A 58-year-old postmenopausal woman from Delhi presents with vaginal bleeding for 3 months. She has a BMI of 34 kg/m², and reports irregular menses until age 52. 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 retained MLH1 and MSH2 expression. What is the most likely molecular subtype according to the TCGA classification?

Explanation

## Clinical Context This patient presents with classic features of endometrial carcinoma: postmenopausal bleeding, obesity (metabolic syndrome), and histologically confirmed adenocarcinoma with myometrial invasion. ## Molecular Classification (TCGA) The TCGA classification divides endometrial carcinomas into four molecular subtypes: | Subtype | MMR Status | p53 Status | Prognosis | Frequency | |---------|-----------|-----------|-----------|----------| | **POLE-mutant** | Proficient | Wild-type | Favorable | 7% | | **MSI-H / MMRd** | Deficient (MLH1, MSH2, MSH6, PMS2) | Variable | Intermediate | 28% | | **p53 wild-type (p53wt)** | Proficient | Wild-type | Favorable | 39% | | **p53 mutant (p53mut)** | Proficient | Mutant | Poor | 26% | ## Key Finding: Retained Mismatch Repair Proteins **Key Point:** Retained (intact) MLH1 and MSH2 expression indicates **proficient mismatch repair (pMMR)**. This excludes the MSI-H/MMRd subtype. **High-Yield:** The patient's clinical profile—obesity, metabolic syndrome, grade 2 adenocarcinoma with inner myometrial invasion, and proficient MMR—is consistent with the most common endometrial carcinoma subtype: **p53 wild-type (p53wt)**. ## Pathologic Features Supporting p53wt - Grade 2 adenocarcinoma (not high-grade) - Myometrial invasion limited to inner half (not deeply invasive) - Proficient mismatch repair (no loss of MLH1/MSH2) - No mention of POLE mutations - Obesity-related endometrial carcinoma phenotype **Clinical Pearl:** p53wt tumors account for ~39% of endometrial carcinomas and are associated with better prognosis than p53mut tumors. They typically present with lower-grade histology and earlier-stage disease. ## Why Not MSI-H/MMRd? MSI-H tumors show **loss** of mismatch repair proteins on immunohistochemistry. This patient has **retained** MLH1 and MSH2, ruling out MSI-H. ## Why Not p53 Mutant? p53mut tumors are typically high-grade, deeply invasive, and have a poor prognosis. This patient's grade 2, inner myometrial invasion pattern is inconsistent with p53mut biology.