The 2020 WHO classification of endometrial carcinoma introduced a molecular classification with four prognostically distinct subtypes. Which molecular subtype carries the worst prognosis and is characterized by TP53 mutations with copy number high (CN-high) pattern?
- A POLE-ultramutated subtype: POLE exonuclease domain mutations, highest mutation burden, excellent prognosis
- B MMR-deficient (Lynch-like) subtype: MSI-H, mismatch repair deficiency, intermediate prognosis
- C NSMP (No Specific Molecular Profile) subtype: CN-low, intermediate prognosis, ER/PR-positive, mostly endometrioid grade 1–2
- D p53-mutant/CN-high subtype (serous-like): TP53 mutation, aneuploidy, high CNV, poor prognosis similar to serous carcinoma regardless of histologic type ✓
Explanation
The 2020 WHO/ProMisE/TCGA molecular classification of endometrial carcinoma identifies four groups: (1) POLE-ultramutated — best prognosis, POLE exonuclease domain mutations causing hypermutation with high TMB; (2) MMR-deficient — MSI-H, intermediate prognosis; (3) NSMP (no specific molecular profile) — CN-low, good prognosis, mostly low-grade endometrioid; and (4) p53-mutant/CN-high — worst prognosis, TP53 mutation, widespread chromosomal aneuploidy, copy number alterations as in serous carcinoma, often FIGO stage III/IV at presentation regardless of histological type. This molecular subtype corresponds to the former category of serous endometrial carcinoma and aggressive endometrioid grade 3 carcinomas sharing serous-like molecular features. Immunohistochemically, aberrant p53 (either diffuse strong [missense] or complete absence [null, frameshift/nonsense]) is used as a surrogate for TP53 mutation.
Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.
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Written and medically reviewed by the StethoPrep medical team.