Progression model for pancreatic cancer.

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 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 techniques, 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 lesions 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 carcinoma. 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. Nonetheless, Brat et al. (18) have reported three patients who developed 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. Although there have only been a handful of such cases reported, they provide strong support that duct lesions in the pancreas can progress to invasive cancer (20). Molecular genetic analyses have provided the third and most convincing line of evidence that pancreatic duct lesions are the precursors to infiltrating adenocarcinomas of the pancreas. Almost all of the genetic alterations that have been identified in infiltrating ductal adenocarcinomas of the pancreas have also been identified in these duct lesions, and remarkably, the prevalence of these genetic alterations increases as the degree of cytological and architectural atypia in the duct lesions increases (Fig. 1; Refs. 21–27). Pancreatic duct lesions with minimal cytological and architectural atypia have been shown to harbor activating point mutations in the K-ras oncogene and to overexpress the HER2/neu gene product (17, 21, 24, 28–31). For example, Day et al. (21) reported that HER-2/neu is only rarely overexpressed in histologically normal pancreatic ductal epithelium, but it is overexpressed in almost all duct lesions with significant cytological and architectural atypia. Similarly, ;45% of papillary pancreatic duct lesions without atypia harbor K-ras gene mutations, and the prevalence of these mutations in K-ras increases with increasing degrees of atypia in the duct lesions (reviewed in Ref. 22). These alterations in K-ras and Her-2/neu are believed to be “early” genetic events in the development of pancreatic neoplasia because they occur in pancreatic duct lesions with minimal atypia. Inactivation of the p16 tumor suppressor gene appears to occur slightly later. For example, the p16 tumor suppressor gene is located on chromosome 9p, and Yamano et al. (32) have shown loss of heterozygosity at 9p in ;13% of histologically low-grade pancreatic duct lesions, whereas 90% of the histologically high-grade duct lesions that they examined had loss of heterozygosity of this chromosome arm. Similarly, Moskaluk et Received 1/26/00; revised 4/24/00; accepted 5/8/00. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1 Supported by NIH Grant P50-CA 62924. 2 To whom requests for reprints should be addressed, at The Johns Hopkins Hospital, Meyer 7-181, 600 North Wolfe Street, Baltimore, MD 21287. Phone: (410) 955-9132; Fax: (410) 955-0115; E-mail: [email protected]. 2969 Vol. 6, 2969–2972, August 2000 Clinical Cancer Research