1. PANCREAS Randolph K Peterson, M.D. Department of Laboratory Medicine and Pathology Med 6724. Gastrointestinal/Hepatobiliary System

2. PANCREAS: GENERAL Surrounded by vital structures Inaccessible Exocrine & endocrine portions Enzymes = precursors, inhibitors

4. ACUTE PANCREATITIS  There are many etiologies. The most common is believed to be transient or partial OBSTRUCTION resulting in bile reflux into the pancreatic duct system with activation of pancreatic enzymes and subsequent tissue destruction. 80% of cases are associated with biliary tract disease (M;F= 1:3), or alcoholism  Post-operative due to surgical trauma  Parathyroid adenoma/carcinoma (10-20% develop pancreatitis)  Rarely hypercalcemia, drugs (thiazides, furosemide, estrogen)

5. ACUTE PANCREATITIS (2) Presents in 2 forms: – Acute pancreatitis – Acute hemorrhagic/necrotizing pancreatitis Histologically there is ductal dilation, edema, inflammation, fibrosis, fat necrosis, and calcification. Large abscess formation may occur. 20% overall mortality rate – 10-15% with non-necrosis/hemorrhage – 50% with

6. ACUTE PANCREATITIS: RISK FACTORS (1) Alcohol (75%) Gallstones (50%) Trauma (also cardiopulmonary bypass: 1-8%) Pancreatic duct obstruction by tumor Germline mutation involving trypsin (cationic trypsinogen gene PRSS1) or of its inhibitor (serine protease inhibitor Kazal type 1: SPINK1) Chronic pancreatitis (?) MOST IMPORTANT

7. ACUTE PANCREATITIS: RISK FACTORS (2) Inflammation (virus [hepatitis, mumps, CMV, coxsackie]; ulcer) Ischemia (atherosclerosis; cardiopulmonary bypass) Drugs ("The Pill," thiazide; others) Hyperlipoproteinemia Hypercalcemia Idiopathic (10%)

8. ACUTE PANCREATITIS: PATHOGENESIS Normal: Enzymes secreted as inactive precursors In duodenum, trypsinogen trypsin Injury: Trauma, drugs, ischemia  acinar necrosis Obstruction:"Common channel" of pancreatic duct  reflux Trypsinogen trypsin  activates complement + kinin  DIC  shock, renal failure  acinar necrosis, lipase, amylase release Bile reflux  lecithin lysolecithin (cytotoxic)  degrades lung surfactant Hyperlipidemia: fatty acids  fat necrosis + calcium  calcium soaps Hypercalcemia: trypsinogen activation? enterokinase duodenal reflux phospholipase A lipase

11. ACUTE PANCREATITIS: PATHOGENESIS Normal: Enzymes secreted as inactive precursors In duodenum, trypsinogen trypsin Injury: Trauma, drugs, ischemia  acinar necrosis Obstruction:"Common channel" of pancreatic duct  reflux Trypsinogen trypsin  activates complement + kinin  DIC  shock, renal failure  acinar necrosis, lipase, amylase release Bile reflux  lecithin lysolecithin (cytotoxic)  degrades lung surfactant Hyperlipidemia: fatty acids  fat necrosis + calcium  calcium soaps Hypercalcemia: trypsinogen activation? enterokinase duodenal reflux phospholipase A lipase

14. ACUTE PANCREATITIS: PATHOPHYSIOLOGY Kinin activation (kallikrien, bradykinin) by trypsin (?)  vasodilatation Glucagon  (early), insulin  (late)  sugar  Lung: ARDS (shock? circulating proteases Shock:volume down (vasoactive peptides?retroperitoneal edema? DIC: circulating proteases (?);Kidney function down

26. ACUTE PANCREATITIS: CLINICAL FEATURES Pain Fever Nausea, vomiting, ileus Jaundice – Gallstones? – CBD compression? – Liver? Coma Death

27. ACUTE PANCREATITIS: DIAGNOSIS (1) Serum, urine amylase: –  24 hrs (but also  in gut obstruction) – salivary gland Serum, urine lipase:  3 rd day Triglycerides  Calcium  (±) Bilirubin ±

29. ACUTE PANCREATITIS: COMPLICATIONS Retroperitoneal fluid accumulation Shock  liver, kidney, lung  † Inflammatory pseudocyst Abscess (gram negative) Distant fat necrosis (CNS) ARDS (acute respiratory distress syndrome): – Lung capillary injury by trypsin, lipase

30. ACUTE PANCREATITIS: Rx Supportive (watch fluid balance!) Abscess: drain, antibiotics Pseudocysts: – Half resolve spontaneously – Half drain surgically (internal? External) GI bleed: Rx like ulcer Prognosis: About 10% die Preventive: remove gallstones; no alcohol

33. CHRONIC PANCREATITIS Definition: chronic (or recurrent), progressive pancreatic destruction with pain, malabsorption, diabetes mellitus. 2 Types: – Chronic obstructive pancreatitis: narrowing or obstruction due to stone or tumor. Less severe than below – Chronic calcifying pancreatitis: most commonly seen in alcoholics. Damage is irregular and patchy. More severe with changes in duct epithelium with calcifying ductal “plugs”, acinar atrophy, and fibrosis. 30% = CFTR gene mutation (but not effects of cystic fibrosis)

34. CHRONIC PANCREATITIS: Complications Ductal dilatation with overall loss of pancreatic tissue Acinar destruction Islet destruction Psuedocyst formation Widespread “metastatic fat necrosis due to release of lipase Avasular bone necrosis Stetorrhea Diabetes

48. CHRONIC PANCREATITIS: RISK FACTORS ETOH: – Chronic pancreatitis present in half of alcoholics (at autopsy) – Gallstone-induced acute pancreatitis does not lead to chronic pancreatitis Tropical residence Trauma Hyperparathyroidism Hyperlipidemia

49. CHRONIC PANCREATITIS: DIAGNOSIS & Rx Clinical history X-ray (calcifications). CT scan; endoscopic retrograde pancreatography Malabsorption and/or diabetes Absorption tests Function tests: Administer pancreatic enzyme substrate & measure product in urine (bentiromide or pancreatolauryl “tubeless” tests May be difficult to exclude pancreatic carcinoma Rx: exogenous enzymes; pancreaticojejunostomy

50. PANCREATIC NEOPLASMS: CARCINOMA (1) Clinically silent until late – >85% beyond pancreas at Dx Except ampulla area  jaundice Risk factors: – Smoking – diet :fat, meat;(hyperinsulinemia?) – partial gastrectomy – male > female – >60 – Black (2x)

51. PANCREATIC NEOPLASMS: CARCINOMA (2) Incidence in U.S. = 9/100,000 Mutant K-RAS genes common – others: ─ CDKN2 (formerly p16) ─ SMAD/DPC4 depleted in pancreatic cancer (tumor suppressor) Also: BRCA2 & MLH1 (latter—mismatch repair gene) These occur in stepwise sequence beginning with in situ lesions (pancreatic intraepithelial neoplasm (PanIN) that demonstrate telomere shortening, then as above)

52. PANCREATIC NEOPLASMS: Dx (1)  Clinical: weight loss, painless jaundice, back pain, palpable gallbladder, thrombophlebitis  CT scan if tumor > 2.0 cm; ultrasound (?); ERCP (endoscopic retrograde cholangiopancreatography); 85% beyond pancreas when diagnosed  Tumor markers: C19-9 (carcinoembryonic antigen) for Dx or recurrence, not screen

53. PANCREATIC NEOPLASMS: Dx (2) Biopsy: – Needle aspiration (for unresectable lesions only—Dx confirmation) – Biopsy – Mutant K-ras oncogene (PCR: polymerase chain reaction) on biopsy? Rare: intraductal papillary mucinous tumors – Dx: ERCP (endoscopy)

54. Pancratic tumors: Benign Microcystic Cystadenoma – Multiple small cysts lined by flat cuboidal epithelium with abundant glycogen – Prominent vasularization, central scar Mucinous cystic adnoma – Young female predominance – Simple cystic spaces lined by tall mucin secreting cells. – No anaplasia or wall invasion

55. PANCREATIC CARCINOMA: PATHOLOGIC TYPES  Ductal Adenocarcinoma 85% of pancratic cancers 4 th most common cause of ca mortality in US Elderly patients, slight male pred. 2/3 in head; 1/3 in tail, multiple in 20% Desmoplasia common 85% beyond pancreas at dx Mets to LN, liver, peritoneum, lung, adrenal, bone, skin, CNS

56. PANCREATIC CARCINOMA: PATHOLOGIC TYPES (2)  Papillary and solid epithelial neoplasm Most cases in young women Probably begins as solid tunor with degeneration forming papillea and cystic spaces. Ecellent prognosis.  Mucinous Cystic Tumors (may be benign, see cystadenoma) Young female predominance Large encapsulated multi- or uni- locular cystic masses with tall mucin secreating cells. Invasion of wall or presence of anaplasia indicates malignancy 5 yr survival 50%

57.  Rarer types include: Acinar tumor: solid mass obstructing architecture of acinar cells Anaplastic carcinoma : poor differentiation with extreamly poor prognosis Giant cell tumor: prognosis similair to ductal adenocarcinoma  Other considerations: tumors of the Ampula present earlier and may have better prognosis.

61. PANCREATIC NEOPLASMS: CLINICAL Silent Weight loss Pain  back (adjacent structure involvement) Jaundice = CBD invasion (body and tail = late)  Nontender  gallbladder (Courvoisier’s sign) Migratory thrombophlebitis (Trousseau sign) Pruritis Acute pancreatitis (occasional) Gut invasion  melena

63. PANCREATIC NEOPLASMS: CLINICAL Silent Weight loss Pain  back (adjacent structure involvement) Jaundice = CBD invasion (body and tail = late)  Nontender  gallbladder (Courvoisier’s sign) Migratory thrombophlebitis (Trousseau sign) Pruritis Acute pancreatitis (occasional) Gut invasion  melena

82. PANCREATIC NEOPLASMS: CLINICAL Silent Weight loss Pain  back (adjacent structure involvement) Jaundice = CBD invasion (body and tail = late)  Nontender  gallbladder (Courvoisier’s sign) Migratory thrombophlebitis (Trousseau sign) Pruritis Acute pancreatitis (occasional) Gut invasion  melena

83. PANCREATIC NEOPLASMS: Rx (1) Whipple resection: – 5-20% resectable – Of these, 20% operative mortality – 4% five-year surgical Paliative bypass: – Choledochoduodenostomy – Gastrojejunostomy

84. PANCREATIC NEOPLASMS: Rx (2)  Chemotherapy: poor results  RoRx: palliative (only a little)  Cystadenocarcinomas of body & tail: Sometimes Whipple or modification—better prognosis

86. Tumors of the Endocrine Pancreas Much less common than carcinoma of exocrin pancreas Generally a monotonous proliferation of small cells. Indication of malignancy include invasion and mets. Malignant tumors are more likely to be functional! – Beta tumor (insulinoma) Most common 90% solitary 10% malignant – Alpha tumor (glucogonoma) Adult females If functional usually malignant; not functional usually benign. – G-cell tumor (gastrinoma)