Endometrial Neoplasia

Summary

Definition

Endometrial neoplasia encompasses abnormal proliferative lesions originating from the endometrial lining of the uterus, ranging from benign hyperplasia to malignant tumors such as endometrial carcinoma. This spectrum includes both precancerous conditions, such as atypical endometrial hyperplasia, and invasive malignancies—most often adenocarcinoma—characterized by uncontrolled glandular tissue growth driven by genetic, hormonal, or environmental influences.

• Postmenopausal bleeding (PMB) is any uterine bleeding occurring after menopause; while often caused by vaginal or endometrial atrophy, endometrial carcinoma.

• PMB is considered cancer until proven otherwise.

Epidemiology

• Endometrial carcinoma is the most common gynecologic malignancy in developed countries.

• Peak incidence occurs between 55–70 years; mean age at diagnosis is 61 years.

• Type I endometrial cancer accounts for ~80% of cases; Type II for 10–20%.

• Increased incidence is partly attributed to the widespread use of unopposed estrogen therapy for menopausal symptoms.

• 70% of endometrial cancers are diagnosed at an early stage, yielding high survival rates.

Pathophysiology

Most endometrial carcinomas arise due to unopposed estrogen exposure, which stimulates endometrial proliferation without the regulatory effect of progesterone.

• Type I (estrogen-dependent): Typically develops from atypical hyperplasia/endometrial intraepithelial neoplasia (EIN); usually endometrioid histology with a favorable prognosis.

• Type II (estrogen-independent): Often arises from atrophic endometrium or polyps; includes serous and clear cell carcinomas, with poorer prognosis.

• Type I cancer has a better prognosis than Type II.

Risk Factors

Shared between EIN and Endometrial Carcinoma:

• Nulliparity or low parity

• Early menarche, late menopause

• Chronic anovulation (e.g., PCOS)

• Obesity (BMI > 30)

• Diabetes mellitus (especially T2DM)

• Hypertension

• Unopposed estrogen therapy

• Tamoxifen use

• Family history of endometrial carcinoma or Lynch syndrome

• Chronic liver disease

• High socioeconomic status

• Previous pelvic radiotherapy

Note: Smoking and progesterone use are protective against Type I carcinoma but not Type II.

Protective Factors

• Multiparity

• Early childbearing

• Combined oral contraceptive use

• Regular physical activity

• Lifelong soy-rich diet

Histological Types

• Endometrioid adenocarcinoma (80%) – best prognosis

• Mucinous carcinoma (5%)

• Clear cell carcinoma (5%)

• Serous carcinoma (4%) – worst prognosis

• Squamous carcinoma (1%)

Clinical Features

• Most common: Postmenopausal bleeding (spotting to heavy bleeding)

• Vaginal discharge (serosanguinous or purulent)

• Pelvic pain, pelvic mass

• Advanced disease: Cachexia, abdominal distension, changes in bowel/bladder habits

• Rare: Pyometra (due to cervical obstruction by tumor)

Diagnostic Approach

• Either transvaginal ultrasonography (TVUS) or endometrial biopsy may be used first.

• TVUS:

• Endometrial thickness ≤4 mm in postmenopausal women without risk factors → carcinoma unlikely, no further testing required.

• Thickness >4 mm → endometrial sampling indicated.

• Endometrial biopsy:

• High sensitivity, low cost, minimal complications.

• Indicated for all women with PMB and risk factors, or persistent/recurrent bleeding.

• Hysteroscopy: Direct visualization with the option for targeted biopsy or removal of focal lesions (polyps, submucous fibroids).

Staging

Surgical staging after histologic diagnosis, including:

• Total abdominal hysterectomy (TAH)

• Bilateral salpingo-oophorectomy (BSO)

• Pelvic and para-aortic lymphadenectomy

• Peritoneal washings

Treatment

Endometrial Hyperplasia / EIN

• Without atypia: Progestin therapy (oral, injectable, or levonorgestrel IUD)

• With atypia: Total hysterectomy (fertility-sparing options with high-dose progestins may be considered in selected young patients)

• Endometrial ablation and supracervical hysterectomy are contraindicated.

2. Endometrial Carcinoma

• Surgical mainstay: TAH + BSO, with staging procedures.

• Adjuvant therapy:

• Radiation therapy: For high-risk features (lymph node metastasis, >50% myometrial invasion, positive margins, high-grade tumors)

• Chemotherapy: For metastatic or recurrent disease (progestins, cytotoxic agents, or targeted therapy)

• Palliative care: For advanced disease to control symptoms.

Prognostic Factors

• Favorable: Well-differentiated tumors, early stage, younger age, endometrioid histology.

• Unfavorable: Poor differentiation, deep myometrial invasion, lymphovascular spread, serous/clear cell histology.

Prevention

• Combine estrogen with progestin in postmenopausal hormone therapy.

• Treat chronic anovulation in reproductive-aged women with progestins.

• Regular follow-up for women with risk factors.

• Prophylactic hysterectomy in high-risk genetic syndromes (e.g., Lynch syndrome).