A 58-year-old postmenopausal woman has an endometrial biopsy showing high-grade serous endometrial carcinoma. IHC shows p53 strong diffuse positivity ('block staining') in virtually all tumor cells and loss of mismatch repair proteins (MLH1/PMS2). According to the 2023 FIGO molecular classification of endometrial cancer, which molecular subtype does this represent?

• A MMR-deficient (MMRd) — classified on the basis of MMR protein loss alone, regardless of p53 status
• B POLE-ultramutated — defined by proofreading-domain mutations in POLE with the best prognosis
• C p53-abnormal (p53abn) — this is the most aggressive subtype characterised by TP53 mutations, copy number high, serous/high-grade morphology, and worst prognosis ✓
• D Non-specific molecular profile (NSMP) — classified when no defining molecular alteration is present

Explanation

The 2023 FIGO/WHO molecular classification of endometrial carcinoma uses a hierarchical algorithm: (1) POLE ultramutated (best prognosis) → (2) MMR-deficient → (3) p53-abnormal → (4) NSMP. When multiple molecular alterations coexist (as here: both MMRd and p53abn), the hierarchical rule applies: p53-abnormal is the overriding classification if TP53 mutation is confirmed, as p53abn POLE/MMR co-aberrations retain the high-risk p53abn behaviour. Strong diffuse p53 expression ('block-positive') or complete loss both indicate TP53 mutation. p53abn EC has the highest relapse rate, requires platinum-based chemotherapy, and corresponds to copy-number high tumors typically of serous or high-grade endometrioid morphology.

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

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Written and medically reviewed by the StethoPrep medical team.