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Endometrial Hyperplasia & Endometrial Cancer

Name: Endometrial Hyperplasia & Endometrial Cancer
Creator: Veli Bakalov, MD

Unopposed estrogen, postmenopausal bleeding, and the path from hyperplasia to cancer

Obstetrics & Gynecology·Gynecologic Oncology·4 min read·8 high-yield points·Reviewed by Veli Bakalov, MD @HemeOncBuddy

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Unopposed estrogen (obesity, PCOS/anovulation, nulliparity, early menarche, late menopause, estrogen-only therapy, granulosa cell tumor) drives endometrioid hyperplasia and cancer; progestins and combined OCPs protect.
Tamoxifen raises endometrial cancer risk because it is a uterine estrogen agonist; raloxifene does not.
Lynch syndrome confers up to ~40–60% lifetime endometrial cancer risk, and endometrial cancer is often the sentinel malignancy.
Postmenopausal bleeding is evaluated with transvaginal ultrasound (stripe ≤4 mm reassuring) or endometrial biopsy; persistent bleeding after a thin stripe needs endometrial sampling, then hysteroscopy with D&C if sampling is nondiagnostic or bleeding persists after a benign result.
Biopsy the endometrium for AUB at age 45 or older, or younger with unopposed estrogen exposure or failed therapy, and for AGC at 35 or older.
Hyperplasia without atypia is treated with progestin (LNG-IUD preferred) and resampling; atypical hyperplasia/EIN is treated with total hysterectomy because up to 40% harbor cancer.
Endometrioid carcinoma is estrogen-driven and favorable; serous and clear cell carcinomas occur in older thin women with TP53 mutations and spread early.
Endometrial cancer is staged surgically with total hysterectomy, BSO, and sentinel lymph nodes, and every tumor is tested for mismatch repair deficiency (Lynch screening, immunotherapy eligibility).

Pathogenesis and risk factors

Unopposed estrogen. Estrogen makes the endometrium proliferate; progesterone halts proliferation and causes secretory change and shedding. When estrogen acts without progesterone, the endometrium progresses from hyperplasia without atypia to atypical hyperplasia (endometrial intraepithelial neoplasia, EIN) to endometrioid carcinoma. In obesity, adipose aromatase converts androstenedione to estrone and low SHBG raises free estrogen; in chronic anovulation (PCOS) there is no corpus luteum to supply progesterone.

Factors that shift endometrial cancer risk

Raise risk	Lower risk
Obesity, diabetes, hypertension	Combined oral contraceptives (benefit persists for years)
Chronic anovulation, PCOS	Progestin therapy, LNG-IUD
Nulliparity; early menarche, late menopause	Parity
Estrogen-only therapy with an intact uterus	Adding a progestin to menopausal estrogen
Tamoxifen	Physical activity
Granulosa cell tumor; Lynch syndrome; Cowden (PTEN) syndrome	—

Tamoxifen vs raloxifene. Tamoxifen blocks estrogen in the breast but is a partial agonist in the uterus, causing hyperplasia, polyps, endometrial cancer, and rarely uterine sarcoma. Raloxifene is an endometrial antagonist and aromatase inhibitors lower estrogen, so neither raises risk. Asymptomatic tamoxifen users are not screened with ultrasound or biopsy, but any bleeding is evaluated promptly.

Lynch syndrome. Germline mismatch repair mutations (MLH1, MSH2, MSH6, PMS2, or EPCAM deletions silencing MSH2) carry a lifetime endometrial cancer risk of up to ~40–60%, comparable to the colon cancer risk, and endometrial cancer is the first ("sentinel") cancer in about half of affected women. Carriers may have endometrial biopsy every 1–2 years from 30–35 and hysterectomy with bilateral salpingo-oophorectomy after childbearing.

Evaluating abnormal bleeding

Postmenopausal bleeding. About 90% of endometrial cancers present with abnormal bleeding, which is why most are caught at stage I; roughly 1 in 10 women with postmenopausal bleeding has cancer. Any amount of bleeding after menopause is evaluated.

First steptransvaginal ultrasound or office endometrial biopsy—either is acceptable
Stripe ≤4 mmcancer very unlikely (negative predictive value >99%); no biopsy if bleeding stops
Stripe >4 mm, not well seen, or bleeding persists despite a thin stripeendometrial biopsy (office sampling acceptable)
Nondiagnostic biopsy, or bleeding persists after a benign biopsyhysteroscopy with dilation and curettage

A thin stripe does not end the workup if bleeding continues: serous carcinoma can arise in a thin, atrophic endometrium, and an insufficient biopsy is not a negative biopsy.

Who else needs endometrial sampling.

Abnormal uterine bleeding at age ≥45.
AUB before 45 with unopposed estrogen exposure (obesity, PCOS), failed medical therapy, or persistent bleeding.
Atypical glandular cells on cervical cytology at ≥35 or with risk factors (together with colposcopy and endocervical sampling), and atypical endometrial cells at any age.
Benign-appearing endometrial cells on cytology in a postmenopausal woman.

Endometrial hyperplasia

Hyperplasia without atypia. Crowded glands without nuclear atypia; only about 1–3% progress to carcinoma. Treat with progestin—the LNG-IUD is preferred because it achieves higher regression than oral medroxyprogesterone or megestrol—and resample the endometrium every 3–6 months until regression. Address the estrogen source: weight loss, treatment of anovulation, and a progestin for anyone on estrogen with a uterus.

Atypical hyperplasia / EIN. A true precursor: up to about 40% of patients already have carcinoma in the hysterectomy specimen. Total hysterectomy is standard; supracervical hysterectomy, morcellation, and endometrial ablation are inappropriate. Patients who want to preserve fertility, or who cannot undergo surgery, receive high-dose progestin (LNG-IUD or megestrol) with endometrial sampling every 3–6 months, followed by hysterectomy after childbearing. The same progestin approach is an option for grade 1 endometrioid cancer confined to the endometrium in a patient wanting children.

Endometrial carcinoma

Endometrioid vs serous and clear cell carcinoma

Feature	Endometrioid (~80%)	Serous / clear cell
Patient	Obese peri- or postmenopausal woman	Older, thin woman
Driver	Unopposed estrogen	Estrogen-independent
Precursor	Atypical hyperplasia / EIN	Atrophic endometrium
Molecular	PTEN, KRAS, mismatch repair loss	TP53 mutation
Histology	Glandular, usually low grade	Papillae and psammoma bodies (serous); hobnail cells (clear cell)
Behavior	Often stage I, favorable	Early peritoneal spread, poor prognosis

Carcinosarcoma is another aggressive, high-risk histology.

Molecular classification. Tumors fall into four groups: POLE-ultramutated (excellent prognosis), mismatch repair–deficient, no specific molecular profile, and p53-abnormal (worst prognosis).

Staging surgery. Diagnosis comes from endometrial biopsy. Staging is surgical: total hysterectomy, bilateral salpingo-oophorectomy, and sentinel lymph node mapping (or lymphadenectomy) with peritoneal washings, usually by laparoscopy or robotics—unlike cervical cancer, minimally invasive surgery is standard. Serous and clear cell tumors also get omentectomy and peritoneal biopsies, as in ovarian cancer.

FIGO stages. I, confined to the uterus (IA <50% myometrial invasion, IB ≥50%); II, cervical stromal invasion; III, serosa, adnexa, vagina, parametrium, or pelvic/para-aortic nodes; IV, bladder or bowel mucosa or distant spread. Grade, lymphovascular space invasion, histology, and molecular class refine risk.

Adjuvant therapy. Low-risk disease (stage IA, low-grade endometrioid, no LVSI) needs surgery alone. High-intermediate risk disease gets vaginal brachytherapy. Stage III–IV disease gets carboplatin plus paclitaxel with or without radiation, and PD-1 inhibitors (dostarlimab, pembrolizumab) are added for advanced or recurrent disease. POLE-mutated tumors may be de-escalated and p53-abnormal tumors escalated.

Universal mismatch repair testing. Every endometrial cancer is tested by immunohistochemistry for MLH1, PMS2, MSH2, and MSH6 (or by MSI testing). Loss of MLH1/PMS2 prompts MLH1 promoter hypermethylation testing: methylation means a sporadic tumor, whereas an unmethylated result—or loss of MSH2/MSH6—leads to germline Lynch testing. Mismatch repair–deficient (MSI-high) tumors respond to PD-1 inhibitors.