A 58-year-old postmenopausal woman from Delhi presents with vaginal bleeding for 3 months. She has a BMI of 32 kg/m², blood pressure 140/90 mmHg, and fasting blood glucose 128 mg/dL. Pelvic ultrasound shows an endometrial thickness of 18 mm with an irregular, heterogeneous mass. Endometrial biopsy reveals adenocarcinoma with invasion into the inner half of the myometrium. Immunohistochemistry shows loss of MLH1 expression. What is the most likely molecular subtype according to TCGA classification?

Explanation

## Molecular Classification of Endometrial Carcinoma The TCGA (The Cancer Genome Atlas) classification divides endometrial carcinomas into four molecular subtypes based on genomic and epigenetic features. ### Clinical and Pathologic Clues in This Case **Key Point:** Loss of MLH1 expression on immunohistochemistry is pathognomonic for microsatellite instability (MSI), which corresponds to the MSI/Hypermethylated subtype in TCGA classification. **High-Yield:** MLH1 loss typically results from promoter hypermethylation in the MSI pathway, not from mutations. This is the hallmark of Lynch syndrome-associated or sporadic MSI endometrial cancers. ### TCGA Molecular Subtypes | Subtype | Genomic Features | IHC Markers | Prognosis | Frequency | |---------|------------------|------------|-----------|----------| | **MSI/Hypermethylated** | High mutation burden, MLH1 promoter methylation | MLH1 loss, PMS2 loss | Intermediate | 28% | | **POLE-mutated** | POLE exonuclease domain mutations | Mismatch repair intact | Favorable | 7% | | **Copy-number high (serous-like)** | TP53 mutations, chromosome instability | p53 abnormal | Poor | 26% | | **Copy-number low (endometrioid)** | PTEN, PIK3CA, KRAS mutations | Mismatch repair intact | Favorable | 39% | ### Why This Patient Has MSI/Hypermethylated Subtype 1. **MLH1 loss** = defective mismatch repair → MSI phenotype 2. **Metabolic risk factors** (obesity, diabetes) are associated with sporadic MSI endometrial cancers 3. **Endometrioid morphology** with myometrial invasion fits the MSI spectrum **Clinical Pearl:** MSI endometrial cancers have intermediate prognosis and are candidates for immune checkpoint inhibitor therapy (pembrolizumab) due to their high neoantigen burden. ### Differential Molecular Subtypes - **POLE-mutated:** Would show intact mismatch repair proteins (MLH1, PMS2, MSH2, MSH6 all present) - **Copy-number high (serous-like):** Associated with TP53 mutations; typically shows aggressive histology and p53 immunostaining abnormalities - **Copy-number low (endometrioid):** Most common; PTEN/PIK3CA mutations; mismatch repair proteins intact [cite:Robbins 10e Ch 22]