Exocrine Pancreas Kimiko Suzue, MD PhD

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

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

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

Fig 19-1

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

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

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

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

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)

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)

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

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

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 year mortality rate of 50% With hereditary pancreatitis, have 40% lifetime risk of pancreatic cancer

Chronic Pancreatitis

Acute and Chronic Pancreatitis - Consequences

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

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

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

Serous Cystadenoma

Mucinous Cystadenoma

Intraductal Papillary Mucinous Neoplasm

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

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

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

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

Molecular Carcinogenesis of Pancreatic Adenocarcinoma

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%

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

Whipple Procedure

Pancreatic CA

Pancreatic Adenocarcinoma

Pancreatic Ductal Adenocarcinoma

Chronic Pancreatitis Adenocarcinoma

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