Perineural extension of pancreatic adenocarcinoma has been explained as a mechanical extension along planes of least resistance. This study tests whether the cancer is limited to following these planes and if substances involved in cell signaling are involved in the interaction of cancer cells with nerves.Samples of tissue from patients undergoing resection of pancreatic cancer were studied by electron microscopy and light microscopy. Transforming growth factor alpha (TGF-alpha) and epidermal growth factor receptor (EGFR) were localized in sections.The adenocarcinoma is not confined to the periphery of nerves. It penetrates the perineurium and becomes intimately associated with Schwann cells and axons in the endoneurium. Neural elements are damaged. Neural invasion likely is a factor in associated pain. TGF-alpha is abundant in nerves in the pancreas. EGFR is prominent in the cells of the adenocarcinoma.The interaction of pancreatic cancer with nerves involves more than the cancer following a perineural space. Interaction of TGF-alpha in nerves with EGFR on cancer cells constitutes a possible paracrine mechanism that provides a growth advantage for pancreatic adenocarcinoma and serves as an example of potential interactions that might be active in biological interaction of cancer with nerves.