Endometrial Cancer

Endometrial cancer is a malignancy of the lining of the uterine corpus and is the most common gynecologic cancer in many high-income countries. It is classically associated with prolonged exposure to estrogen unopposed by progesterone, and it often presents early because of abnormal uterine bleeding.

Definition

Endometrial cancer is a malignant neoplasm arising from the epithelium of the endometrium (the inner lining of the uterine corpus), most often as endometrioid adenocarcinoma, with less common non-endometrioid (e.g., serous) and other high-grade subtypes.

Scope

This entry covers the cell of origin and main histologic and molecular subtypes of endometrial cancer, the hormonal and metabolic risk factors that drive the common (endometrioid) type, hereditary contributions such as Lynch syndrome, and the molecular reclassification that has reshaped how the disease is understood. It is a reference topic and does not provide individualized clinical guidance.

Core questions

• How does unopposed estrogen exposure promote endometrial carcinogenesis?
• How do the traditional histologic types and the newer molecular subgroups relate to disease behavior?
• Which hereditary syndromes increase endometrial cancer risk?
• Why does endometrial cancer often present at an early stage?

Key concepts

• Unopposed estrogen and endometrial hyperplasia
• Endometrioid versus non-endometrioid (serous) carcinoma
• Molecular subgroups (POLE-ultramutated, MSI-high, copy-number low, copy-number high)
• Lynch syndrome and hereditary risk
• Obesity and metabolic risk factors
• Abnormal uterine bleeding as an early sign
• FIGO staging

Mechanisms

The common endometrioid subtype arises in a setting of estrogenic stimulation unopposed by progesterone, which promotes endometrial proliferation, hyperplasia, and progression to carcinoma; obesity, nulliparity, early menarche, late menopause, and unopposed estrogen therapy increase this exposure (Morice, 2016). A minority of tumors are non-endometrioid (such as serous carcinoma), which are typically high-grade and not estrogen-driven. The Cancer Genome Atlas (2013) reclassified endometrial carcinoma into four molecular subgroups — POLE-ultramutated, microsatellite-instability-high, copy-number low, and copy-number high — that cut across traditional histology and carry prognostic significance. Lynch syndrome (hereditary mismatch-repair deficiency) accounts for a notable share of younger-onset cases.

Clinical relevance

Endometrial cancer commonly causes abnormal uterine bleeding, which often leads to detection at an early, more favorable stage. Understanding its hormonal and molecular drivers explains patterns of risk and prognosis. This entry is educational reference material and is not a basis for individual diagnosis or treatment decisions.

Epidemiology

Endometrial cancer is the most frequently diagnosed gynecologic cancer in many high-income countries, and its incidence has been rising in parallel with obesity (Bray, 2024). It occurs predominantly after menopause, though a subset arises in younger women, including those with Lynch syndrome. The estrogen-related risk-factor profile links it epidemiologically to metabolic conditions.

History

The long-standing clinical division of endometrial cancer into estrogen-driven (type I) and non-estrogen-driven (type II) tumors framed twentieth-century understanding of the disease. The Cancer Genome Atlas analysis (2013) then introduced a molecular classification that refined prognosis beyond histology, and contemporary reviews integrated hormonal, hereditary, and molecular perspectives (Morice, 2016).

Debates

Molecular classification versus traditional histologic typing

The four-group molecular classification improves prognostic stratification and partly supersedes the type I/type II dichotomy, but how best to integrate molecular markers with histology in routine practice continues to be refined.

Key figures

• Philippe Morice
• Cyrus Kandoth
• Douglas Levine

Seminal works

• tcga-2013
• morice-2016

Frequently asked questions

What is the main modifiable risk factor for endometrial cancer?

Excess estrogen exposure, much of which relates to obesity; adipose tissue increases circulating estrogen unopposed by progesterone, promoting endometrial proliferation.

Why is endometrial cancer often found early?

It frequently causes abnormal or postmenopausal uterine bleeding, a noticeable symptom that commonly prompts evaluation while the cancer is still confined to the uterus.