Most common gynecologic malignancy in the US — postmenopausal bleeding is the cardinal red flag.
Also known as: endometrial cancer, uterine cancer, endometrial adenocarcinoma, endometrial hyperplasia
Overview
Malignancy arising from the endometrial lining of the uterus, most commonly endometrioid adenocarcinoma. Bokhman's traditional dual classification distinguishes Type I (estrogen-dependent endometrioid, ~80%, usually low-grade, favorable prognosis) from Type II (non-estrogen-dependent serous, clear cell, carcinosarcoma, higher grade, worse prognosis). The Cancer Genome Atlas (TCGA) molecular subtypes (POLE ultramutated, MSI-high, copy-number low, copy-number high) increasingly guide prognosis and therapy.
Epidemiology
Most common gynecologic malignancy in developed countries; ~68,000 new US cases/year, ~14,500 deaths (ACS 2026). Median age at diagnosis ~62. Incidence rising with obesity epidemic.
Try two board-style Endometrial Cancer questions
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Question 1ReproductiveMedium
A 55-year-old woman presents 18 months after menopause with vaginal bleeding. Her BMI is 38 kg/m2, and she has hypertension and type 2 diabetes mellitus. Endometrial biopsy shows a grade 1 endometrioid adenocarcinoma, and preoperative evaluation shows disease confined to the endometrium without myometrial invasion or extrauterine spread. Which of the following is the most appropriate definitive treatment?
APlatinum-based adjuvant chemotherapy
BHysterectomy with salpingo-oophorectomy
CRadical hysterectomy with pelvic lymphadenectomy
DContinuous high-dose oral progestin therapy
EExternal beam whole-pelvic radiation
Reveal answer & full explanation
Correct answer: B — Hysterectomy with salpingo-oophorectomy
APlatinum-based adjuvant chemotherapy
BHysterectomy with salpingo-oophorectomy✓
CRadical hysterectomy with pelvic lymphadenectomy
DContinuous high-dose oral progestin therapy
EExternal beam whole-pelvic radiation
Why Hysterectomy with salpingo-oophorectomy is correct
Total hysterectomy with bilateral salpingo-oophorectomy is the definitive, curative treatment for stage I endometrioid endometrial carcinoma
This grade 1 tumor confined to the endometrium is stage IA, which carries a >90% 5-year survival after surgery
Surgery also provides definitive staging, including sentinel lymph node assessment, to guide any adjuvant therapy
Risk factors here (obesity, diabetes, unopposed estrogen exposure) are typical, and postmenopausal bleeding must be treated as cancer until proven otherwise
Why the others are wrong
Continuous high-dose oral progestin therapy — a fertility-sparing option reserved for young patients wishing to preserve the uterus or for poor surgical candidates; in a 55-year-old it is not definitive and undertreats the cancer (right-treatment-wrong-patient)
Platinum-based adjuvant chemotherapy — reserved for advanced, high-grade, or metastatic disease; using it as primary therapy for stage IA grade 1 disease is right-treatment-wrong-stage
External beam whole-pelvic radiation — primary radiation is used only when a patient cannot undergo surgery; here it is not the definitive first treatment and is at most adjuvant
Radical hysterectomy with pelvic lymphadenectomy — the standard operation for early-stage cervical cancer, and its extent can make it look like the most thorough cancer surgery, but stage IA grade 1 endometrioid cancer is treated with total hysterectomy and bilateral salpingo-oophorectomy, usually with sentinel lymph node mapping for staging; parametrial resection adds bladder and ureteral morbidity without benefit, and routine full lymphadenectomy has not improved survival in early-stage disease (right-surgery-wrong-cancer)
Question 2ReproductiveEasy
A 42-year-old female (G4P3) has postmenopausal bleeding 18 months after her last period. She is obese with hypertension and type 2 diabetes mellitus. Which of the following is the most important next step?
AVaginal estrogen cream
BOral progestin therapy
CEndometrial biopsy
DPap smear with HPV co-test
EDilation and curettage
Reveal answer & full explanation
Correct answer: C — Endometrial biopsy
AVaginal estrogen cream
BOral progestin therapy
CEndometrial biopsy✓
DPap smear with HPV co-test
EDilation and curettage
Why Endometrial biopsy is correct
Postmenopausal bleeding (PMB) is defined as any vaginal bleeding 12 or more months after the last period
Common causes include atrophic vaginitis (40%), endometrial polyp, hyperplasia, and carcinoma (about 10%)
This patient has multiple endometrial cancer risk factors: obesity, hypertension, and type 2 diabetes mellitus (T2DM) — all cause a hyperestrogen state
Endometrial biopsy (EMB) is the first-line evaluation with sensitivity 90-96% for endometrial cancer, performed as an office Pipelle curette procedure
Transvaginal ultrasound (TVUS) is performed alongside biopsy in most patients (ACOG 2026): an endometrial stripe above 4 mm warrants tissue, and TVUS alone is acceptable only for a single episode with a fully visualized stripe of 4 mm or less, no risk factors, and reliable follow-up
Why the others are wrong
Vaginal estrogen cream — atrophic vaginitis causes about 40% of PMB, but it can be treated as the cause only after endometrial sampling excludes carcinoma, especially with obesity, hypertension, and diabetes (premature closure)
Pap smear with HPV co-test — evaluates cervical pathology and does not assess the endometrium (confused-with cervical screening)
Dilation and curettage — samples the endometrium but requires anesthesia and is reserved for office sampling that is insufficient or nondiagnostic, for cervical stenosis, or for bleeding that persists after a benign biopsy, so it is not the initial step (right-test-wrong-sequence)
Oral progestin therapy — the obesity-driven hyperestrogen state makes opposing estrogen with a progestin seem logical, and progestins do treat endometrial hyperplasia without atypia, but empiric hormonal therapy before tissue sampling can mask or delay a diagnosis of carcinoma in a high-risk patient with PMB (treatment-before-diagnosis)
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Unopposed estrogen exposure: obesity (peripheral conversion; the strongest modifiable risk factor, roughly 2-4x risk at BMI 30-39 and about 7x at BMI 40 or higher), nulliparity, early menarche, late menopause, anovulatory cycles (PCOS), estrogen-only HRT, granulosa cell tumor
Lynch syndrome (HNPCC) — 40-60% lifetime risk; consider age <50 at diagnosis
Cowden syndrome (PTEN)
Older age
Pathophysiology
Type I cancers arise from chronic unopposed estrogen stimulation producing endometrial hyperplasia → atypical hyperplasia (endometrial intraepithelial neoplasia, EIN) → endometrioid adenocarcinoma; mutations in PTEN, KRAS, mismatch repair genes. Type II cancers arise from atrophic endometrium independent of estrogen, with TP53 mutations and aneuploidy.
Clinical presentation
Symptoms
Postmenopausal bleeding (cardinal symptom — present in ~90%)
Heavy or irregular bleeding in perimenopause
Intermenstrual bleeding in premenopausal women
Pelvic pain, weight loss (advanced)
Abnormal vaginal discharge
Signs / physical exam
Often normal pelvic exam in early disease
Enlarged or tender uterus
Adnexal mass (synchronous ovarian primary or metastasis)
Obesity is the most common physical finding
Classic findings
Postmenopausal obese, diabetic woman with new vaginal bleeding; endometrial stripe >4 mm on TVUS.
Differential diagnosis
Endometrial polyp — Bleeding without dysplasia; saline sonohysterography or hysteroscopy
Endometrial hyperplasia (without/with atypia) — Premalignant; managed with progestin or hysterectomy
Submucosal fibroid — Heavy or intermenstrual bleeding; TVUS
Atrophic endometrium / vaginitis — Common cause of postmenopausal bleeding; pale thin mucosa
Cervical cancer — Postcoital bleeding, visible lesion
Anticoagulant-associated bleeding — Workup still required — coagulopathy does not explain new bleeding without evaluation
Hormone therapy-related bleeding — Common during first 6 months of continuous HT; evaluate if persistent
Diagnostic workup
Diagnostic criteria
Tissue diagnosis required. FIGO 2009 (with 2023 revision) surgical staging: I (confined to uterus), II (cervical stromal invasion), III (local/regional spread), IV (distant or bladder/bowel invasion).
Labs
CBC, BMP
Pregnancy test if reproductive age
CA-125 in select high-risk or advanced cases (not screening)
Imaging
Transvaginal ultrasound, performed together with endometrial sampling for most postmenopausal bleeding (ACOG 2026); TVUS alone (fully visualized stripe ≤4 mm) suffices only for a single episode with no risk factors (e.g., obesity, diabetes, nulliparity, estrogen or tamoxifen exposure) and prompt follow-up available, and any persistent or recurrent bleeding needs tissue regardless of thickness
CT chest/abdomen/pelvis — staging in high-grade or advanced disease
Lynch syndrome screening (universal MMR/MSI testing on all endometrial cancers) per NCCN/SGO
Premenopausal AUB: endometrial biopsy is the first-line test at age 45 or older, or younger with unopposed estrogen exposure (obesity, PCOS), failed medical management or persistent AUB; the 4 mm TVUS cutoff applies only after menopause (ACOG PB 128)
Diagnostic algorithm
flowchart TD
A[Postmenopausal bleeding] --> B["TVUS + endometrial biopsy<br/>(most patients, ACOG 2026)"]
A -.->|"Select: single episode, no risk<br/>factors, reliable follow-up"| T["Ultrasound-only triage:<br/>fully visualized stripe ≤4 mm<br/>→ observe"]
T -->|"Stripe >4 mm, not fully seen,<br/>recurrent or persistent bleeding"| D[Endometrial biopsy]
P["Premenopausal AUB: age 45 or older,<br/>or younger with unopposed estrogen<br/>(obesity, PCOS), failed medical<br/>management or persistent AUB"] -->|"Biopsy first; 4 mm cutoff<br/>does not apply"| D
B --> F{Pathology}
D --> F
F -->|Hyperplasia<br/>without atypia| G[Progestin × 3-6 mo<br/>Re-biopsy]
F -->|Atypical hyperplasia<br/>EIN| H[Hysterectomy preferred<br/>30-40% concurrent cancer]
F -->|Endometrial cancer| I[MRI pelvis + staging<br/>MMR/MSI testing]
I --> J{Stage}
J -->|I-II| K[TH + BSO ± LND<br/>± adjuvant therapy]
J -->|III-IV| L["Cytoreduction +<br/>carboplatin/paclitaxel +<br/>checkpoint inhibitor ± radiation"]
J -->|Recurrent| M[Chemo, immunotherapy,<br/>hormone therapy]
Evaluation of postmenopausal bleeding through endometrial cancer treatment.
Adjuvant therapy by risk: observation (low risk), vaginal brachytherapy (intermediate), external-beam radiation ± chemotherapy (high-intermediate or high)
Stage III-IV: surgery/cytoreduction when feasible + carboplatin/paclitaxel with an immune checkpoint inhibitor (dostarlimab or pembrolizumab; durvalumab for dMMR) ± radiation
Recurrent/metastatic: chemotherapy; immunotherapy (pembrolizumab + lenvatinib for MMR-proficient; pembrolizumab or dostarlimab for MMR-deficient); hormone therapy for low-grade endometrioid
Endometrial hyperplasia
Without atypia: progestin therapy (medroxyprogesterone, megestrol, levonorgestrel IUD) for 3-6 months; repeat biopsy
With atypia (EIN): hysterectomy is preferred — 30-40% risk of concurrent endometrial cancer; fertility-sparing levonorgestrel IUD or high-dose progestin with close surveillance if highly motivated patient
Fertility-sparing for early endometrioid
Grade 1 endometrioid limited to endometrium (no myometrial invasion on MRI), no extrauterine disease, strong fertility desire
Concurrent ovarian primary or metastasis in ~5% of premenopausal cases
PANCE pearls
Any postmenopausal bleeding requires endometrial evaluation regardless of TVUS findings if bleeding persists or recurs.
Endometrial stripe >4 mm in postmenopausal woman with bleeding mandates endometrial sampling.
Universal MMR/MSI screening on all endometrial cancers identifies Lynch syndrome and guides immunotherapy eligibility.
Atypical endometrial hyperplasia (EIN) coexists with endometrial cancer in 30-40% of cases — hysterectomy is the standard.
Tamoxifen increases endometrial cancer risk ~2-3x; any abnormal bleeding warrants prompt evaluation.
Progestin therapy can reverse endometrial hyperplasia and (less reliably) early grade 1 endometrioid cancer in fertility-sparing settings.
References
NCCN Uterine 2024 — NCCN Clinical Practice Guidelines in Oncology: Uterine Neoplasms
ACOG PB 149 — ACOG Practice Bulletin No. 149: Endometrial Cancer
ACOG CC 5 (2023) — ACOG Clinical Consensus No. 5: Management of Endometrial Intraepithelial Neoplasia or Atypical Endometrial Hyperplasia. Obstet Gynecol 2023;142:735-44
FIGO 2023 — FIGO Staging of Endometrial Cancer 2023 (Berek et al., Int J Gynaecol Obstet 2023)
ACOG CPU 2026 — ACOG Clinical Practice Update: Updated Guidance Regarding the Role of Transvaginal Ultrasonography in Evaluating the Endometrium of Individuals With Postmenopausal Bleeding. Obstet Gynecol 2026;148:e87-e91
ACOG PB 128 — ACOG Practice Bulletin No. 128: Diagnosis of Abnormal Uterine Bleeding in Reproductive-Aged Women. Obstet Gynecol 2012;120:197-206
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