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Endometrial Cancer for ABIM

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Endometrial Cancer for the American Board of Internal Medicine Exam
Definition and Epidemiology
  • Definition
    • Endometrial cancer is a malignancy originating from the lining of the uterus (endometrium) and is the most common gynecologic cancer in the United States.
    • The two main types are:
    • Type I (Endometrioid): Estrogen-dependent, often with endometrial hyperplasia; accounts for 80-90% of cases.
    • Type II (Non-endometrioid): Estrogen-independent, includes serous and clear cell histologies; more aggressive with a poorer prognosis.
  • Epidemiology
    • Predominantly affects postmenopausal women, with the highest incidence between ages 55-64.
    • The incidence has been rising due to increased obesity rates, which contribute to prolonged estrogen exposure.
Risk Factors
  • Hormonal Factors:
    • Unopposed Estrogen: Increases risk due to stimulation of endometrial proliferation without progesterone counteraction.
    • Obesity: Peripheral aromatization of androgens to estrogens in adipose tissue raises estrogen levels, promoting endometrial growth.
    • Polycystic Ovarian Syndrome (PCOS): Chronic anovulation leads to continuous estrogen exposure without progesterone.
  • Family History and Genetic Factors:
    • Lynch Syndrome (HNPCC): Increases the risk of type I endometrial cancer, especially in younger women.
    • Cowden Syndrome: Associated with PTEN mutations, increasing risk of endometrial, breast, and thyroid cancers.
  • Other Risk Factors:
    • Early Menarche and Late Menopause: Prolonged exposure to estrogen.
    • Nulliparity: Lack of progesterone exposure during pregnancy.
    • Tamoxifen Use: Partial estrogen agonist effect on the endometrium.
Pathophysiology
  • Type I (Endometrioid) Pathway:
    • Estrogen stimulates endometrial hyperplasia, which can progress to atypia and, eventually, endometrial carcinoma.
    • Often associated with mutations in PTEN, KRAS, and microsatellite instability (MSI).
Endometrioid Cancer Pathophysiology
  • Type II (Non-endometrioid) Pathway:
    • Arises independently of estrogen exposure, frequently in the context of atrophic endometrium.
    • Characterized by p53 mutations, which are linked to more aggressive behavior.
Clinical Manifestations
  • Abnormal Uterine Bleeding (AUB):
    • Most common presenting symptom, especially postmenopausal bleeding.
    • In premenopausal women, may present as irregular, heavy bleeding or intermenstrual bleeding.
  • Pelvic Pain and Pressure:
    • More common in advanced disease due to tumor growth and local invasion.
  • Asymptomatic:
    • Some cases, particularly in early stages, are asymptomatic and discovered incidentally on imaging or biopsy.
Diagnosis
  • Clinical Evaluation:
    • Abnormal uterine bleeding in postmenopausal women is an indication for further evaluation.
    • Physical examination may be unremarkable in early disease but can reveal an enlarged uterus in advanced stages.
  • Transvaginal Ultrasound (TVUS):
    • First-line imaging for evaluating endometrial thickness in postmenopausal women with bleeding.
    • Endometrial thickness >4 mm in postmenopausal women is concerning and warrants further investigation.
  • Endometrial Biopsy:
    • Gold standard for diagnosis, providing histologic evaluation of endometrial tissue.
    • Typically performed in-office and recommended for postmenopausal bleeding or high-risk premenopausal women with AUB.
  • Hysteroscopy with Biopsy:
    • Allows direct visualization and biopsy of the endometrium, useful for focal lesions or insufficient biopsy samples.
  • Imaging for Staging:
    • MRI: Preferred for local staging and assessing myometrial invasion.
    • CT and PET-CT: Utilized for evaluating distant metastases and lymph node involvement.
Staging
  • FIGO Staging System:
    • Stage I: Confined to the uterus.
    • IA: Less than 50% myometrial invasion.
    • IB: More than 50% myometrial invasion.
    • Stage II: Involves cervical stroma but not beyond the uterus.
    • Stage III: Local spread to the pelvic or para-aortic lymph nodes.
    • Stage IV: Invasion of bladder, bowel, or distant metastasis (e.g., lung, liver).
Treatment
  • Surgical Management:
    • Total Hysterectomy with Bilateral Salpingo-Oophorectomy (THBSO): Standard for most cases, often accompanied by lymph node sampling in higher stages.
    • Fertility-Sparing Options: Considered in young patients with low-grade, early-stage disease; involves high-dose progestins with close surveillance.
  • Adjuvant Therapy:
    • Radiation Therapy: External beam radiation or brachytherapy used postoperatively for higher-stage or high-risk patients to reduce recurrence.
    • Chemotherapy: Generally reserved for high-grade or advanced disease (stages III-IV) and type II tumors. Common agents include carboplatin and paclitaxel.
  • Hormonal Therapy:
    • For patients with estrogen receptor-positive tumors or those unsuitable for surgery, progestin therapy may be used.
    • High-dose progestins (e.g., megestrol acetate) or a levonorgestrel intrauterine device (LNG-IUD) are often effective in low-grade disease.
Prognosis and Follow-Up
  • Prognostic Factors:
    • Determined by stage, histologic grade, depth of myometrial invasion, and lymph node involvement.
    • Type II cancers generally have a poorer prognosis compared to type I due to their aggressive nature.
  • Follow-Up:
    • Surveillance includes regular pelvic exams and imaging if symptoms suggest recurrence, particularly in higher-risk patients.
Complications
  • Recurrence:
    • Recurrence risk is highest in advanced-stage, high-grade, or type II tumors.
    • Common recurrence sites include the pelvis, vagina, lungs, and liver.
  • Treatment-Related Complications:
    • Surgical Risks: Bleeding, infection, and possible injury to adjacent organs.
    • Radiation Therapy Effects: Can cause radiation cystitis, proctitis, and bowel or bladder dysfunction.
    • Hormonal Therapy Side Effects: Weight gain, fluid retention, and thromboembolism risks with progestin use.
Key Points
  • Endometrial Cancer is the most common gynecologic malignancy, primarily affecting postmenopausal women.
  • Types:
    • Type I (endometrioid) is estrogen-dependent and linked to endometrial hyperplasia.
    • Type II (non-endometrioid) is estrogen-independent and more aggressive.
  • Risk Factors include unopposed estrogen exposure, obesity, nulliparity, PCOS, Lynch syndrome, and tamoxifen use.
  • Symptoms: The hallmark presentation is abnormal uterine bleeding, especially postmenopausal bleeding.
  • Diagnosis:
    • Transvaginal ultrasound is first-line for evaluating endometrial thickness.
    • Endometrial biopsy confirms diagnosis; MRI is useful for staging.
  • Staging: FIGO staging system assesses local invasion, nodal involvement, and distant metastasis.
  • Treatment:
    • Surgery (THBSO) is the mainstay for most cases, often with lymph node sampling.
    • Adjuvant radiation and chemotherapy are indicated for high-risk or advanced stages.
    • Hormonal therapy may be used in specific cases, particularly for fertility preservation or inoperable patients.
  • Prognosis:
    • Prognosis is excellent for early-stage, type I cancers but poorer for type II and advanced disease.
  • Complications: Recurrence risk is elevated in advanced-stage and high-grade disease; treatment-related side effects vary by modality.

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