The 2019 WHO classification of endometrial carcinoma identifies four molecular subtypes with distinct prognoses. Which molecular subtype has the best prognosis despite high histological grade?

• A MSI-hypermutated (mismatch repair deficient) subtype
• B Copy-number high (serous-like) subtype with TP53 mutations
• C NSMP (no specific molecular profile) subtype
• D POLE-ultramutated subtype with exonuclease domain mutations in POLE causing extreme hypermutation ✓

Explanation

POLE-ultramutated endometrial carcinomas harbor somatic mutations in the exonuclease (proofreading) domain of DNA polymerase epsilon (POLE), resulting in extremely high mutation burden (>100 mutations/Mb). Paradoxically, despite often being high-grade (grade 3 endometrioid), POLE-mutant tumors have excellent prognosis with very low recurrence rates, likely due to immunogenic neoantigen load generating robust anti-tumor T-cell responses. This is the ProMisE/TCGA 'ultramutated' group with the best outcomes. Copy-number high (TP53-mutant, serous-like) has the worst prognosis.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.