Reproductive · PANCE / PANRE

Endometrial Cancer

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; ~66,000 new US cases/year, ~12,000 deaths. Median age at diagnosis ~62. Incidence rising with obesity epidemic.

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Risk factors

  • Unopposed estrogen exposure: obesity (peripheral conversion), nulliparity, early menarche, late menopause, anovulatory cycles (PCOS), estrogen-only HRT, granulosa cell tumor
  • Tamoxifen use
  • Diabetes mellitus, hypertension, metabolic syndrome
  • 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 — endometrial thickness >4 mm in postmenopausal woman warrants biopsy; <4 mm has high NPV but biopsy still indicated if persistent bleeding
  • Endometrial biopsy (Pipelle) — first-line tissue diagnosis; office procedure
  • Hysteroscopy with directed biopsy or dilation and curettage — if Pipelle nondiagnostic or insufficient
  • MRI pelvis — preoperative staging (myometrial invasion depth)
  • 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

Diagnostic algorithm

flowchart TD
  A[Postmenopausal bleeding<br/>OR AUB with risk factors] --> B[TVUS]
  B --> C{Endometrial<br/>thickness?}
  C -->|>4 mm or persistent bleed| D[Endometrial biopsy]
  C -->|≤4 mm, single episode| E[Observation;<br/>biopsy if recurrent]
  D --> F{Pathology}
  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/>chemo ± radiation]
  J -->|Recurrent| M[Chemo, immunotherapy,<br/>hormone therapy]
Evaluation of postmenopausal bleeding through endometrial cancer treatment.

Treatment

First-line

  • Stage I-II: total hysterectomy + bilateral salpingo-oophorectomy ± pelvic/para-aortic lymphadenectomy (or sentinel lymph node mapping)
  • Adjuvant therapy by risk: observation (low risk), vaginal brachytherapy (intermediate), external-beam radiation ± chemotherapy (high-intermediate or high)
  • Stage III-IV: maximal cytoreductive surgery + adjuvant chemotherapy (carboplatin + paclitaxel) ± 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
  • Levonorgestrel IUD ± megestrol; repeat biopsy q3-6 months
  • Definitive hysterectomy after childbearing complete

Lynch syndrome surveillance

  • Annual endometrial biopsy starting age 30-35
  • Consider risk-reducing hysterectomy + BSO after childbearing complete
  • Colonoscopy screening per Lynch protocols

Complications

  • Postoperative complications (DVT/PE, infection, bowel injury)
  • Lymphedema after lymphadenectomy
  • Pelvic radiation toxicity (cystitis, proctitis, vaginal stenosis)
  • Recurrence — most within 2-3 years
  • 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 CO 631 — ACOG Committee Opinion 631: Endometrial Intraepithelial Neoplasia
  • FIGO 2023 — FIGO Staging of Endometrial Cancer 2023 (Berek et al., Int J Gynaecol Obstet 2023)

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Educational use only. This outline is a study aid for PA students and is not medical advice or a substitute for clinical judgment. FirstPassPA is an independent study tool and is not affiliated with, endorsed by, or sponsored by NCCPA. PANCE® and PANRE® are registered trademarks of the National Commission on Certification of Physician Assistants.