Pancreatic Cancer

Disease / Phenomenon

Pancreatic cancer, most commonly pancreatic ductal adenocarcinoma, is among the most lethal malignancies, largely because it produces few specific symptoms until it has spread. Early signs are vague — indigestion, back or upper abdominal discomfort, unexplained weight loss, loss of appetite — and painless jaundice from bile duct obstruction is often the first clear indicator. New-onset diabetes in an older adult without other risk factors can be an early manifestation. Surgical resection offers the best prospect for long-term survival but is possible in only a minority of patients at diagnosis. Risk factors include smoking, chronic pancreatitis, obesity, diabetes, heavy alcohol use, and inherited syndromes involving BRCA2, PALB2, or Lynch syndrome genes.

The molecular sequence is well mapped: activating KRAS mutations occur in the great majority of tumors and initiate the process, followed by loss of the tumor suppressors CDKN2A, TP53, and SMAD4 as lesions progress from pancreatic intraepithelial neoplasia to invasive carcinoma. A defining feature is the dense desmoplastic stroma, in which cancer-associated fibroblasts deposit collagen and hyaluronan, raising interstitial pressure, collapsing vasculature, and impeding drug delivery. Immune exclusion, metabolic adaptation including autophagy dependence, and epithelial-mesenchymal transition support progression. This page separates these processes into pathways and biomarkers.