Chapter 089. Pancreatic Cancer (Part 1)

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Harrison's Internal Medicine Chapter 89. Pancreatic Cancer Pancreatic Cancer: Introduction Over 90% of pancreatic cancers are ductal adenocarcinomas of the exocrine pancreas. These tumors occur twice as frequently in the pancreatic head compared to the rest of the organ, and tend to be aggressive, often presenting when locally inoperable or after distal metastases have occurred. Patients with pancreatic cancer have a poor prognosis, with a 5-year survival of only 5%. The discussion of pancreatic cancer here will be limited to ductal adenocarcinomas. Other types of pancreatic neoplasms include islet cell tumors and neuroendocrine tumors (Chap. 344). Incidence and Etiology Epidemiology The lifetime risk...

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Chapter 089. Pancreatic Cancer (Part 1) Harrison's Internal Medicine > Chapter 89. Pancreatic Cancer Pancreatic Cancer: Introduction Over 90% of pancreatic cancers are ductal adenocarcinomas of the exocrine pancreas. These tumors occur twice as frequently in the pancreatic head compared to the rest of the organ, and tend to be aggressive, often presenting when locally inoperable or after distal metastases have occurred. Patients with pancreatic cancer have a poor prognosis, with a 5-year survival of only 5%. The discussion of pancreatic cancer here will be limited to ductal adenocarcinomas. Other types of pancreatic neoplasms include islet cell tumors and neuroendocrine tumors (Chap. 344). Incidence and Etiology Epidemiology
The lifetime risk of being diagnosed with pancreatic cancer in the United States is 1.27%. In the United States, it is estimated that approximately 37,170 people will be diagnosed with pancreatic cancer in 2007. Consistent with its associated poor prognosis, 33,370 are expected to die from this disease in the same year, making it the fourth leading cause of cancer-related death. The median age of diagnosis of pancreatic cancer is 72 years, with the peak incidence of diagnosis between the ages of 65 and 84; it is rarely diagnosed in those below the age of 50. The incidence is slightly higher in men than women, and it is also higher in African Americans than in Caucasians. Etiology Cigarette smoking, obesity, and nonhereditary chronic pancreatitis appear to be risk factors for the development of pancreatic cancer. With smoking, the risk seems to increase with the number of cigarettes consumed and decreases with smoking cessation. Less clear, and sometimes conflicting associations, have been observed for other environmental factors such as diet, coffee and alcohol consumption, previous partial gastrectomy or cholecystectomy, and Helicobacter pylori. An epidemiologic association between diabetes mellitus and pancreatic cancer has also been demonstrated; however, it is uncertain if diabetes is a precedent of, or consequence of, pancreatic cancer.
Genetic Considerations Five to 10% of patients with pancreatic cancer also have an affected first- degree relative, suggesting that in some cases genetic factors are involved. These patients seem to present earlier than sporadic cases. The risk of pancreatic cancer is increased in certain syndromes, whether directly or indirectly, such as hereditary chronic pancreatitis, Peutz-Jeghers syndrome, Von Hippel-Lindau syndrome, familial atypical multiple-mole melanoma syndrome, ataxia-telangiectasia, Gardner's syndrome [a variant of familial adenomatous polyposis (FAP)] and Lynch syndrome II, a subtype of hereditary nonpolyposis colorectal cancer (HNPCC). Heavy smokers who also have homozygous deletions of the gene for glutathione-S transferase T1 (GSTT1), a carcinogen metabolizing enzyme, may be at particular risk. Activating mutations in the K-ras oncogene are found in nearly all pancreatic cancer. Loss-of-function mutations in several tumor suppressor genes occur in this disease, including p53, CDKN2A gene (also called multiple tumor suppressor-1 gene, leading in many cases to loss of function of p16), DPC4, and BRCA2. A feature almost unique to pancreatic cancer is the combination of K- ras and CDKN2A mutations.
Clinical Features Presenting Features Common presenting features of pancreatic cancer include pain (present in >80% of patients with locally advanced or metastatic disease), obstructive jaundice, weight loss, and anorexia. Patients with jaundice may also have pruritus, pale stools, and dark urine; they often have tumors in the pancreatic head, and tend to be diagnosed earlier and with earlier stage disease. Other symptoms tend to be more insidious, so that in the absence of jaundice, the interval between onset and diagnosis can be prolonged. Pain, for example, is often more of a problem in patients with lesions in the body or tail of the pancreas where the primary tumor is more likely to become quite large or to invade adjacent structures (such as the splanchnic nerves) before becoming manifest; these patients frequently have inoperable disease. When present, pain is often felt as a dull ache in the upper abdomen and may radiate to the back, and characteristically may improve upon leaning forward. It may initially be intermittent, and may worsen with meals. These patients may suffer from marked weight loss, which may result from a combination of anorexia, early satiety, malabsorption or diarrhea/steatorrhea. Other less common presenting features include the diagnosis of glucose intolerance (particularly within 2 years of cancer diagnosis), previous pancreatitis, migratory superficial thrombophlebitis (Trousseau's syndrome), gastrointestinal hemorrhage from varices, and splenomegaly.