39-08: Carcinoma of the Pancreas & Ampulla of Vater

ESSENTIALS OF DIAGNOSIS

GENERAL CONSIDERATIONS

Carcinoma is the most common neoplasm of the pancreas. About 75% are in the head and 25% in the body and tail of the organ. Pancreatic carcinomas account for 3% of all cancers and 7% of cancer deaths. The incidence is increasing, and over the next two decades pancreatic cancer is expected to surpass colorectal cancer as the second leading cause of cancer-related deaths in the United States. Ampullary carcinomas are much less common. Risk factors for pancreatic cancer include age, tobacco use (which is thought to cause 20–25% of cases), heavy alcohol use, obesity, chronic pancreatitis, diabetes mellitus, prior abdominal radiation, family history, and possibly gastric ulcer and exposure to arsenic and cadmium. New-onset diabetes mellitus after age 45 years occasionally heralds the onset of pancreatic cancer. In patients with diabetes, metformin use and possibly aspirin use may reduce the risk of pancreatic cancer slightly, but insulin use and glucagon-like peptide-1–based therapy (eg, sitagliptin) may increase the risk. A risk model for pancreatic cancer in persons with new-onset diabetes mellitus has been proposed and includes the following factors: age, BMI, change in BMI, smoking, use of PPIs and diabetes medications as well as levels of hemoglobin A_1C, cholesterol, hemoglobin, creatinine, and alkaline phosphatase. About 7% of patients with pancreatic cancer have a family history of pancreatic cancer in a first-degree relative, compared with 0.6% of control patients. Point mutations in codon 12 of the KRAS oncogene are found in 70–100% of pancreatic cancers; inactivation of the tumor suppressor genes CDKN2A on chromosome 9, TP53 on chromosome 17, and SMAD4 on chromosome 18 is found in 95%, 75%, and 55% of pancreatic cancers, respectively; mutation of the palladin gene (PALLD) is reported to be common. A subset of pancreatic cancers is associated with DNA mismatch repair deficiency and have better outcomes after surgery and responsiveness to immunotherapy. Most pancreatic cancers originate from pancreatic intraepithelial neoplasias, which measure less than 5 mm in diameter and can only be seen with a microscope.

In 5–10% of cases, pancreatic cancer occurs as part of a hereditary syndrome, including familial breast cancer (carriers of BRCA2 have a 7% lifetime risk of pancreatic cancer), hereditary pancreatitis (PSS1 mutation), familial atypical multiple mole melanoma (p16/CDKN2A mutation), Peutz-Jeghers syndrome (STK11/LKB1 mutation), ataxia-telangiectasia (ATM mutation), and Lynch syndrome (hereditary nonpolyposis colorectal cancer [MLH1, MSH2, MSH6 mutations]). Polymorphisms of the genes for methylene tetrahydrofolate reductase and thymidylate synthase have been reported to be associated with pancreatic cancer.

Neuroendocrine tumors account for 1–2% of pancreatic neoplasms and may be functional (producing gastrin, insulin, glucagon, vasoactive intestinal peptide, somatostatin, growth hormone–releasing ...