Fig. 17.6 Mucinouscysticneoplasm.(A)Cross-sectionthroughamucinousmultiloculatedcystinthetailofthepancreas.Thecystsarelargeandfilledwithtenaciousmucin.(B)Thecystsarelinedbycolumnarmucinousepithe-lium,withadenselycellular“ovarian”stroma.
Infiltrating ductal adenocarcinoma of the pancreas (more commonly referred to as pancreatic cancer) is the third leading cause of cancer deaths in the United States, preceded only by lung and colon cancers. Although it is substantially less common than the other two malignancies, pancreatic carcinoma is near the top of the list of killers because it carries one of the highest mortality rates. Close to 49,000 Americans were diagnosed with pancreatic cancer in 2015, and virtually all will die in a short period after diagnosis; the 5-year survival rate is a dismal 8%.
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Like all cancers, pancreatic cancer arises as a consequence of inherited and acquired mutations in cancer-associated
Fig. 17.7 Intraductal papillary mucinous neoplasm. (A) Cross-section through the head of the pancreas showing a prominent papillary neoplasm distending the main pancreatic duct. (B) The papillary mucinous neoplasm involves the main pancreatic duct (left) and is extending down into the smaller ducts and ductules (right).
genes. In a pattern analogous to that seen in the multi-step progression of colon cancer (Chapter 6), there is a progressive accumulation of genetic changes in pancreatic epithelium as it proceeds from nonneoplastic, to noninvasive precursor lesions, to invasive carcinoma (
Fig. 17.8 ). While both intraductal papillary mucinous neoplasms and mucinous cystic neoplasms can progress to invasive adenocarcinoma, the most common antecedent lesions of pancreatic cancer arise in small ducts and ductules, and are called pancreatic intraepithelial neoplasias (PanINs). Evidence in favor of the precursor relationship of PanINs to frank malignancy includes the observations that these microscopic lesions often are found adjacent to infiltrating carcinomas and the two share a number of genetic alterations. Moreover, the epithelial cells in PanINs show dramatic telomere shortening, potentially predisposing these lesions to pathogenic chromosomal abnormalities that may contribute to acquisition of the full spectrum of cancer hallmarks.
The recent sequencing of the pancreatic cancer genome has confirmed that four genes are most commonly affected by somatic mutations in this neoplasm: KRAS, CDKN2A/ p16, SMAD4,andTP53:
KRAS is the most frequently altered oncogene in pancreatic cancer; it is activated by a point mutation in greater than 90% of cases. These mutations impair the intrinsic GTPase activity of the KRAS protein so that it is constitutively active. In turn, KRAS activates a number of intracellular signaling pathways that promote carcinogenesis (Chapter 6).
The p16 (CDKN2A) gene is the most frequently inactivated tumor suppressor gene in pancreatic cancer, being turned off in 95% of cases. The p16 protein has a critical role in cell-cycle control; inactivation removes an important checkpoint.
The SMAD4 tumor suppressor gene is inactivated in 55% of pancreatic cancers and only rarely in other tumors; it codes for a protein that plays an important role in signal transduction downstream of the transforming growth factor-β receptor.