A 58-year-old postmenopausal woman from Delhi presents with vaginal bleeding for 3 months. She has a BMI of 34 kg/m², hypertension on amlodipine, and type 2 diabetes mellitus. On examination, the uterus is normal size and non-tender. Transvaginal ultrasound shows an endometrial thickness of 18 mm with heterogeneous echotexture. Endometrial biopsy reveals a grade 2 adenocarcinoma with invasion into the inner half of the myometrium. Immunohistochemistry shows intact MLH1, MSH2, MSH6, and PMS2 expression. What is the most likely molecular subtype according to the TCGA classification?

Explanation

## Clinical Context This is a typical presentation of endometrial carcinoma in a postmenopausal woman with metabolic risk factors (obesity, diabetes, hypertension). The key diagnostic clue is the **intact mismatch repair (MMR) protein expression** on immunohistochemistry. ## TCGA Molecular Subtypes of Endometrial Carcinoma | Subtype | Frequency | MMR Status | POLE Mutation | TP53 | CNV | Prognosis | |---------|-----------|-----------|---------------|------|-----|----------| | MSI-H | 25–30% | **Deficient** | Absent | Wild-type | Low | Intermediate | | POLE-mutated | 7–10% | Intact | **Present** | Wild-type | Low | Favorable | | TP53-mutated (CNH) | 20–25% | Intact | Absent | **Mutated** | **High** | Poor | | MSS/p53-WT | 40–50% | **Intact** | Absent | Wild-type | Low | Favorable | ## Why This Patient is MSS/p53-WT **Key Point:** The intact expression of all four MMR proteins (MLH1, MSH2, MSH6, PMS2) **definitively excludes MSI-H** and points toward a microsatellite-stable (MSS) tumor. **High-Yield:** In the absence of: - POLE mutation (not mentioned in the stem) - TP53 mutation / CNH (would require additional molecular testing or immunostaining showing p53 overexpression) The default classification is **MSS with intact p53** — the most common TCGA subtype (~40–50% of endometrial carcinomas). ## Clinical Significance **Clinical Pearl:** MSS/p53-WT endometrial carcinomas are associated with: - Favorable prognosis compared to TP53-mutated (CNH) tumors - Standard adjuvant therapy: radiation ± chemotherapy depending on stage and grade - No specific indication for immunotherapy as monotherapy (unlike MSI-H tumors, which respond to checkpoint inhibitors) **Warning:** Do not confuse intact MMR protein expression with mismatch repair *proficiency*. Intact staining = proficient MMR = microsatellite stable.