The pathogenesis of endometrial carcinoma involves several key factors:
## Hormonal Imbalance
The most common type of endometrial cancer, Type I endometrioid carcinoma, is strongly associated with prolonged exposure to unopposed estrogen[1][3]. This can occur due to:
- Obesity
- Late menopause
- Nulliparity
- Polycystic ovary syndrome
- Estrogen-only hormone replacement therapy
Excess estrogen stimulates endometrial proliferation without the counterbalancing effects of progesterone, leading to endometrial hyperplasia and potentially malignant transformation[1].
## Genetic Mutations
Several genetic alterations are implicated in endometrial carcinogenesis:
- **PTEN mutations** are common in Type I endometrioid cancers and endometrial intraepithelial neoplasia (EIN) precursor lesions[1][2].
- **KRAS** and **β-catenin** mutations are also seen in Type I cancers[2].
- **TP53 mutations** are characteristic of more aggressive Type II serous and clear cell carcinomas[1][2].
## Precursor Lesions
- Type I cancers often arise from endometrial intraepithelial neoplasia (EIN), previously called atypical endometrial hyperplasia[1].
- Type II cancers may develop from "p53 signatures" in atrophic endometrium, progressing through endometrial glandular dysplasia to serous intraepithelial carcinoma[1].
## Other Factors
- Microsatellite instability due to mismatch repair deficiencies is seen in some endometrial cancers, especially in Lynch syndrome[1].
- Insulin resistance and hyperandrogenemia may play a role, though the mechanisms are not fully understood[1].
## Molecular Subgroups
Recent classification systems categorize endometrial cancers based on molecular features rather than just histology, considering factors like mutation burden and copy number alterations[1].
In summary, the pathogenesis of endometrial carcinoma involves a complex interplay of hormonal factors, genetic mutations, and precursor lesions, with different pathways leading to the development of Type I and Type II cancers.
Citations:
[1] https://www.ncbi.nlm.nih.gov/books/NBK525981/
[2] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3822435/
[3] https://www.mayoclinic.org/diseases-conditions/endometrial-cancer/symptoms-causes/syc-20352461
[4] https://www.sciencedirect.com/science/article/pii/S0749208119300130
[5] https://emedicine.medscape.com/article/254083-overview