Pathophysiology
Ductal epithelium acquires KRAS activation (>90%), then CDKN2A, TP53 and SMAD4 loss. Progresses from PanIN to invasive adenocarcinoma. Chronic pancreatitis, smoking, obesity, type 2 diabetes and BRCA2/PALB2 mutations increase risk.
Sources: NCCN Pancreatic Adenocarcinoma (v2.2025); ASCO Metastatic Pancreatic Cancer Guideline (J Clin Oncol 2020;38:3217); ESMO Pancreatic Cancer Clinical Practice Guideline (Ann Oncol 2023;34:987)
Clinical presentation
Painless obstructive jaundice with palpable non-tender gallbladder (Courvoisier sign), weight loss, epigastric pain radiating to the back, new-onset diabetes, migratory thrombophlebitis (Trousseau) and dark urine/pale stool for head lesions. Body/tail tumours present late with pain.
Diagnosis
Multiphase pancreatic-protocol CT is initial imaging; MRI/MRCP if CT indeterminate; EUS-guided fine-needle biopsy for tissue. CA 19-9 monitors treatment response but is not diagnostic. Staging determines resectability (borderline vs unresectable per vascular involvement).
Management
Resectable head tumours: Whipple (pancreaticoduodenectomy) + adjuvant mFOLFIRINOX. Borderline/locally advanced: neoadjuvant FOLFIRINOX or gemcitabine/nab-paclitaxel then reassessment. Metastatic: mFOLFIRINOX (fit ECOG 0-1) or gemcitabine + nab-paclitaxel; germline BRCA1/2 mutants respond to olaparib maintenance.
Palliation
Biliary stenting (ERCP) for jaundice, duodenal stents or gastrojejunostomy for gastric outlet obstruction, coeliac plexus neurolysis for pain, and pancreatic enzyme replacement for steatorrhoea.
