TCGA (The Cancer Genome Atlas) molecular classification of endometrial carcinoma identifies four subtypes. A 52-year-old woman's endometrial carcinoma shows MSI-High status on immunohistochemistry (loss of MLH1 and PMS2 expression). Which molecular subtype does this represent, and what is the therapeutic implication?
- A POLE ultramutated subtype—best prognosis; no adjuvant therapy needed
- B Copy number high (p53-abnormal) subtype—worst prognosis; requires platinum-based chemotherapy
- C MSI-High (mismatch repair deficient, MMRd) subtype—intermediate prognosis; responds to immune checkpoint inhibitors (pembrolizumab) ✓
- D NSMP (No Specific Molecular Profile) subtype—intermediate prognosis; hormone receptor positive; responds to progestins
Explanation
The TCGA molecular classification divides endometrial carcinoma into four prognostically distinct subtypes: (1) POLE ultramutated (best prognosis, ~7%), (2) MMRd/MSI-High (intermediate-favorable prognosis, ~28%), (3) NSMP/low copy number (intermediate prognosis, ~39%), and (4) Copy number high/p53-abnormal (worst prognosis, ~26%). MLH1/PMS2 loss on IHC indicates mismatch repair deficiency (MMRd), most often due to MLH1 promoter hypermethylation (sporadic) or Lynch syndrome (germline MLH1/MSH2/MSH6/PMS2 mutations). The critical therapeutic implication: MMRd tumors are responsive to immune checkpoint inhibitors (pembrolizumab, dostarlimab) approved for recurrent endometrial cancer in MMRd/MSI-H tumors. KEYNOTE-158 and GARNET trials support this.
Reference: Shaw's Textbook of Gynaecology, 17th ed.
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