1. Exocrine Pancreas Kimiko Suzue, MD PhD

7. Exocrine Pancreas 80%-85% of Pancreas Acinar cells produce digestive enzymes Amylase Lipase –Proenzymes Trypsinogen Chymotrypsinogen Procarboxypeptidase Proelastase Prophospholipase

8. Pancreatic Disorders Congenital Anomalies Pancreatitis –Acute –Chronic Non-neoplastic Cysts Neoplasms

9. Congenital Anomalies Agenesis (very rare, PDX1 homeobox gene) Pancreas Divisum (failure of 2 ducts to fuse) (3%-10%) Annular Pancreas –Pancreas encircles duodenum (rare) –Risk of duodenal obstruction Ectopic Pancreas (2% of postmortem exams) –Usually incidental –May cause pain from localized inflammation –Rarely may cause mucosal bleeding

11. Fig 19-1

12. Prevention of Pancreatic Autodigestion Enzymes synthesized as inactive proenzymes (except amylase and lipase) Enzymes are segregated in membrane-bound compartments Pancreas contains intracellular trypsin inhibitor Activating enzyme (enterokinase) is geographically separate from the pancreas Acinar cells are remarkably resistant with degrading systems for active enzymes

13. Acute Pancreatitis Acute inflammation of pancreas Microvascular leakage causes edema Necrosis of fat by lipolytic enzymes Proteolytic digestion of pancreatic parenchyma Blood vessel destruction leads to interstitial hemorrhage

17. Acute Pancreatitis - Causes Alcohol Gallstones Medications (thiazides) Trauma Hypertriglyceridemia Hypercalcemia Acute ischemia Infections (mumps) Mutations in trypsinogen (PRSS1), trypsin inhibitor (SPINK1)

19. Acute Pancreatitis – Clinical Features Abdominal pain which radiates to back Nausea and vomiting Elevated serum lipase and amylase Hypocalcemia

20. Acute Pancreatitis – Complications Systemic inflammatory response –Leukocytosis –Hemolysis –Disseminated intravascular coagulation –Fluid sequestration –Acute respiratory distress syndrome –Diffuse fat necrosis Peripheral vascular collapse and shock –(5% die from shock in first week)

21. Acute Pancreatitis – Complications Pancreatic pseudocysts –Formed by fibrous tissue walling-off liquefactive necrosis and pancreatic enzymes –Lack an epithelial lining –Account for 75% of pancreatic cysts –Presents as abdominal mass with persistently elevated serum amylase –May spontaneously resolve but may also become infected or rupture (releasing enzymes into abdominal cavity)

23. Chronic Pancreatitis Inflammation of pancreas with fibrosis and irreversible destruction of exocrine parenchyma Secondary diabetes—late complication when islets cells become destroyed Most often from repeated bouts of acute pancreatitis due to alcohol

24. Chronic Pancreatitis - Causes Alcohol abuse Long-standing obstruction of pancreatic duct -calculi, pseudocysts, trauma, neoplasms Cystic fibrosis (CFTR gene mutation) Hereditary pancreatitis due to mutation in trypsinogen gene PRSS1 or serine protease inhibitor SPINK1

25. Chronic Pancreatitis - Clinical features Epigastric abdominal pain which radiates to back Progressive parenchymal destruction and fibrosis leads to pancreatic insufficiency (malabsorption with steatorrhea and fat-soluble vitamin deficiencies) Dystrophic calcification of pancreatic parenchyma on imaging Pancreatic pseudocyst formation 20-25 year mortality rate of 50% With hereditary pancreatitis, have 40% lifetime risk of pancreatic cancer

28. Chronic Pancreatitis

29. Acute and Chronic Pancreatitis - Consequences

30. Pancreatic Disorders Congenital Anomalies Pancreatitis –Acute –Chronic Non-neoplastic Cysts Neoplasms

31. Pancreatic neoplasms, cell lineages Ductal (>90%) -Gland or tubule formation and mucin production Acinar -Sheets/nests/acini, pancreatic enzyme production Endocrine

32. Cystic Pancreatic Neoplasms 5-15% of pancreatic cysts are neoplastic 5% of pancreatic neoplams are cystic Benign (debated) –Serous cystadenoma –Mucinous cystadenoma Premalignant –Mucinous cystic neoplasm with dysplasia –Intraductal papillary mucinous neoplasm Malignant –Intraductal papillary mucinous neoplasm with associated invasive carcinoma –Cystadenocarcinoma –Solid pseudopapillary neoplasm

33. Serous Cystadenoma

34. Mucinous Cystadenoma

35. Intraductal Papillary Mucinous Neoplasm

36. Cystic Pancreatic Neoplasms 5-15% of pancreatic cysts are neoplastic 5% of pancreatic neoplams are cystic Serous cystic neoplasms Mucinous cystic neoplasms Intraductal papillary mucinous neoplasms Solid pseudopapillary neoplasm

37. Typically Solid Pancreatic Neoplasms Ductal adenocarcinomas Pancreatic endocrine neoplasms Acinar cell carcinoma Pancreatoblastoma

38. Pancreatic Adenocarcinoma General Features Arises in the exocrine portion: ducts 70-80% of pancreatic neoplasms 80% occur between ages of 60 and 80 years Five-year survival less than 5% Ninety (90%) of patients die within 6-12 months Patients present with jaundice or non-specific symptoms (back pain, weight loss) Major risk factors: –smoking and chronic pancreatitits

39. Adenocarcinoma of the Pancreas Clinical Features Weight Loss Abdominal Pain Jaundice Painless jaundice in an elderly person is CARCINOMA of the head of the pancreas until proven otherwise Back pain Palpable gallbladder Secondary diabetes mellitus Migratory thrombophlebitis (Trousseau sign) Serum tumor marker is CA19-9

40. Molecular Carcinogenesis of Pancreatic Adenocarcinoma

41. KRAS – activated oncogene in 90% of pancreatic ACA P16- inactivated tumor suppressor gene in 95% of pancreatic ACA SMAD4- inactivated tumor suppressor gene in 55% P53- inactivated tumor suppressor gene in 50-70%

42. Adenocarcinoma of the Pancreas General Features Head: 60% –Obstructive Jaundice –Gallbladder distention Body and Tail: 20% –Diffuse Infiltration –Massive Liver Metastases Diffuse: 20%

44. Whipple Procedure

46. Pancreatic CA

47. Pancreatic Adenocarcinoma

48. Pancreatic Ductal Adenocarcinoma

50. Chronic Pancreatitis Adenocarcinoma

51. Pancreatic Disorders Congenital Anomalies Pancreatitis –Acute –Chronic Non-neoplastic Cysts Neoplasms