An endometrial biopsy shows glands with back-to-back architecture, minimal intervening stroma, nuclear atypia, and mitoses. There is no myometrial invasion. IHC: MLH1 and PMS2 are absent (MSH2 and MSH6 retained). Methylation analysis shows MLH1 promoter hypermethylation. What is the most likely molecular subtype of this endometrial carcinoma according to TCGA/ProMisE classification?

• A POLE (ultramutated) subtype — excellent prognosis
• B MSI-high/MMRd (mismatch repair deficient) subtype due to somatic MLH1 promoter hypermethylation — intermediate prognosis; Lynch syndrome must be ruled out ✓
• C No specific molecular abnormality (NSMP) subtype — treated based on histologic grade alone
• D p53-abnormal (SCNA-high) subtype — worst prognosis; immediate platinum-based chemotherapy indicated

Explanation

The TCGA molecular classification of endometrial carcinoma (implemented as ProMisE algorithm) defines four subtypes: (1) POLE ultramutated — POLE exonuclease domain mutations, excellent prognosis; (2) MMRd (mismatch repair deficient/MSI-high) — absent MMR proteins by IHC or MSI by PCR, intermediate prognosis; (3) NSMP (no specific molecular profile) — copy number low, intermediate prognosis; (4) p53-abnormal (copy number high) — p53 mutations/TP53 abnormality, worst prognosis. Absent MLH1/PMS2 with retained MSH2/MSH6 indicates MLH1/PMS2 pair dysfunction, confirmed as somatic by MLH1 promoter hypermethylation (germline Lynch syndrome typically shows MSH2 loss, though MLH1 germline mutations do occur). This is MMRd subtype from epigenetic silencing. MLH1-hypermethylated MMRd endometrial cancer is sporadic, though Lynch syndrome must still be excluded by germline testing.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

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Written and medically reviewed by the StethoPrep medical team.