A 55-year-old man with primary sclerosing cholangitis (PSC) has dominant strictures on ERCP and elevated serum CA 19-9. Brush cytology shows aneuploidy. Which molecular mechanism primarily drives malignant transformation to cholangiocarcinoma in PSC?

• A TP53 mutation from bile acid-induced DNA damage in biliary epithelium
• B IDH1/IDH2 mutation-driven 2-hydroxyglutarate accumulation causing hypermethylation
• C FGFR2 fusion kinase activation from chromosomal translocation
• D Chronic NF-kB activation from bile stasis and bacterial products driving inflammatory carcinogenesis ✓

Explanation

In PSC-associated cholangiocarcinoma, chronic biliary obstruction, repeated bacterial cholangitis, and bacterial products (LPS, secondary bile acids) chronically activate NF-kB and STAT3 signaling in biliary epithelial cells (cholangiocytes). This drives a cycle of inflammation, proliferation, oxidative DNA damage, and epigenetic reprogramming leading to TP53 and KRAS mutations and ultimately carcinogenesis. IDH1/IDH2 mutations are predominantly found in intrahepatic cholangiocarcinoma (iCCA) without an inflammatory background and drive hypermethylation via 2-HG but are not the PSC mechanism. FGFR2 fusions also occur in iCCA but are not PSC-specific.

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

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Written and medically reviewed by the StethoPrep medical team.