A postmenopausal woman with endometrial carcinoma shows deficient MLH1 and PMS2 immunostaining on mismatch repair (MMR) protein IHC, and methylation of the MLH1 promoter is detected. This is best classified as:

• A Lynch syndrome-associated endometrial carcinoma
• B POLE-ultramutated endometrial carcinoma
• C Copy-number high (serous-like) endometrial carcinoma
• D Microsatellite instability-high (MSI-H) endometrioid endometrial carcinoma with sporadic MLH1 epigenetic silencing ✓

Explanation

MLH1 promoter hypermethylation accounts for ~90% of MSI-H endometrial cancers and represents an acquired epigenetic silencing event — not a Lynch syndrome germline mutation. Lynch syndrome should be suspected if MLH1 is deficient WITHOUT methylation, or if MSH2, MSH6, or PMS2 are deficient. TCGA classifies endometrial carcinoma into 4 molecular groups: POLE-ultramutated (best prognosis), MSI-H (intermediate), copy-number low (microsatellite stable, mostly endometrioid), and copy-number high (p53-aberrant, serous-like, worst prognosis). Distinguishing sporadic MLH1 methylation from Lynch syndrome is clinically crucial for family counseling.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.