Inactivation of the TP53 tumor suppressor gene occurs in 50% to 70% of pancreatic cancers. Its gene
Fig. 17.8 Progression model for the development of pancreatic cancer. It is postulated that telomere shortening and mutations of the KRAS oncogene occur at early stages, inactivation of the p16 tumor suppressor gene occurs at intermediate stages, and inactivation of the TP53, SMAD4, and BRCA2 tumor suppressor genes occurs at late stages. Note that while there is a general temporal sequence of changes, the accumulation of multiple mutations is more important than their occurrence in a specific order. PanIN, Pancreatic intraepithelial neoplasm. The numbers following the labels on the top refer to stages in the development of PanINs. (Modified from Maitra A, Hruban RH: Pancreatic cancer, Annu Rev Pathol Mech Dis 3:157, 2008.) product, p53, acts both to enforce cell-cycle checkpoints and as an inducer of apoptosis or senescence (Chapter 6). BRCA2 is also mutated late in a subset of pancreatic cancers.
Pancreatic cancer is primarily a disease of older adults, with 80% of cases occurring between 60 and 80 years of age. The strongest environmental influence is smoking, which doubles the risk. Long-standing chronic pancreatitis and diabetes mellitus are also associated with a modestly increased risk for pancreatic cancer. These two entities have a bidirectional link with pancreatic cancer. Thus, for example, tumors arising in the head of the pancreas often cause chronic pancreatitis in the distal parenchyma, while diabetes caused by duct obstruction and subsequent pancreatitis may be the manifestation of an underlying neoplasm. In fact, approximately 1% of the older adult population with new-onset diabetes harbor an unsuspected pancreatic cancer. Familial clustering of pancreatic cancer has been reported, and a growing number of inherited genetic defects are now recognized that increase pancreatic cancer risk. For example, germ line mutations of the familial breast/ ovarian cancer gene BRCA2 are seen in approximately 10% of cases arising in individuals of Ashkenazi Jewish heritage.
Approximately 60% of pancreatic cancers arise in the head of the gland, 15% in the body, and 5% in the tail; in the remaining 20%, the neoplasm diffusely involves the entire organ. Carcinomasofthepancreasusuallyarehard,gray-white,stellate,poorlydefinedmasses(
Fig.17.9A
Twofeaturesarecharacteristicofpancreaticcancer:Itishighlyinvasive(even“early”invasivepancreaticcancersinvadeperipancreatictissuesextensively),anditelicitsanintensehostreactionintheformofdensefibrosis(desmoplastic response).