Clinical Significance
The integration of molecular classification into clinical practice has become pivotal for the risk stratification of endometrial carcinoma (EC). Key guidelines and systems, such as those from the World Health Organization (WHO), European Society of Gynaecological Oncology (ESGO), and others, now emphasize the relevance of molecular subtypes in managing EC. This approach offers a more consistent framework for categorizing EC, enabling both predictive and prognostic insights crucial for treatment decisions and future research initiatives.
Molecular subtype assignments can be derived from diagnostic biopsies or curettings, demonstrating high concordance with results from hysterectomy specimens. Approximately 3% of ECs exhibit multiple molecular features, highlighting the complexity of tumor biology.
Molecular Subtypes
In 2013, The Cancer Genome Atlas (TCGA) characterized over 370 ECs, identifying four distinct molecular subtypes, each linked to unique genomic architectures and clinical outcomes. Subsequent developments have led to a clinically applicable classification system that can be performed on standard formalin-fixed, paraffin-embedded samples. This collaboration has refined the terminology and identified tumors with mixed characteristics.
The Four Molecular Subtypes
1. DNA Polymerase Epsilon (POLε)-Mutated Subtype (POLεmut):
- Characteristics: These tumors are stable in copy number (CN) and exhibit recurrent mutations in the exonuclease domain of the POLε gene, integral for DNA replication. They have an exceptionally high somatic mutation frequency, often exceeding 100 mutations per megabase (Mb). Endometrioid histology is common, and these tumors show significant lymphocyte infiltration.
- Prognosis: Patients are typically younger, and despite aggressive pathological features, the prognosis is excellent, with over 96% five-year survival rates. Current research suggests that adjuvant therapy may not improve outcomes for these patients.
2. Mismatch Repair-Deficient Subtype (MMRd):
- Characteristics: This subtype has low CN alterations but a high mutational burden due to dysfunctional mismatch repair proteins. It is often linked to Lynch syndrome. The mutational frequency exceeds 10 mutations/Mb.
- Prognosis: The response to immune checkpoint inhibitors has been promising, leading to FDA approvals for treating metastatic MMRd EC.
3. No Specific Molecular Profile (NSMP):
- Characteristics: This genomically stable subtype exhibits moderate mutational load and is often MMR proficient. These tumors typically express estrogen and progesterone receptors and have favorable responses to hormonal therapy.
- Prognosis: While generally associated with good outcomes, the prognosis can be unfavorable in certain subgroups, particularly those that are ER negative.
4. p53 Abnormal Subtype (p53abn):
- Characteristics: High CN alterations and a mutation profile akin to high-grade serous ovarian and basal-like breast carcinomas define this subtype. p53 mutations are characteristic, and these tumors account for a significant proportion of EC mortality.
- Prognosis: Patients often present with advanced disease at diagnosis, but combined treatment approaches have shown improved outcomes.
Risk Stratification
Multiple systems have been developed to distinguish between patients who can be managed with surgery alone and those who require additional adjuvant therapy. Effective risk stratification remains a challenge, as it is critical to determine the likelihood of recurrence.Histogenesis and Precursor Lesions
Endometrial carcinoma often develops from atypical endometrial hyperplasia, with specific molecular alterations indicating early oncogenic events. Different subtypes arise from distinct precursor lesions, such as serous endometrial intraepithelial carcinoma for serous ECs.Histological Classification
The WHO classifies EC into various subgroups, with endometrioid carcinoma being the most prevalent. The histopathological features and grading systems help guide prognosis and treatment decisions.
Key Histological Types
• Endometrioid Carcinoma: Represents 75-80% of cases and is often low grade with good prognosis.
• Serous Carcinoma: Accounts for about 10% of cases, associated with aggressive behavior and poor outcomes.
• Clear Cell Carcinoma: Comprises less than 5% of EC, with variable prognosis based on molecular features.
• Mixed Carcinoma: Contains multiple histologic components and is usually homogenous in molecular subtype.
• Carcinosarcoma: A rare, aggressive biphasic tumor often characterized by p53 abnormalities.Pathology Reporting
Accurate pathology reporting is crucial for effective treatment planning. Key factors, including MMR status and p53 immunostaining, should be assessed to guide clinical management. Molecular testing, including POLε mutations and HER2 status, can further refine treatment approaches.In summary, understanding the integration of molecular subtypes in endometrial carcinoma is essential for optimizing patient care and informing future therapeutic strategies.
