Pathology and molecular pathogenesis
The normal pancreatic architecture is characteristic of a secretory gland: a background of acinar cells accounts for approximately 80% of the cell number and volume of the gland; 1% to 2% are clusters of islet cells; 10% to 15% are single-layered, cuboidal ductal cells; and there is a sparse interlacing network of blood vessels, lymphatics, nerves, and collagenous stroma. This architecture is markedly altered in carcinoma, in which the predominant histologic feature is a dense collagenous stroma with atrophic acini, remarkably preserved islet cell clusters, and a slight to moderate increase in the number of ducts, both normal-appearing and cancerous. The diagnosis of ductal adenocarcinoma rests on the identification of mitoses, nuclear and cellular pleomorphism, discontinuity of ductal epithelium, and evidence of perineural, vascular, or lymphatic invasion.
CLINICAL SIGNS AND SYMPTOMS
The lack of obvious clinical signs and symptoms delays diagnosis in most patients. Jaundice, due to extrahepatic biliary obstruction, is present in approximately 50% of patients at diagnosis and is associated with a less advanced stage of disease than are other signs or symptoms. Small tumors of the pancreatic head may obstruct the intrapancreatic portion of the bile duct and cause the patient to seek medical attention when the tumor is still localized and potentially resectable. In the absence of extrahepatic biliary obstruction, few patients present with potentially resectable disease.
The pain typical of locally advanced pancreatic cancer is a dull, fairly constant pain of visceral origin localized to the region of the middle and upper back. The pain is due to tumor invasion of the celiac and mesenteric plexus. Vague, intermittent epigastric pain occurs in some patients; its etiology is less clear. Fatigue, weight loss, and anorexia are common even in the absence of mechanical gastric outlet obstruction. Pancreatic exocrine insufficiency due to obstruction of the pancreatic duct may result in malabsorption and steatorrhea. Although malabsorption and mild changes in stool frequency are common, diarrhea occurs infrequently.
Glucose intolerance is present in most patients with pancreatic cancer. Although the exact mechanism of hyperglycemia remains unclear, both altered beta-cell function and impaired tissue insulin sensitivity are present. The importance of islet cell function to the development of exocrine cancer is suggested by the work of Bell and Stayer, who demonstrated that pretreatment of hamsters with streptozocin and the resulting destruction of islet cells prevented the induction of pancreatic cancer in these animals by the carcinogen N-nitrosobis-(2-oxopropyl)amine (BOP). This work was substantiated by studies in Chinese hamsters demonstrating that only genetically diabetic animals did not develop cancers in response to N-nitroso-(2-oxopropyl)amine.
In the absence of jaundice, patient complaints are nonspecific, as are clinical signs on physical examination. However, important staging information with direct implications for therapy can be obtained from the physical examination. This information includes performance status, cardiopulmonary function, and the presence or absence of left supraclavicular adenopathy and ascites.