It has been 10 years since Vogelstein and colleagues (1, 2) proposed a progression model for colorectal neoplasia in which they hypothesized that the progression from normal colonic epithelium, to small adenomatous polyps, to infiltrating adenocarcinoma is associated with the activation of oncogenes and the inactivation of tumor suppressor genes. Mutations in the APC gene initiate the adenomatous process, resulting in the clonal growth of a single cell (3–5). Over the years, additional mutations can occur in these adenomas, resulting in waves of clonal expansion and competition among persistent subclones, increasing severity of dysplasia, and eventually in the development of an invasive adenocarcinoma (1, 2, 6, 7). This genetic progression model not only has formed the basis of our understanding of the mechanisms underlying the development of colorectal neoplasia, but it also has important implications for chemoprevention, for the development of genetic screening tests for the presymptomatic diagnosis of colorectal carcinomas, and for the development of prognostic genetic markers (8–10). Pancreatic cancer is the fourth leading cause of cancer death in both men and women; yet, at the time the progression model was proposed for colorectal neoplasms, remarkably little was known about pancreatic cancer. For example, in 1988, the only significant genetic alteration that had been identified in pancreatic cancer was mutation of the K-ras oncogene (11). The last 10 years has seen, however, an explosion in our understanding of pancreatic cancer, and pancreatic cancer is now one of the better characterized neoplasms at the genetic level. We believe that there is now sufficient pathological, clinical, and genetic evidence for us to develop a rational progression model for pancreatic cancer.

The first clue that there may be a distinctive precursor lesion to infiltrating adenocarcinoma of the pancreas came from careful morphological studies (12). In 1976, Cubilla and Fitzgerald (13) reported a seminal paper in which they identified histologically distinct proliferative lesions in the pancreatic ducts and ductules adjacent to infiltrating adenocarcinomas of the pancreas. They called these duct lesions “hyperplasias” and