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Endometrial Cancer for USMLE Step 3

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Endometrial Cancer for the USMLE Step 3 Exam
Definition and Epidemiology
  • Definition
    • Endometrial cancer is a malignancy originating from the endometrium (the uterine lining) and is the most common gynecologic cancer in the United States.
    • Two main types:
    • Type I (Endometrioid): Estrogen-dependent, linked with endometrial hyperplasia, accounting for 80-90% of cases.
    • Type II (Non-endometrioid): Estrogen-independent, includes serous and clear cell histologies and is more aggressive.
  • Epidemiology
    • Primarily affects postmenopausal women, with peak incidence between ages 55 and 65.
    • Incidence has increased in parallel with rising obesity rates, as obesity leads to excess estrogen production.
Risk Factors
  • Hormonal and Metabolic Factors:
    • Unopposed Estrogen: Estrogen exposure without progesterone stimulation increases the risk of endometrial hyperplasia and subsequent carcinoma.
    • Obesity: Leads to peripheral conversion of androgens to estrogens in adipose tissue.
    • Polycystic Ovarian Syndrome (PCOS): Anovulation causes prolonged estrogen exposure.
  • Genetic Predispositions:
    • Lynch Syndrome (HNPCC): Mutation in DNA mismatch repair genes increases the risk of endometrial cancer, often presenting at a younger age.
    • Cowden Syndrome: PTEN mutations lead to an increased risk for multiple cancers, including endometrial.
  • Other Factors:
    • Early Menarche and Late Menopause: Increase cumulative estrogen exposure.
    • Nulliparity: Absence of pregnancy reduces lifetime progesterone exposure.
    • Tamoxifen Use: Has a partial estrogen agonist effect on endometrial tissue.
Pathophysiology
  • Type I Pathway:
    • Estrogen exposure promotes endometrial hyperplasia, which can progress to atypical hyperplasia and then to carcinoma.
    • Often involves PTEN and KRAS mutations.
Endometrioid Cancer Pathophysiology
  • Type II Pathway:
    • Arises independently of estrogen exposure, typically from atrophic endometrium.
    • Associated with p53 mutations and has a more aggressive clinical course.
Clinical Manifestations
  • Abnormal Uterine Bleeding (AUB):
    • The most common symptom, especially postmenopausal bleeding.
    • In premenopausal women, can present as heavy, irregular, or intermenstrual bleeding.
  • Pelvic Pain and Mass:
    • Pelvic discomfort or pressure may occur in advanced cases due to local spread.
  • Asymptomatic:
    • Early cases may be discovered incidentally during imaging or biopsy for other indications.
Diagnosis
  • Transvaginal Ultrasound (TVUS):
    • First-line imaging to evaluate endometrial thickness in postmenopausal bleeding; a thickness >4 mm often warrants biopsy.
  • Endometrial Biopsy:
    • Gold standard for diagnosis; provides histopathologic confirmation of hyperplasia or carcinoma.
    • Recommended for any postmenopausal bleeding or high-risk premenopausal women with AUB.
  • Hysteroscopy:
    • Allows direct visualization and biopsy, especially useful in cases with focal lesions or insufficient biopsy results.
Staging
  • FIGO Staging System:
    • Stage I: Confined to the uterus.
    • IA: Invasion <50% of myometrium.
    • IB: Invasion ≥50% of myometrium.
    • Stage II: Cervical stromal invasion.
    • Stage III: Local/regional spread, including pelvic or para-aortic lymph nodes.
    • Stage IV: Invasion of bladder, bowel, or distant metastasis.
Treatment
  • Surgical Management:
    • Total Hysterectomy with Bilateral Salpingo-Oophorectomy (THBSO) is standard, often with lymph node sampling for staging.
  • Adjuvant Therapy:
    • Radiation Therapy: Used postoperatively for high-risk cases or advanced disease to reduce recurrence risk.
    • Chemotherapy: Typically reserved for high-grade or advanced disease; carboplatin and paclitaxel are commonly used agents.
  • Hormonal Therapy:
    • High-dose progestins or a levonorgestrel IUD may be effective in estrogen receptor-positive tumors and for patients desiring fertility preservation.
Key Points
  • Endometrial Cancer is the most common gynecologic malignancy, usually presenting with postmenopausal bleeding.
  • Types:
    • Type I is estrogen-dependent, associated with hyperplasia.
    • Type II is estrogen-independent, often aggressive, and associated with p53 mutations.
  • Risk Factors include unopposed estrogen, obesity, nulliparity, PCOS, Lynch syndrome, and tamoxifen use.
  • Diagnosis:
    • Transvaginal ultrasound and endometrial biopsy are essential for assessment.
  • Staging: FIGO staging is based on the extent of myometrial invasion, cervical involvement, and extrauterine spread.
  • Treatment:
    • THBSO is standard; adjuvant radiation and chemotherapy may be used in advanced disease.
    • Hormonal therapy may be effective for select cases, especially for fertility preservation.

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