It has been Ͼ10 years since Vogelstein and colleagues (1, 2) proposed a progression model for colorectal neoplasia in which they hypothesized that the progression from normal co-lonic 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 develop-ment of an invasive adenocarcinoma (1, 2, 6, 7). This genetic progression model not only has formed the basis of our under-standing 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 understand-ing 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 showed that they were more common in pancreata with cancer than they were in pancreata without cancer. Kozuka et al. (14) reported similar findings shortly thereafter, and more recently, Furukawa et al. (15), using three-dimensional mapping tech-niques, have demonstrated a stepwise progression from mild dysplasia to severe dysplasia in these pancreatic duct lesions (14 –16). These observations were, however, static, and it was not universally agreed upon whether these pancreatic duct le-sions represented the intraductal extension of an invasive cancer or a true precursor to invasive cancer (17). Clinical studies were needed to establish the temporal relationship between pancreatic duct lesions and invasive car-cinoma. These studies proved to be more difficult then one might hope because, unlike the colon, skin, breast, cervix, and prostate, the pancreas is not readily accessible to biopsy. None-theless, Brat et al. (18) have reported three patients who devel-oped infiltrating ductal pancreatic adenocarcinoma 17 months to 10 years after the histological identification of atypical papillary duct lesions in their pancreata. Similarly, Brockie et al. (19) reported two patients with atypical papillary duct lesions who developed invasive pancreatic ductal carcinomas years later.
Mendeley saves you time finding and organizing research
There are no full text links
Choose a citation style from the tabs below