POLEmut EC | MMRd EC | NSMP EC | p53abn EC | |
Frequency | 5–15% | 20–30% | 30–60% | 10–25% |
Surrogate markers | NGS (POLE sequencing) | MMR proteins IHC: PMS, MSH6 (MLH1, MSH2) | p53-IHC | |
Sanger | MSI assay | NGS (TP53 sequencing) | ||
Hot-spot targeted techniques | ||||
Molecular features | Ultramutated (>100 mut/Mb) | Hypermutated (>10 mutations/Mb) | Low TMB | Low TMB |
Somatic copy number alteration-low | Somatic copy number alteration-low | Somatic copy number alteration-low | Somatic copy number alteration-high | |
20% with MMR deficiency or MSI | MSI | MSS | MSS | |
20% with p53 mutant-expression/TP53 mutations | 10% with p53 mutant-expression/TP53 mutations | TP53 wild-type | TP53 mutated | |
PTEN mutations | Frequent homologous recombination deficiency | |||
PI3CA mutations | 20–25% Her2 amplification | |||
CTNNB1 mutations | ||||
Associated histological features | Mostly high-grade endometrioid | Mostly high-grade endometrioid | Mostly low-grade endometrioid | Mostly high-grade, all histologies |
Ambiguous morphology | Substantial LVSI | Squamous metaplasia | Substantial LVSI | |
Tumor giant cells | MELF-like invasion | ER/PR positive | High-grade atypia | |
High immune infiltrate (intra-epithelial CD8+ lymphocytes and TLS) | High immune infiltrate (intra-epithelial CD8+ lymphocytes and TLS) | |||
Associated clinical features | Low BMI | High BMI | High BMI | Low BMI |
Early stage | Advanced stage | |||
Younger patients | 10% Lynch syndrome carriers | Older patients | ||
Local recurrences | Distant recurrences | |||
Prognosis | Excellent | Intermediate | Intermediate-poor; stage and histologic-grade dependent | Poor |
Potential biomarkers for prognosis refinement | TLS | CD8 intra-epithelial lymphocytes | CD8 intra-epithelial lymphocytes | |
Molecular mechanism (MLH1 promoter methylation vs germline mutations) | L1CAM | |||
CTNNB1 mutations | ||||
ER/PR expression |
BMI, body mass index; EC, endometrial carcinoma; ER, estrogen receptor; IHC, immunohistochemistry; L1CAM, L1 cell adhesion molecule; LVSI, lymphovascular space invasion; MELF, microcystic elongated and fragmented-type invasion; MMR, mismatch repair; MMRd, mismatch repair-deficient; MSI, microsatellite instability; MSS, microsatellite stable; NGS, next generation sequencing; NSMP, no specific molecular profile; p53abn, p53-abnormal; POLEmut, polymerase epsilon-ultramutated; PR, progesterone receptor; TLS, tertiary lymphoid structure; TMB, tumor mutational burden.