The distinction of ductal adenocarcinoma from chronic pancreatitis remains one of the most difficult challenges in surgical pathology. The glandular units of invasive carcinoma are often well formed with well-polarized cells, appearing deceptively benign. Conversely, the ducts of chronic pancreatitis may be atypical and pseudoinfiltrative as a result of acinar atrophy and fibrosis. We recently noted isolated solitary ductal units (ISDs) in adipose tissue to be a reliable indicator of adenocarcinoma. In this study, the frequency of ISDs was investigated in 105 pancreatic resections with ductal adenocarcinoma and 32 with chronic pancreatitis only. ISD was defined as a solitary gland lying individually in adipose tissue, either directly abutting adipocytes or separated from them by only a thin rim of fibromuscular tissue. ISD was detected in 50/105 (47.6%) of pancreatic resections for ductal adenocarcinoma, but not in any resections with chronic pancreatitis only (specificity 100%; sensitivity 47.6%). Most of the ISDs were very well differentiated and cytologically bland. A small subset of these units represented vascular invasion, in which the carcinoma cells epithelialized the vessel lining, transforming the vessel into a duct-like structure, virtually indistinguishable from normal ducts or PanINs. The vascular nature of these units was verified by Elastic-Van Gieson stain and muscular markers highlighting the elastic lamina and muscular wall, respectively. ISDs were often located in histologic sections taken for the evaluation of the retroperitoneal margin and pancreatic-free surfaces where adipose tissue is more abundant. In conclusion, ISD lying in adipose tissue unaccompanied by other elements, present in 47.6% of pancreatic resections when peripancreatic soft tissues away from the tumor are sampled, is a very specific finding for carcinoma that may be instrumental in the diagnosis and staging of carcinoma as well as margin evaluation.