The ProMisE molecular classification (2014) for endometrial carcinoma identifies 4 molecular subgroups with prognostic and treatment implications. The group with the best prognosis, characterized by POLE (polymerase epsilon) ultramutated genotype, shows which feature on immunohistochemistry?
- A Loss of mismatch repair protein expression (MLH1, MSH2, MSH6, PMS2)
- B Strong diffuse p53 overexpression (p53 abn)
- C Normal p53 and retained MMR expression with POLE hotspot mutation ✓
- D Retained p53 with MSI-high microsatellite instability
Explanation
POLE-ultramutated endometrial cancer (the best prognosis group) arises from somatic hotspot mutations in the exonuclease domain of POLE (Pol-ε), causing an extremely high tumor mutation burden (TMB). On immunohistochemistry, these tumors show normal/retained p53 staining and retained MMR protein expression; POLE mutation is confirmed by sequencing. Despite often being Grade 3 or high-grade histology, POLE-mutated tumors have excellent prognosis (near-zero risk of recurrence in early-stage disease). MMR-deficient (MSI-high) tumors have intermediate prognosis and respond to immune checkpoint inhibitors. p53-abnormal tumors (serous-like, copy number high) have the worst prognosis. The ProMisE classification is now incorporated into ESGO/ESTRO 2021 risk stratification for adjuvant therapy decisions.
Reference: Shaw's Textbook of Gynaecology, 17th ed.
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Written and medically reviewed by the StethoPrep medical team.