🔬 Uterine Cancer Classification: From Histology to Modern Molecular Insights

Uterine cancer most commonly endometrial cancer encompasses a diverse group of tumors arising from the uterine lining. Classification plays a crucial role in guiding prognosis, treatment decisions, and research directions. Traditionally, uterine cancers have been categorized based on histopathology, but recent advances have introduced molecular subtyping that offers deeper biological understanding and clinical precision.

Histopathological Classification

The most common form is endometrial carcinoma, which originates in the endometrium. According to Cancer Research UK, the majority of these cancers are adenocarcinomas, with endometrioid adenocarcinoma being the predominant subtype. The World Health Organization (WHO) further organizes uterine tumors into categories such as endometrial epithelial tumors, mesenchymal tumors, and mixed epithelial–mesenchymal tumors, reflecting their cellular origin.

Endometrial cancers have historically been divided into:

• Type I (Endometrioid): Estrogen-dependent, often low-grade, and associated with endometrial hyperplasia.
• Type II (Non-endometrioid): Includes serous and clear cell carcinomas, typically high-grade and more aggressive.

WHO’s 2020 update also emphasizes precursor lesions such as endometrial hyperplasia without atypia and atypical hyperplasia/endometrioid intraepithelial neoplasia, which carry varying risks of progression to carcinoma.

Molecular Classification

Modern classification integrates genomic profiling, as highlighted in recent clinical reviews. The four major molecular subtypes include:

• POLE-ultramutated: Excellent prognosis due to high mutational burden.
• Microsatellite instability–high (MSI-H): Intermediate prognosis; linked to mismatch repair deficiency.
• Copy-number low (NSMP): Often endometrioid, with favorable to intermediate outcomes.
• Copy-number high (p53-abnormal): Typically serous-like, aggressive, and associated with poor prognosis.

This molecular framework enhances risk stratification and supports personalized treatment approaches, including targeted therapies and immunotherapy.

Why Classification Matters

Accurate classification informs surgical planning, adjuvant therapy, and long-term surveillance. As research evolves, integrating histological and molecular data is becoming the gold standard for improving patient outcomes.