleeding between periods, or increasingly irregular cycles. Women under 40 with persistent abnormal bleeding should be evaluated, especially if they have risk factors.

Advanced Stage Symptoms

When endometrial cancer spreads beyond the uterus, additional symptoms may develop:

• Abdominal bloating or swelling
• Changes in bowel or bladder habits
• Persistent pelvic or back pain
• Leg swelling (lymphedema)
• Shortness of breath (if spread to lungs)
• Bone pain (if spread to bones)

Causes

Endometrial cancer develops when cells in the endometrium undergo genetic mutations that cause them to grow and multiply uncontrollably. Understanding the underlying causes helps in both prevention and treatment strategies.

Hormonal Imbalance

The primary driver of most endometrial cancers is prolonged exposure to estrogen without the balancing effect of progesterone. This hormonal imbalance causes the endometrium to grow excessively (hyperplasia), which can eventually lead to cancer. Situations creating this imbalance include:

• Estrogen therapy without progesterone
• Polycystic ovary syndrome (PCOS)
• Estrogen-producing tumors
• Late menopause (after age 55)
• Early menstruation (before age 12)
• Never having been pregnant

Genetic Mutations

Hereditary factors: Lynch syndrome (hereditary nonpolyposis colorectal cancer or HNPCC) significantly increases endometrial cancer risk. Women with Lynch syndrome have a 40-60% lifetime risk of developing endometrial cancer, often at younger ages. Other genetic conditions like Cowden syndrome also increase risk.

Acquired mutations: Most endometrial cancers result from mutations acquired during a person's lifetime. Common genetic alterations include:

• PTEN tumor suppressor gene mutations
• PIK3CA oncogene mutations
• KRAS mutations
• Microsatellite instability
• p53 tumor suppressor gene mutations (in aggressive types)

Endometrial Hyperplasia

This precancerous condition involves abnormal thickening of the endometrium. Types include:

• Simple hyperplasia without atypia - Low cancer risk (1%)
• Complex hyperplasia without atypia - Moderate risk (3%)
• Simple hyperplasia with atypia - Higher risk (8%)
• Complex hyperplasia with atypia - Highest risk (29%)

Metabolic and Inflammatory Factors

Obesity plays a crucial role through multiple mechanisms:

• Adipose tissue converts androgens to estrogen
• Insulin resistance and hyperinsulinemia
• Chronic inflammation
• Altered adipokine production
• Increased IGF-1 (insulin-like growth factor)

Previous Cancer Treatment

Certain cancer treatments increase endometrial cancer risk:

• Tamoxifen therapy for breast cancer
• Pelvic radiation therapy
• Some chemotherapy regimens

Risk Factors

Multiple factors can increase a woman's likelihood of developing endometrial cancer. Understanding these helps identify high-risk individuals who may benefit from increased surveillance or preventive measures.

Major Risk Factors

• Age: Risk increases with age, particularly after menopause. Average age at diagnosis is 60
• Obesity: Women with BMI >30 have 2-3 times higher risk; severe obesity increases risk up to 7-fold
• Hormone therapy: Estrogen-only replacement therapy significantly increases risk
• Tamoxifen use: Breast cancer treatment that acts as estrogen in the uterus
• Lynch syndrome: 40-60% lifetime risk of endometrial cancer
• PCOS: Chronic anovulation leads to unopposed estrogen exposure

Reproductive Factors

• Never having been pregnant (nulliparity)
• Early menarche (before age 12)
• Late menopause (after age 55)
• Infertility or inability to ovulate
• Irregular menstrual cycles
• Total years of menstruation

Medical Conditions

• Type 2 diabetes - 2-fold increased risk
• Hypertension - Often coexists with other risk factors
• Gallbladder disease
• Thyroid disease
• Previous breast or ovarian cancer
• Endometrial hyperplasia

Lifestyle Factors

• High-fat diet
• Sedentary lifestyle
• Lack of physical activity
• High caloric intake
• Western dietary patterns

Protective Factors

Certain factors may reduce endometrial cancer risk:

• Combined oral contraceptive use - Risk reduction persists for years after discontinuation
• Pregnancy and breastfeeding - Each pregnancy reduces risk by about 20%
• IUD use, particularly progestin-releasing types
• Regular physical activity
• Maintaining healthy weight
• Coffee consumption (possible protective effect)

Diagnosis

Early and accurate diagnosis of endometrial cancer is crucial for optimal outcomes. The diagnostic process involves multiple steps to confirm cancer presence, determine type, and assess extent of disease.

Initial Evaluation

Medical history includes:

• Detailed menstrual history and bleeding patterns
• Reproductive history (pregnancies, contraception)
• Hormone use (HRT, tamoxifen)
• Family history of cancer, especially Lynch syndrome
• Previous gynecologic conditions
• Current medications and medical conditions

Physical examination:

• Pelvic examination to assess uterus size and mobility
• Rectovaginal examination
• Evaluation for enlarged lymph nodes
• Abdominal examination for masses or fluid

Diagnostic Tests

Transvaginal ultrasound: First-line imaging showing endometrial thickness. In postmenopausal women, thickness >4-5mm warrants further evaluation. Also assesses myometrial invasion and adnexal masses.

Endometrial biopsy: Office procedure obtaining tissue sample using thin catheter. 90-95% accurate for detecting cancer. May miss focal lesions or be inadequate in some cases.

Hysteroscopy with D&C: Direct visualization of uterine cavity with targeted biopsies. Gold standard when biopsy is inadequate or suspicion remains high. Performed under anesthesia.

Additional imaging for staging:

• MRI - Best for assessing myometrial invasion and cervical involvement
• CT scan - Evaluates lymph nodes and distant metastases
• PET/CT - For suspected advanced disease
• Chest X-ray - Screens for lung metastases

Laboratory Tests

• Complete blood count - Check for anemia from bleeding
• CA-125 - May be elevated in advanced disease
• Liver and kidney function tests
• Genetic testing for Lynch syndrome if indicated

Staging

FIGO (International Federation of Gynecology and Obstetrics) staging:

• Stage I: Cancer confined to uterus
• Stage II: Cancer invades cervical stroma
• Stage III: Local/regional spread
• Stage IV: Distant metastases

Pathological Assessment

Microscopic examination determines:

• Histologic type (endometrioid, serous, clear cell, etc.)
• Grade (1-3, indicating differentiation)
• Depth of myometrial invasion
• Lymphovascular space invasion
• Hormone receptor status
• Molecular markers (MSI, p53, etc.)

Treatment Options

Treatment for endometrial cancer depends on multiple factors including stage, grade, histologic type, and patient's overall health. A multidisciplinary approach often provides the best outcomes.

Surgery

Primary surgical treatment typically includes:

• Total hysterectomy - Removal of uterus and cervix
• Bilateral salpingo-oophorectomy - Removal of both ovaries and fallopian tubes
• Lymph node assessment - Sentinel node mapping or lymphadenectomy
• Peritoneal washings for cytology
• Omentectomy for high-risk histologies

Surgical approaches:

• Minimally invasive (laparoscopic or robotic) - Preferred when feasible
• Open surgery - For large uteri or extensive disease
• Vaginal approach - Selected cases

Radiation Therapy

Types and indications:

• Vaginal brachytherapy - Reduces vaginal recurrence in intermediate-risk
• External beam radiation - For high-risk features or positive margins
• Combined approach - For advanced stages
• Palliative radiation - For symptom control

Systemic Therapy

Chemotherapy:

• Carboplatin and paclitaxel - Standard regimen
• Used for advanced stage or high-risk disease
• Adjuvant therapy after surgery
• Primary treatment for inoperable cases

Hormone therapy:

• Progestins (megestrol acetate, medroxyprogesterone)
• For hormone receptor-positive tumors
• Fertility-sparing option in select young women
• Palliative treatment for recurrent disease

Targeted therapy and immunotherapy:

• Pembrolizumab for MSI-high or dMMR tumors
• Lenvatinib plus pembrolizumab for advanced disease
• Bevacizumab in combination regimens
• Clinical trials for novel agents

Treatment by Stage

Early stage (I-II): Surgery often curative. Adjuvant therapy based on risk factors including grade, histology, lymphovascular invasion, and depth of invasion.

Advanced stage (III-IV): Multimodal approach with surgery (if feasible), followed by chemotherapy and/or radiation. Some cases treated with primary chemotherapy.

Recurrent disease: Treatment depends on prior therapy and site of recurrence. Options include surgery, radiation, chemotherapy, hormone therapy, or clinical trials.

Fertility-Sparing Treatment

For select young women with early-stage, low-grade disease:

• High-dose progestin therapy
• Close monitoring with biopsies
• Hysterectomy after childbearing complete
• Requires careful patient selection and counseling

Prevention

While not all cases of endometrial cancer can be prevented, several strategies can significantly reduce risk, particularly for women with known risk factors.

Weight Management

• Maintain healthy BMI through balanced diet and exercise
• Even modest weight loss (5-10%) can reduce risk
• Focus on sustainable lifestyle changes
• Consider bariatric surgery for severe obesity
• Regular monitoring of weight and waist circumference

Hormonal Considerations

• Use combined estrogen-progesterone HRT rather than estrogen alone
• Consider risks and benefits of hormone therapy with healthcare provider
• Use lowest effective dose for shortest duration
• Regular monitoring during tamoxifen therapy
• Consider alternatives to systemic hormone therapy

Reproductive Choices

• Combined oral contraceptives reduce risk by 30-50%
• Protection persists for decades after discontinuation
• IUDs, particularly progestin-releasing types
• Discuss family planning with healthcare provider

Medical Management

• Treat PCOS to regulate menstrual cycles
• Manage diabetes with good glycemic control
• Control hypertension
• Regular gynecologic care and screening
• Prompt evaluation of abnormal bleeding

Lifestyle Modifications

• Regular physical activity - At least 150 minutes weekly
• Mediterranean or plant-based diet patterns
• Limit red meat and processed foods
• Moderate coffee consumption may be protective
• Avoid smoking
• Limit alcohol intake

High-Risk Management

For women with Lynch syndrome or strong family history:

• Annual endometrial sampling starting age 30-35
• Transvaginal ultrasound surveillance
• Consider prophylactic hysterectomy after childbearing
• Genetic counseling and testing
• Coordinate care with genetics specialists

When to See a Doctor

Early detection of endometrial cancer significantly improves outcomes. Knowing when to seek medical evaluation is crucial for all women, especially those with risk factors.

Immediate Evaluation Needed

• Any vaginal bleeding after menopause, even spotting
• Heavy vaginal bleeding requiring pad changes every hour
• Bleeding lasting more than 7 days
• Severe pelvic pain with bleeding
• Signs of severe anemia (chest pain, severe fatigue, shortness of breath)

Schedule Appointment For

• Bleeding between periods (premenopausal women)
• Periods becoming progressively heavier or longer
• Irregular menstrual cycles after previously regular periods
• Unusual vaginal discharge, especially if blood-tinged
• Pelvic pain or pressure not related to menstruation
• Unexplained weight loss
• Pain during intercourse

Risk-Based Screening

Average risk women: No routine screening recommended. Report any abnormal bleeding promptly.

High-risk women should discuss screening:

• Lynch syndrome carriers - Annual screening from age 30-35
• Women on tamoxifen - Regular gynecologic exams
• PCOS with chronic anovulation
• Obesity with other risk factors
• Strong family history of endometrial cancer

Follow-up Care

After endometrial cancer treatment:

• Regular oncology follow-ups as scheduled
• Report any new vaginal bleeding
• New pelvic pain or pressure
• Unexplained weight loss
• Persistent bloating or GI symptoms
• Leg swelling or pain

Related Conditions

Several conditions are associated with or may be confused with endometrial cancer:

Frequently Asked Questions

References

1. American Cancer Society. "Endometrial Cancer Statistics." Cancer Facts & Figures. 2023.
2. Crosbie EJ, et al. "Endometrial cancer." Lancet. 2022;399(10333):1412-1428.
3. National Comprehensive Cancer Network. "NCCN Guidelines: Uterine Neoplasms." Version 1.2024.
4. Lu KH, Broaddus RR. "Endometrial Cancer." New England Journal of Medicine. 2020;383:2053-2064.
5. Makker V, et al. "Lenvatinib plus pembrolizumab in advanced endometrial cancer." New England Journal of Medicine. 2022;386:437-448.
6. Society of Gynecologic Oncology. "Endometrial Cancer Treatment Guidelines." SGO Clinical Practice. 2023.