[Frontiers in Bioscience 3, d1148-1160, November 15, 1998] |
MOLECULAR PATHOBIOLOGY OF PANCREATIC ADENOCARCINOMA
Shamlal Mangray and Thomas C King
Department of Pathology and Laboratory Medicine, Brown University School of Medicine, Providence, RI
Received 8/24/98 Accepted 9/4/98
Pancreatic cancer is the fifth leading cause of cancer death in the United States. Based on population data and cancer incidence rates collected by the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program, it is estimated that 29,000 new cases of cancer of the pancreas will be diagnosed in the United States in 1998, and 28,900 cancer deaths will result from pancreatic cancer (1). In 50 percent of cases, pancreatic cancer will be locally advanced at diagnosis precluding cure by surgical means. The overall five year survival for pancreatic cancer is less than 5 percent. Until recently, therapeutic approaches including chemotherapy and radiation have been unrewarding. The recent application of novel chemoradiation protocols has shown encouraging activity in locally advanced pancreatic adenocarcinoma with acceptable toxicity (2). These hybrid protocols may permit useful therapy for patients with this deadly disease in the near future.
Identified predisposing factors for the development of pancreatic adenocarcinoma are advanced age and cigarette smoking. The majority of cases occur in the seventh and eight decades and are infrequent before age forty. Rare cases have been described in children, however. Cigarette smoking in college has been estimated to increase the risk of developing pancreatic adenocarcinoma later in life by 2.6 fold. The association with smoking is dependent on the duration and number of cigarettes smoked but the possible role of passive smoking has not been addressed (3).
The vast majority of cases of pancreatic cancer are adenocarcinomas arising from the pancreatic ducts. The typical histomorphology of ductal adenocarcinoma is one of small neoplastic glands surrounded by an intense non-neoplastic stromal reaction together with inflammatory cells. Rare tumors arise from pancreatic acinar tissue or from neuroendocrine cells in the islets of Langerhans. These tumors tend to have a much different biologic behavior than usual ductal pancreatic adenocarcinoma and are not considered further here. Cystic tumors of the pancreas (both mucinous and serous) also occur and in their pure form have a substantially better prognosis than ductal carcinomas. These cystic lesions are also excluded from consideration here.
Accompanying some ductal adenocarcinomas are precursor lesions ranging from flat mucinous lesions to atypical papillary intraductal lesions. Many of these precursor lesions are absent or have been overgrown by the invasive tumor. In some cases, these precursor lesions have been shown to harbor genetic mutations (K-ras gene mutations are most common) suggesting a multi-step progression to malignancy analogous to adenomatous polyps of the colon (4-6).
Although a full understanding of the biology of pancreatic adenocarcinoma is currently out of reach, its genetic composition is being unraveled at a steady pace. The study of cases that appear to have a hereditary basis has permitted the identification of genetic loci through linkage studies that may influence tumorigenesis and tumor progression. By analogy to other tumors, some of these oncogenes and tumor suppressor genes are likely involved in development of sporadic cases of pancreatic adenocarcinoma. Other previously characterized oncogenes and tumor suppressor genes appear to play an important role in sporadic tumors as well. It is increasingly clear that molecular genetic alterations in tumors are a significant determining factor for response to specific therapeutic protocols. Identification of specific gene defects in individual tumors may permit the choice of the most beneficial treatment modality for each patient. In this article we review the literature on the genetics of pancreatic adenocarcinoma and discuss the possible implications for genetic screening [which might permit diagnosis at an earlier stage] as well as the impact of gene alterations on novel treatment modalities.