A 58-year-old postmenopausal woman from Delhi presents with vaginal bleeding for 3 months. She has a BMI of 32 kg/m², history of hypertension, and type 2 diabetes mellitus. Pelvic examination reveals a bulky uterus. Transvaginal 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 intact MLH1, MSH2, MSH6, and PMS2 expression. What is the most likely molecular subtype of this tumor according to the TCGA classification?

Explanation

## Clinical Presentation & Risk Factors **Key Point:** This patient has classic risk factors for endometrial carcinoma: postmenopausal status, obesity (BMI 32), diabetes, and hypertension — hallmarks of **estrogen-dependent (Type I) endometrioid adenocarcinoma**. ## Molecular Subtype Classification (TCGA) The TCGA classification divides endometrial carcinomas into four molecular subtypes: | Subtype | Frequency | Key Features | Prognosis | |---------|-----------|--------------|-----------| | **POLE mutated** | 7–10% | Exonuclease domain mutations; ultramutated; often early stage | Favorable | | **MSI-H** | 25–30% | Mismatch repair deficiency; Lynch syndrome or sporadic MLH1 hypermethylation | Intermediate | | **NSMP** | 40–50% | No specific molecular alterations; PTEN/PIK3CA mutations common; endometrioid type | Intermediate | | **CNH/p53 mutated** | 20–25% | TP53 mutations; high copy number alterations; serous/clear cell histology | Poor | ## Why This Case Is NSMP 1. **Intact mismatch repair proteins (MLH1, MSH2, MSH6, PMS2)** → Definitively rules out **MSI-H** subtype. 2. **No POLE mutation mentioned** → Rules out **POLE mutated** subtype. 3. **Classic Type I endometrioid adenocarcinoma** with estrogen-dependent risk factors (obesity, diabetes, hypertension) → This clinical profile is most strongly associated with the **NSMP** subtype, which accounts for ~40–50% of all endometrial carcinomas and is the dominant subtype in low-grade endometrioid tumors. 4. **CNH/p53 mutated** subtype is characteristically associated with **Type II endometrial cancers** (serous carcinoma, clear cell carcinoma, high-grade endometrioid), aggressive histology, and TP53 mutations — none of which are described here. Without a TP53 immunostain result or high-grade/serous histology, CNH/p53 cannot be favored over NSMP. **Clinical Pearl:** Per the TCGA (Cancer Genome Atlas) and WHO 2020 classification, NSMP is the **most common** molecular subtype in low-grade endometrioid endometrial carcinoma with intact MMR and no POLE mutation. It is characterized by PTEN loss, PIK3CA mutations, and KRAS mutations — consistent with the estrogen-driven pathway. (Reference: TCGA Research Network, *Nature* 2013; WHO Classification of Tumours, Female Genital Tumours, 5th ed., 2020.) ## Prognostic Implications **High-Yield:** NSMP carries an intermediate prognosis. CNH/p53 mutated tumors have the worst prognosis (~40–50% 5-year OS) but require histological and molecular evidence (serous/high-grade histology, TP53 mutation/aberrant p53 IHC) for classification — evidence absent in this stem. The TCGA molecular classification is now integrated into clinical practice for prognostication and treatment selection (e.g., checkpoint inhibitor therapy for MSI-H tumors, adjuvant chemotherapy decisions for CNH tumors).